Role of 5-HT in Cerebral Edema after Traumatic Brain Injury

*Priya Badyal, Jaspreet Kaur and Anurag Kuhad*

## **Abstract**

The pathogenesis of edema after traumatic brain injury is complex including the destruction of micro-vessels and alterations in microcirculation around the primary injury and leakage of plasma constituents into the tissue, due to permeability changes of the vessel walls. Many functional molecules like histamine, serotonin, arachidonic acid, prostaglandins and thromboxane have been shown to induce blood–brain barrier (BBB) disruption or cell swelling. It is believed that released 5-HT binds to 5-HT2 receptors stimulating cAMP and prostaglandins in vessels that cause more vesicular transport in endothelial cells leading to serum component's extravasation. The additional amount of serotonin into the tissue due to injury maintains the state of increased vascular permeability that ultimately causes edema. Serotonin is clearly involved in early cytotoxic edema after TBI. Reduction of serotonin in the nervous tissue reduces swelling and the milder cell changes in the brain or spinal cord of traumatized rats. Inhibition of serotonin synthesis before closed head injury (CHI) in rat models or administration of serotonin antiserum after injury attenuates BBB disruption and brain edema volume swelling, and brain pathology. Maintaining low serotonin levels immediately after injury may show neuroprotection and combat various secondary outcomes that occur after traumatic brain injury.

**Keywords:** TBI, 5-HT (5-Hydroxytryptamine), cerebral edema, BBB permeability, brain damage, neuroprotection

## **1. Introduction**

Traumatic brain injury (TBI), the principal cause of morbidity and mortality is a serious medical problem in people under 40 years of age. As a major cause of death, it is a major worldwide concern and due to lifetime disability it also puts a huge burden on society [1]. Despite the scale of this public health crisis, no effective TBI therapies currently exist [2]. The hope for effective treatment is derived from the fact that much of the post-traumatic damage to the injured brain is caused by a secondary injury cascade of consecutive pathophysiological events, including opening of the blood–brain barrier (BBB), formation of edema, excitotoxicity, inflammatory response activation, oxidative stress and ultimately cell death, which exacerbates the primary injury [3]. While a variety of factors lead to elevated TBI-related mortality and morbidity, the occurrence of cerebral edema with brain swelling remains the most important outcome that contributes to morbidity and mortality [4]. In the first week after traumatic brain injury, considering the prevalence of cytotoxic (or cellular) edema, brain swelling can only occur with the addition of water from the

vasculature to the cranial vault. As such, blood–brain barrier permeability control has been a subject of recent research that aims to treat brain edema [4]. Many functional molecules like histamine, serotonin, arachidonic acid, prostaglandins and thromboxane have been shown to induce BBB disruption or cell swelling. It is believed that released 5-HT binds to 5-HT2 receptors stimulating cAMP and prostaglandins in vessels that cause more vesicular transport in endothelial cells and also leading to serum components extravasation [5].

It is well known that serotonin (5-hydroxytryptamine, 5-HT) is involved in emotional disorders, such as depression and schizophrenia [6]. 5-HT has a role in cerebral edema after TBI [7]. Serotonin has been reported to increase nitrogenoxide (NO) tissue levels, and NO contributes to inflammation by increasing vascular permeability, which leads to edema formation [8, 9]. Activation of the 5-HT2B receptor induces endothelium-dependent NO release [10]. Increased calcium levels in endothelium lead to NO formation through the eNOS pathway, followed by a cGMP-dependent mechanism to increase vascular permeability [11]. Therefore, it seems likely that 5-HT may play a significant role in edema after traumatic insults to the brain. Therefore, in the present chapter the role of endogenous 5-HT in BBB breakdown and in edema formation is discussed as a pharmacological approach to alleviate cerebral edema after TBI.

## **2. Pathophysiology of cerebral edema**

After brain injury, secondary complications like cerebral edema are a pressing medical problem and can increase mortality to nearly 80% if severe [12]. Cerebral edema and brain swelling are estimated to account for up to 50% of patient mortality following traumatic brain injury [4]. Cerebral edema is now understood to develop in stages, where each stage is marked by distinct morphological and molecular changes [13]. Minutes after acute central nervous system (CNS) injury, cytotoxic edema or cellular swelling manifests itself. After cytotoxic edema, ionic edema, an extracellular edema that arises in the presence of an intact blood brain barrier (BBB), forms immediately. Hours after the initial insult, vasogenic edema, an extracellular edema which involves extravasation of plasma proteins manifested [13]. Neurons are considered as fragile cells and cannot survive without support from other cell types. So, in addition to provide neuroprotection, a new aim for acute brain injury research is to investigate and attenuate mechanisms of endothelial, astrocytic, and microglial dysfunction and, thereby, create an environment permissible to neuronal survival. It follows that cerebral edema, a phenomenon arising from astrocyte and endothelium dysfunction, is an important subject for fundamental research and therapeutic intervention [13].

The term BBB refers to an organization of different cell types that separates the luminal contents of the cerebral vasculature from the brain interstitium. Brain ISF, which interacts openly with cerebrospinal fluid (CSF), is designed for neuronal activity and differs from blood serum because it includes higher levels of Cl− and Mg2+ and lower concentrations of K+ , Ca2+ and HCO3− [14]. The Virchow Robin space and the astrocyte endfeet that are part of BBB are recognised as important anatomical components of the so-called "cerebral glymphatic system" [15]. This system is designed to account for CSF movements observed in the healthy brain that can operate from the parenchyma to clear solutes such as amyloid beta and promote the transport of tiny lipophilic molecules, particularly during sleep [15–17].

A pathological rise in the water mass contained by the interstitial space of the brain is cerebral edema. Cytotoxic edema is swelling of oncotic cells, resulting in fluid accumulation intracellular rather than extracellular and is best considered as

## *Role of 5-HT in Cerebral Edema after Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.96460*

a precursor to extracellular ionic edema. A mass effect that exerts pressure on the surrounding shell of tissue is caused by brain swelling. The rigid enclosure of the skull magnifies this pressure rise, which puts an upper limit on the volume to which the brain can expand. It exerts mechanical forces on the skull interior as the brain swells, thereby increasing intracranial tissue pressure. Capillary lumens collapse as tissue pressure reaches capillary pressure, precipitating a feed forward phase in which the surrounding shell ischemia induces more edema development and further swelling in the next shell [18].

Two key theories exist about the immediate source of the new water mass required for brain swelling. In one theory, water, driven by osmotic forces, travels from the capillary lumen into the parenchyma and is transmitted through capillary endothelial cells. In support of the first theory, local blood perfusion status is closely correlated with the formation of ionic edema [19]. Magnetic resonance imaging (MRI) reveals that edema is first observed in regions of peri-infarction that are actively perfused in human stroke [20]. However, acceptance of this theory is not universal, as there are doubts about the levels of expression of widely cited molecular mechanisms for influx of ions and water via endothelium in the brain [21]. A recent explanation of the glymphatic system has led to the formulation of a second theory, in which CSF is the immediate source of water and ions. In this theory, swelling occurs when the influx of CSF into the parenchyma is increased and/or interstitial fluid (ISF)efflux is impaired, a condition that precipitates the parenchymatic relative accumulation of ISF [21]. The two theories do not account well for the formation of vasogenic edema.

Cytotoxic edema is a premorbid cellular process also known as cellular edema, whereby extracellular Na+ and other cations enter into neurons and astrocytes and accumulate intracellularly due to failure of energy-dependent mechanisms of extrusion. This process takes place following CNS injury in all CNS cell types, but is especially prevalent in astrocytes. Astrocyte swelling tends to be a response of astrocytes to injury and occurs rapidly following a number of forms of CNS injury, including ischemia, trauma, hypoglycemia, epileptic status, and fulminant hepatic failure [14]. In the development of cerebral edema and swelling, cytotoxic edema is an important initial stage, as it generates the driving force for the influx of ionic and vasogenic edema, which induces swelling. As a consequence of primary active transport or secondary active transport, osmolite cellular influx may occur. A continuous supply of adenosine triphosphate (ATP) is needed for primary active transport to provide energy for "pumps" such as the Na+ /K+ -ATPase and Ca2+ATPase [13]. Secondary active transport utilises the potential energy stored in transmembrane ionic gradients that was previously generated through primary active transport. Secondary active transporters include ion channels and cotransporters such as the Na+ /K+ /Cl− co-transporter (NKCC) [1, 22] and the Na+ /Ca2+ exchanger. After many types of CNS injury, intracellular ATP becomes depleted and due to that mechanism independent of intracellular ATP, like secondary active transport, are more likely to be involved in the formation of ionic edema [13]. NKCC1 is constitutively expressed by astrocytes in all region of the adult brain [22–24]. In vitro experiments using cultured primary astrocytes is shown that NKCC1 leads to cell swelling in conditions of high extracellular potassium [25, 26]. In vivo, swelling is decreased by the NKCC1 inhibitor bumetanide after trauma and ischemia [27–29].

Acute CNS injury activates a program of molecular changes in the neurovascular unit before and after transcription that leads to the development of endothelial "permeability pores" and subsequent loss of BBB integrity. Based on the key substances undergoing transcapillary motion, progressive endothelial dysfunction can be organised into three stages, i.e. ionic edema, vasogenic edema, and hemorrhagic conversion [13].

Vasogenic edema is a type of extracellular edema characterized by BBB breakdown, in which a pore of transendothelial permeability develops that allows the interstitial brain compartment to extravasation of water and plasma proteins such as albumin and IgG. Capillary structural integrity, unlike hemorrhage, is maintained during vasogenic edema in such a way that erythrocyte passage is prevented [30]. It is thought that the three phases of endothelial dysregulation occur sequentially, although the speed of change between phases possibly depends on the form and severity of injury. In addition, since many etiologies of brain endothelial dysregulation and cerebral edema are focal in nature, brain tissue typically displays a complex spatiotemporal pattern of the various stages of endothelial dysregulation. Significant gaps still remain in our understanding of how specific proteins contribute to cerebral edema [13].

## **3. Serotonergic role in development of cerebral edema**

In many brain disorders, edema is a severe complication, including traumatic injury. Traumatic brain edema pathogenesis is complex and involves physical disruption of microvessels, microcirculatory changes in and around the primary injury, and changes in the permeability of the vessel walls that contribute to plasma constituents leaking into the tissue [31]. There are reasons to assume that many of these events are caused by a variety of chemical mediators, such as biogenic amines, arachidonic acid, leucotrienes, histamine and free radicals, that are released or activated in and around the primary lesion [32]. However, the role of serotonin (5-hydroxytryptamine, 5-HT) is not well understood in traumatic brain edema. In multiple neurological disorders and in pathological conditions, several lines of recent evidence suggest a presumptive function of this amine [7]. Major changes in the synthesis of serotonin occur in important brain injuries such as stroke, ischemia and trauma, as well as in experimental cold injury lesions and other neurological diseases [7]. Increased serotonin content occurs after traumatic brain insults in the walls of the cerebral vessels, cerebrospinal fluid and brain [5]. In a wide range of psychiatric disorders and mental disturbances, irregular serotonin levels in the blood and brain have been identified [33]. In cerebral vessels, serotonergic receptors are present and intracarotid, intravenous or intracerebroventricular serotonin infusion substantially affects the cerebral circulation and metabolism as well as increasing the permeability of the blood–brain barrier (BBB) [7, 32, 34]. Therefore, various studies were conducted to examine the function of endogenous 5-HT in BBB breakdown, edema formation and early cellular changes in experimental models of traumatic brain injury. Therefore, it seems probable that 5-HT could play an important role in edema formation and cellular changes following traumatic insults to the brain.

Studies show that endogenous depletion of 5-HT before acute insult to the brain substantially thwarts the production of edema and early cellular changes, suggesting that this amine plays an important role in the pathophysiology of traumatic brain injury [35]. Clearly, physical damage to the brain can initiate a cascade of biochemical and structural events in and around the primary injury [36]. Edema is one of those secondary events that may aggravate a primary injury, and studies suggest that serotonin could be involved in edema-causing micro vascular reactions [7]. Serotonin is present in many neuronal pathways arising from the nuclei of the dorsal raphe and leptomeninges mast cells and in blood platelets [33]. Changes in the concentration of serotonin most possibly occur during the progression of the injury. At the same time as edema is produced, additional quantities of serotonin may be brought in from the blood or from neurons. However, biochemical determinations suggest a

## *Role of 5-HT in Cerebral Edema after Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.96460*

rise in the serotonin content of the traumatized brain [37]. Serotonin is a powerful chemical micro vascular response mediator to cerebral edema [32]. Results of parachlorophenylalanine (pCPA) pretreatment before trauma induction are consistent with the notion that serotonin plays a role as a vascular permeability-increasing compound that contributes to early edema [7, 38]. Para-chlorophenylalanine (pCPA), acts as a selective and irreversible inhibitor of tryptophan hydroxylase, which is a rate-limiting enzyme in the biosynthesis of serotonin. This is further demonstrated by the fact that the degree of cell changes in the periphery of the initial lesion is lower in pCPA pretreated rats than in non-treated animals with the same type of injury [7]. Therefore, it seems obvious that the decrease in the content of serotonin in the nervous tissue is somehow reflected in the decreased swelling and milder changes in the brain of traumatized rats. Nevertheless, apart from the effects of serotonin, arachidonic acid release, prostaglandins and thromboxane can synergistically contribute to edema formation.

The microdialysis technique was used in the popular carotid artery for intraarterial recordings. This new application was found to be a genuinely acceptable and effective method that allows direct measurements of HPLC plasma serotonin without any further extraction process [39]. Studies show a significant increase in downstream plasma serotonin concentrations in response to acute non-occlusive common carotid artery thrombosis (CCAT) that appears to be caused solely by endothelium photochemical and not photo thermal impact. As a mediator of blood brain barrier disturbance and/or irregular cerebral blood flow and/or neuronal impairment in ischemic stroke and transient ischemic attacks (TIA's), the rise in serotonin may be of significant importance [39].

## **3.1 Role of 5-HT2 receptors in formation of edema**

5-HT2-receptor antagonists, ketanserin [40] and LY 53857 [41] prevent capsaicin-induced mouse ear edema [42]. Antagonists of the 5-HT1-receptor and 5-HT3 receptor ICS 205–930 and MDL 72222 [43] respectively, had no effect on edema caused by capsaicin [42]. The findings clearly indicate that 5-HT is partially involved in the development of edema via 5-HT2 receptors. 5-HT is known to induce plasma extravasation by direct action on rat microvasculature [44] and to produce vasodilation on peripheral blood vessels through 5-HT1 receptors [44]. A recent study indicated that endogenous nitric oxide, in addition to 5-HT receptors, is involved in a 5-HT-induced increase in vascular permeability in mouse skin [45]. In addition to activation of 5-HT2 receptors, 5-HT plays a role of releasing neuropeptides including SP as the second mediator of increased vascular permeability at inflammatory sites [46]. Mediators like SP, bradykinin and prostaglandins, on the other hand, can release tachykinins from primary afferent terminals [47]. Many functional molecules like histamine, serotonin, arachidonic acid, prostaglandins and thromboxane have been confirmed to induce BBB disruption or cell swelling. It is believed that released 5-HT binds to 5-HT2 receptors that stimulate cAMP and prostaglandins in vessels that cause more vesicular transport in endothelial cells and leading to serum components extravasation. The additional amount of serotonin into the tissue due to injury maintains the state of increased vascular permeability that ultimately causes edema. Changes in serotonin concentration were detected early after focal traumatic injury to the rat spinal cord and were associated with edema formation and alterations in blood flow [35]. Compared to controls, the serotonin concentration in the traumatised section increased more than 100 percent in five hours after the injury. The water content of the traumatised section estimated 5 h after the injury was also gradually increased whereas para-chlorophenylalamine, serotonin synthesis inhibitor, impeded the elevation in water content measured 5 h after the trauma [35].

## **3.2 Effect of antibodies to serotonin in closed head injury**

Closed head injury (CHI) is a serious clinical issue that leads to immediate death for most patients [48]. Swelling of the brain in a closed cranial compartment that results in compression of the brain's vital centers tends to be primarily responsible for instant deaths [49]. CNS microhemorrhage, blood–brain barrier (BBB) permeability breakdown, and brain edema development, alone or in combination, are primarily responsible for cell damage and long-term neurodegenerative changes following CHI [37, 50, 51]. Unfortunately, so far, no effective validated therapies are accessible. Efforts to understand the molecular mechanisms of early pathophysiological events in an animal model of CHI are therefore urgently required to explore the possible therapeutic potential of different neuroprotective agents in order to reduce the development of edema and cell death.

In brain or spinal cord injuries increased plasma and brain levels of serotonin following CHI is seen in previous studies [50, 51]. There was a strong link between this rise in tissue serotonin levels and BBB breakdown and edema formation [52]. This is further reinforced by the fact that previous inhibition by p-chlorophenylalanine (pCPA) of serotonin biosynthesis greatly attenuated the formation of brain edema, BBB damage, and cell injury in brain and spinal cord injury [50, 51, 53]. Taken together, these findings strongly indicate an important role for serotonin in CNS trauma pathophysiology. Subsequent trials of CNS damage using serotonin receptor blocker drugs showed controversial results, however [34, 54, 55]. Blocking of 5-HT2c and 5-HT1A serotonin receptors improves cognitive function and reduces the formation of brain edema at low doses [52, 56, 57], other serotonin receptor antagonists, in fact, exacerbated the pathological outcome following brain injury [58, 59]. Thus, further research is needed into the role of serotonin receptors in mediating brain pathology in CNS injuries. Since serotonin has more than seven receptor types with several subtypes of receptors [52, 56, 58]. There can be no clear view on this topic of amine involvement using a few unspecific receptor antagonists. In addition, the dosage response and time schedule of drug therapy can further affect the final outcome [60].

Results from studies demonstrate that intracerebroventricular administration of monoclonal serotonin antibodies either 30 min before or 30 min after CHI induced profound neuroprotection. Therefore, after CHI, marked decreases in BBB disruption, brain edema formation, and cell injury were noted in serotonin antiserumtreated animals. Such novel results indicate that early intervention in CHI with serotonin antiserum is neuroprotective [60]. Taken together, these findings suggest the active participation of this amine during the early stages of CHI, in the cellular and molecular pathways of brain edema formation and BBB breakdown. The neuroprotective effects of antiserum serotonin in CHI are dose-dependent. This indicates that to induce neuroprotection, enough serotonin antiserum is required to block in vivo brain serotonin. On the other hand, when given 60 min after CHI, even a high concentration of serotonin antiserum was ineffective. This means that serotonin involvement is important for brain pathology within 30 minutes of CHI [60].

Elevation in plasma and brain serotonin concentration by intravenous injection of serotonin (10 to 20 g/kg/min) in animals without CHI disrupts the BBB function within 10 min [52, 59, 60]. This effect of the serotonin on BBB interruption is reversible. To measure BBB disruption, many approaches are used. Extravasation of Evans blue (EB) dye is the most commonly used procedure. Normally, Evans blue does not move through the BBB and hence its presence in brain tissue suggests permeability alterations. Thus, when the same dye was administered 2 to 3 hours after serotonin administration, BBB permeability to Evans blue dye was no longer observed. This means that the dosage and length of exposure to serotonin

## *Role of 5-HT in Cerebral Edema after Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.96460*

play a significant role in development of brain pathology. This principle is further confirmed by the prevention of BBB breakdown by previous serotonin synthesis inhibition, which attenuated an increase in plasma and brain serotonin in CHI [60].

BBB permeability breakdown is associated with vasogenic brain edema formation and cell injury [61–63]. Protein leakage from the vascular compartment via the blood–brain interface into the neuronal microenvironment will alter osmotic balance. A change in osmotic balance will allow the bulk flow of water from the vascular compartment to the cerebral compartments. Furthermore, the release of neurochemical mediators of brain edema, e.g. serotonin, prostaglandin, histamine and neuropeptides, via particular receptor-mediated pathways, will further affect water transfer from blood to the brain. These neurochemicals also cause the BBB process to break down. This hypothesis is consistent with a close relationship between the development of brain edema, the amount of serotonin and BBB disruption in CHI [60].

## **3.3 Serotonergic receptors in brain edema**

Tissue collected after ischemic insult in gerbils showed two binding sites for ketanserin, one with a lower and one with a higher affinity than that found in sham-operated and ischemic animal brains. Ketanserin, a quinazoline derivative, is a selective 5-HT2 serotonin receptor antagonist with weak adrenergic receptor blocking properties. The results strongly suggest that the properties of binding sites for the S2 receptor are altered in ischemia-induced cerebral edema [64]. The demonstrated regulation of the binding sites of ketanserin appears to correlate with the observed attenuated metabolic rate (= increased release) but not with the abnormal brain 5-HT levels. Studies indicate that the variations in 5-HT ischemic patterns are most likely related to the type and model of ischemia and/or brain structure examined, as well as to the 5-HT detection system used [64]. However, in the brains of gerbils subjected to 15 min bilateral carotid artery occlusion without recirculation, 5-HT metabolism is unquestionably disturbed [65–67]. Therefore, there may be numerous explanations for the lack of apparent changes in the kinetic characteristics of 5-HT2 receptor binding sites, especially if the presynaptic region is considered to be the primary site of the ischemically disrupted 5-HT pathway. The most critical of these are: (a) the insufficient lapse of time (15 min of ischemia) and/or the absence of recirculation required for the production of post-synaptic changes; and/or (b) the presence in the subcellular compartment of altered 5-HT2 receptor properties obscured by the analysis of the entire cortical homogenate rather than the relevant fraction [64].

In neuronal and/or glial and/or vascular postsynaptic membranes, the modified 5-HT2 receptors may be localized. Desensitization and hypersensitization of the receptor sites are demonstrated by the detection of 5-HT2 postsynaptic binding sites with lower and higher affinities (indicated by apparent higher KD and lower KD) after 1 h of recirculation than those seen in the ischemic and control cortex. Due to increased release, reduced uptake and reuptake of 5-HT in the presynaptic regions, this could be the result of inappropriately accessible 5-HT at the postsynaptic receptor sites [64]. In general, this phenomenon is consistent with the well-known agonist-specific desensitization of high levels of hormones and neurohormones exposed to cell membranes, whereas their depletion results in supersensitization [68]. In addition, in the recovery period (recirculation of 1 and 2 h), the observed 5-HT2 binding sites with a higher affinity (lower KD) than those seen in ischemic and control brains may indicate either an unmasked pre-existing site or an additional binding site. It can be assumed that the existing disruptions of the 5-HT pathway and its adverse effects are not limited to the presynaptic, but also include the postsynaptic subcellular compartments, based on the observed changes in the properties of S2 receptor binding sites [64].

In addition, it is conceivable that the presynaptically released 5-HT into the synaptic cleft is also able to directly impact the membrane. In this way, unmetabolized 5-HT overflow can lead to increased permeability of the membrane, allowing for more pronounced passive ion transfer and water accumulation in the cells [64]. This inference is confirmed by the additional increase in Na+ observed, a decrease in K<sup>+</sup> concentration and a decrease in Na+ -K+ -ATPase activity at the time of most marked cell swelling. In particular, the concomitant occurrence of changes in the kinetic properties of S2 receptors and the activity of Na+ K+ -ATPase is of concern, since an increase in PGF2a levels was also observed after the same period of ischemia and recirculation. 5-HT can stimulate the development of PGF2a, since this amine increases the formation of PGF1a in cultured cerebrovascular elements. Nevertheless, it remains to be clarified if 5-HT affects directly or indirectly Na+ K+ - ATPase operation [64] list Nevertheless, at the time of the most conspicuously increased cellular water in the brain of gerbils subjected to ischemia and recirculation, the observed alteration of 5-HT2 receptors strongly supports the argument of 5-HT involvement in edema formation and/or progression [64].

## **4. Neuroprotective role of serotonin after TBI**

## **4.1 In cerebral ischemia**

The severity of secondary TBI mechanisms depends on the severity of the injury or the primary insult location. Reductions in cerebral blood flow [69, 70] have been reported to exceed ischemic levels in conditions of extreme TBI. Cerebral ischemia is therefore addressed as one secondary cause of injury that may be involved in brain trauma [69, 71]. There is a massive increase in the concentration of both excitatory and inhibitory neurotransmitters in the extracellular space during cerebral ischemia [72–75]. It has been proposed that over-excitation of neurons triggered by excitatory amino acid neurotransmitters plays a major role in the pathogenesis of ischemic neuronal destruction [76]. Glutamate induces an influx of Ca2+ and Na+ into the neuron by acting on N-methyl-D-aspartate (NMDA) and non NMDA receptors. The neuronal membrane depolarizes strongly and can allow Ca2+ to reach the cell through additional pathways. These events can lead to a neurotoxic accumulation of intracellular Ca2+ [77]. In addition to glutamate antagonists, agents that induce neuronal membrane hyperpolarisation may be able to reduce the influx of Ca2+ via these ionophores and may exert neuroprotective effects. 5-HydroxytryptaminelA (5-HT1A) receptors through Ca2+-independent K+ -conductance mediate an inhibitory, hyperpolarizing effect on cortical and hippocampal neurons [78–80]. It has been shown that 5-HT1A receptor agonists imitate 5-HT's hyperpolarizing activity on the resting membrane potential, increase the firing threshold, and decrease the firing rate of hippocampal CAl, cortical, and dorsal raphe neurons [81]. The complexity of 5-HT's function in cerebral ischemia is probably due to the multiplicity within the brain of 5-HT receptors and their distinct distribution and densities. 5-HT1A receptors mediate the inhibitory effect on neurons, as mentioned above. However, 5-HT also stimulates hippocampal and cortical neurons via 5-HT2 receptors [80, 82].

## **4.2 In neurocognitive and neuropsychiatric disorders following traumatic brain injury**

Due to variable diagnostic criteria, the prevalence of post-TBI depression varies from 6–77% [83], and up to 53% in the first year after injury [84]. The association between TBI and the development of neuropsychiatric disorders is well documented

## *Role of 5-HT in Cerebral Edema after Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.96460*

[85, 86]. Disruption of the serotonergic system is one unifying factor that underlies acquired neuropsychiatric disorders following TBI. As the blood–brain barrier cannot be crossed by serotonin, synthesis must occur de novo in the brain. The shearing of brain stem axons during TBI effectively interferes with pontine and medullary serotonergic projections, resulting in decreased serotonin metabolism and production [87–90]. Selective serotonin reuptake inhibitors (SSRIs) are a class of antidepressant agents which inhibit serotonin reuptake by presynaptic cell monoamine transporters and increase extracellular concentration of serotonin, enabling increased serotonin availability in the synaptic cleft and increase activation of postsynaptic serotonergic receptors, resulting in increased synaptic signaling. SSRIs are involved in regulation of neuronal cell survival and neuroplasticity for the treatment of psychiatric disorders, including depression, obsessive–compulsive disorder, bulimia, and panic disorder [91]. Serotonin modulates mood, arousal, emotion, and working memory, and thus constitute SSRIs an attractive, treatable, and potentially long-term pharmacological intervention for neurocognitive and neuropsychiatric deficits post-TBI [92]. Consequently, the judicious use of SSRIs in post-TBI depression treatment is of great importance and impact.

## **5. Pharmacological interventions after TBI related to serotonin**

A growing number of patients are surviving with residual neurological impairments due to improvements in the treatment of head trauma. A commission of the National Institute of Health reports that there are currently 2.5 to 6.5 million Americans with TBI-related disabilities [93]. Information from various disciplines and professions beginning at the time of injury and continuing through the recovery process is required for successful treatment of TBI. In both the sub-acute (less than 1 month post TBI) and chronic (more than 1 month post TBI) stages, pharmacotherapy is used. Selective serotonin reuptake inhibitors (SSRIs) have been found to be helpful in the treatment of behavioral syndromes in patients with TBI, especially in the sub-acute recovery phases [94], but also in chronic settings. Most studies indicate that SSRIs enhance neurobehavioral, neurocognitive, and neuropsychiatric deficits, especially agitation, depression, psychomotor retardation, and recent memory loss, but most of the information comes from non-randomized studies. Similarly, bupropion boosts the levels of both dopamine and norepinephrine and is a weak serotonin reuptake inhibitor. This agent has been effective in treating restlessness at 150 mg per day [95]. For anxiety, depressed mood, and deficits in psychomotor pace and recent memory, sertraline administered at an average dose of 100 mg daily for 8 weeks was found to be beneficial but shorter treatment durations have shown no benefit [94]. There was a strong link between the rise in tissue serotonin levels and BBB breakdown and edema formation [52]. This is further reinforced by the fact that previous inhibition by p-chlorophenylalanine (pCPA) of serotonin biosynthesis greatly attenuated the formation of brain edema, BBB damage, and cell injury in brain and spinal cord injury [53]. Blocking of 5-HT2c and 5-HT1A serotonin receptors improves cognitive function and reduces the formation of brain edema at low doses [52, 56]. Thus, 5-HT2 receptor functions need to be explored more in the development of cerebral edema and this can be used as pharmacological intervention to reduce cerebral edema.

## **6. Conclusion**

Due to permeability changes in the vessel walls, the pathogenesis of edema after traumatic brain injury is complex, including disruption of micro vessels and changes in microcirculation around the primary injury and leakage of plasma constituents into the tissue. To cause BBB disruption or cell swelling, several functional molecules such as histamine, serotonin, prostaglandins and thromboxane are involved. The 5-HT released is believed to bind to 5-HT2 receptors stimulating cAMP and prostaglandins in vessels that trigger further vesicular transport in endothelial cells, leading to extravasation of the serum portion. Serotonin is involved in early cytotoxic edema after TBI. Reduction of serotonin in the nervous tissue is shown to reduce swelling and the milder cell changes in the brain or spinal cord of traumatized rats. Inhibition of serotonin synthesis before CHI in rat models or administration of serotonin antiserum after injury attenuates BBB disruption and brain edema, volume swelling, and brain pathology. BBB disturbance and brain edema, volume swelling, and brain pathology are attenuated by inhibition of serotonin production before CHI in rat models or the administration of serotonin antiserum after injury. Immediately after injury, maintaining low serotonin levels can demonstrate neuroprotection and fight various secondary outcomes that occur after traumatic brain injury.

## **Author details**

Priya Badyal, Jaspreet Kaur and Anurag Kuhad\* Pharmacology Research Laboratory, University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, India

\*Address all correspondence to: anurag\_pu@yahoo.com; anurag.kuhad@pu.ac.in

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

*Role of 5-HT in Cerebral Edema after Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.96460*

## **References**

[1] Jin Y, Lin Y, Feng JF, Jia F, Gao G, Jiang JY. Attenuation of Cell Death in Injured Cortex after Post-Traumatic Brain Injury Moderate Hypothermia: Possible Involvement of Autophagy Pathway. World Neurosurg. 2015; 84(2):420-30

[2] Li Q, Wu X, Yang Y, Zhang Y, He F, Xu X, et al. Tachykinin NK1 receptor antagonist L-733,060 and substance P deletion exert neuroprotection through inhibiting oxidative stress and cell death after traumatic brain injury in mice. Int J Biochem Cell Biol. 2019;

[3] Bayir H, Kochanek PM, Kagan VE. Oxidative stress in immature brain after traumatic brain injury. Developmental Neuroscience. 2006. 28:420-31

[4] Donkin JJ, Vink R. Mechanisms of cerebral edema in traumatic brain injury: Therapeutic developments. Current Opinion in Neurology. 2010. 23(3):293-9.

[5] Pappius HM, Dadoun R, McHugh M. The effect of p-chlorophenylalanine on cerebral metabolism and biogenic amine content of traumatized brain. J Cereb Blood Flow Metab. 1988; 8(3):324-334

[6] S.M. Hung A, Y.M. Tsui T, C.Y. Lam J, S.M. Wai M, M. Chan W, T. Yew D. Serotonin and its Receptors in the Human CNS with New Findings - A Mini Review. Curr Med Chem. 2011; 18(34):5281-8

[7] Olsson Y, Sharma HS, Pettersson CÅ V. Effects of p-chlorophenylalanine on microvascular permeability changes in spinal cord trauma - An experimental study in the rat using 131I-sodium and lanthanum tracers. Acta Neuropathol. 1990; 79(6):595-603

[8] Chiavegatto S, Nelson RJ. Interaction of nitric oxide and serotonin in aggressive behavior. In: Hormones and Behavior. 2003. 44(3):233-41

[9] Fukumura D, Gohongi T, Kadambi A, Izumi Y, Ang J, Yun CO, et al. Predominant role of endothelial nitric oxide synthase in vascular endothelial growth factor-induced angiogenesis and vascular permeability. Proc Natl Acad Sci U S A. 2001; 98 (5) 2604-2609

[10] Manivet P, Mouillet-Richard S, Callebert J, Nebigil CG, Maroteaux L, Hosoda S, et al. PDZ-dependent activation of nitric-oxide synthases by the serotonin 2B receptor. J Biol Chem. 2000; 275(13):9324-31

[11] Borgdorff P, Fekkes D, Tangelder GJ. Hypotension caused by extracorporeal circulation: Serotonin from pumpactivated platelets triggers nitric oxide release. Circulation. 2002; 106:2588-2593

[12] Kochanek KD, Xu J, Murphy SL, Miniño AM, Kung HC. Deaths: final data for 2009. Natl Vital Stat Rep. 2011; 60(3):1-116

[13] Stokum JA, Gerzanich V, Simard JM. Molecular pathophysiology of cerebral edema. Journal of Cerebral Blood Flow and Metabolism. 2016. 36(3):513-38

[14] Di Terlizzi R, Platt S. The function, composition and analysis of cerebrospinal fluid in companion animals: Part I - Function and composition. Vet J. 2006; 172(3):422-31

[15] Iliff JJ, Wang M, Liao Y, Plogg BA, Peng W, Gundersen GA, et al. A paravascular pathway facilitates CSF flow through the brain parenchyma and the clearance of interstitial solutes, including amyloid β. Sci Transl Med. 2012; 4(147):147ra111

[16] Thrane VR, Thrane AS, Plog BA, Thiyagarajan M, Iliff JJ, Deane R, et al. Paravascular microcirculation facilitates rapid lipid transport and astrocyte

signaling in the brain. Sci Rep. 2013; 3:2582

[17] Iliff JJ, Nedergaard M. Is there a cerebral lymphatic system? In: Stroke. 2013. 44:S93–S95

[18] Hossmann KA, Schuier FJ. Experimental brain infarcts in cats. I. Pathophysiological observations. Stroke. 1980; 11(6):583-92

[19] Bell BA, Symon L, Branston NM. CBF and time thresholds for the formation of ischemic cerebral edema, and effect of reperfusion in baboons. J Neurosurg. 1985; 62(1):31-41

[20] Quast MJ, Huang NC, Hillman GR, Kent TA. The evolution of acute stroke recorded by multimodal magnetic resonance imaging. Magn Reson Imaging. 1993; 11(4):465-71

[21] Thrane AS, Rangroo Thrane V, Nedergaard M. Drowning stars: Reassessing the role of astrocytes in brain edema. Trends in Neurosciences. 2014. 37(11):620-8

[22] Yan Y, Dempsey RJ, Sun D. Expression of Na+-K+-Cl- cotransporter in rat brain during development and its localization in mature astrocytes. Brain Res. 2001; 911(1):43-55

[23] Yan Y, Dempsey RJ, Sun D. Na+- K+-Cl- cotransporter in rat focal cerebral ischemia. J Cereb Blood Flow Metab. 2001; 21(6):711-21

[24] Jayakumar AR, Norenberg MD. The Na-K-Cl Co-transporter in astrocyte swelling. In: Metabolic Brain Disease. 2010. 25(1):31-8

[25] Hamann S, Herrera-Perez JJ, Zeuthen T, Alvarez-Leefmans FJ. Cotransport of water by the Na+-K+-2Cl cotransporter NKCC1 in mammalian epithelial cells. J Physiol. 2010; 588( 21):4089-101

[26] Su G, Kintner DB, Sun D. Contribution of Na+-K+-Clcotransporter to high-[K+]o- induced swelling and EAA release in astrocytes. Am J Physiol - Cell Physiol. 2002; 282(5):C1136-46

[27] Lu KT, Cheng NC, Wu CY, Yang YL. NKCC1-mediated traumatic brain injury-induced brain edema and neuron death via Raf/MEK/MAPK cascade. Crit Care Med. 2008; 36(3):917-22

[28] O'Donnell ME, Tran L, Lam TI, Liu XB, Anderson SE. Bumetanide inhibition of the blood-brain barrier Na-K-Cl cotransporter reduces edema formation in the rat middle cerebral artery occlusion model of stroke. J Cereb Blood Flow Metab. 2004; 24(9):1046-56

[29] Yan Y, Dempsey RJ, Flemmer A, Forbush B, Sun D. Inhibition of Na+- K+-Cl- cotransporter during focal cerebral ischemia decreases edema and neuronal damage. Brain Res. 2003; 961(1):22-31

[30] Vorbrodt AW, Lossinsky AS, Wisniewski HM, Suzuki R, Yamaguchi T, Masaoka H, et al. Ultrastructural observations on the transvascular route of protein removal in vasogenic brain edema. Acta Neuropathol. 1985; 66(4):265-73

[31] Unterberg AW, Stover J, Kress B, Kiening KL. Edema and brain trauma. Neuroscience. 2004; 129(4):1021-9

[32] Wahl M, Unterberg A, Baethmann A, Schilling L. Mediators of blood-brain barrier dysfunction and formation of vasogenic brain edema. Journal of Cerebral Blood Flow and Metabolism. 1988. 8(5):621-34

[33] McEntee WJ, Crook TH. Serotonin, memory, and the aging brain. Psychopharmacology. 1991. 103(2):143-9

*Role of 5-HT in Cerebral Edema after Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.96460*

[34] Sharma HS, Olsson Y, Kumar Dey P. Changes in blood-brain barrier and cerebral blood flow following elevation of circulating serotonin level in anesthetized rats. Brain Res. 1990; 517(1-2):215-23

[35] Sharma HS, Olsson Y, Dey PK. Early accumulation of serotonin in rat spinal cord subjected to traumatic injury. Relation to edema and blood flow changes. Neuroscience. 1990;

[36] Nag S, Manias JL, Stewart DJ. Pathology and new players in the pathogenesis of brain edema. Acta Neuropathologica. 2009. 118(2):197-217

[37] Day PK, Sharma HS. Ambient temperature and development of traumatic brain oedema in anaesthetized animals. Indian J Med Res. 1983;

[38] Sharma HS, Olsson Y. Edema formation and cellular alterations following spinal cord injury in the rat and their modification with p-chlorophenylalanine. Acta Neuropathol. 1990; 79(6):604-10.

[39] Dietrich WD. The Role of Neurotransmitters in Brain Injury. Vol. 10, Journal of Cerebral Blood Flow & Metabolism. 1990. 758-758 p.

[40] Leysen JE, Awouters F, Kennis L, Laduron PM, Vandenberk J, Janssen PAJ. Receptor binding profile of R 41 468, A novel antagonist at 5-HT2 receptors. Life Sci. 1981; 28(9)1015-22

[41] Cohen ML, Fuller RW, Kurz KD. LY53857, a selective and potent serotonergic (5-HT2) receptor antagonist, does not lower blood pressure in the spontaneously hypertensive rat. J Pharmacol Exp Ther. 1983; 227(2):327-32.

[42] Inoue H, Nagata N, Koshihara Y. Participation of Serotonin in

Capsaicin-Induced Mouse Ear Edema. Jpn J Pharmacol. 1995; 69(1):61-8

[43] Fozard JR. MDL 72222: a potent and highly selective antagonist at neuronal 5-hydroxytryptamine receptors. Naunyn Schmiedebergs Arch Pharmacol. 1984; 326(1):36-44

[44] Arvier PT, Chahl LA, Ladd RJ. Modification by capsaicin and compound 48/80 of dye leakage induced by irritants in the rat. Br J Pharmacol. 1977; 59(1):61-8

[45] Fujii E, Irie K, Uchida Y, Tsukahara F, Muraki T. Possible role of nitric oxide in 5-hydroxytryptamineinduced increase in vascular permeability in mouse skin. Naunyn Schmiedebergs Arch Pharmacol. 1994; 350(4):361-4

[46] Mantione CR, Rodriguez R. A bradykinin (BK)1 receptor antagonist blocks capsaicin-induced ear inflammation in mice. Br J Pharmacol. 1990; 99(3): 516-518.

[47] Holzer P. Capsaicin: Cellular targets, mechanisms of action, and selectivity for thin sensory neurons. Pharmacological Reviews. 1991. 43(2):143-201

[48] Ommaya AK, Goldsmith W, Thibault L. Biomechanics and neuropathology of adult and paediatric head injury. British Journal of Neurosurgery. 2002. 16(3):220-42

[49] Goyal K, Yadav R. Traumatic brain injury. In: Acute Neuro Care: Focused Approach to Neuroemergencies. 2020.

[50] Vannemreddy P, Ray AK, Patnaik R, Patnaik S, Mohanty S, Sharma HS. Zinc protoporphyrin IX attenuates closed head injury-induced edema formation, blood-brain barrier disruption, and serotonin levels in the rat. Acta Neurochir Suppl. 2006; 96:151-6.

[51] Dey PK, Sharma HS. Influence of ambient temperature and drug treatments on brain oedema induced by impact injury on skull in rats. Indian J Physiol Pharmacol. 1984; 28(3):177-86

[52] Sharma HS. Influence of Serotonin on the Blood-Brain and the Blood-Spinal Cord Barriers. In: Blood-Spinal Cord and Brain Barriers in Health and Disease. 2004.

[53] Sharma HS, Winkler T, Stålberg E, Mohanty S, Westman J. p-Chlorophenylalanine, an inhibitor of serotonin synthesis reduces blood-brain barrier permeability, cerebral blood flow, edema formation and cell injury following trauma to the rat brain. Acta Neurochir Suppl. 2000; 76:91-5

[54] Nichols CD. Serotonin. In: Encyclopedia of the Neurological Sciences. 2014.

[55] Sharma HS, Westman J, Cervós Navarro J, Dey PK, Nyberg F. Probable involvement of serotonin in the increased permeability of the bloodbrain barrier by forced swimming. An experimental study using Evans blue and 131I-sodium tracers in the rat. Behav Brain Res. 1995; 189-196

[56] Salzman SK, Kelly G, Chavin J, Wang L, Puniak MA, Agresta CA, et al. Characterization of mianserin neuroprotection in experimental spinal trauma: Dose/route response and late treatment. J Pharmacol Exp Ther. 1994; 269(1):322-8

[57] Salzman SK, Puniak MA, Liu Z -j, Maitland-Heriot RP, Freeman GM, Agresta CA. The serotonin antagonist mianserin improves functional recovery following experimental spinal trauma. Ann Neurol. 1991; 30(4):533-41

[58] Faden AI, Salzman S. Pharmacological strategies in CNS trauma. Trends in Pharmacological Sciences. 1992. 13:29-35

[59] Sharma HS, Winkler T, Stålberg E, Olsson Y, Dey PK. Evaluation of traumatic spinal cord edema using evoked potentials recorded from the spinal epidural space. An experimental study in the rat. J Neurol Sci. 1991; 102(2):150-62

[60] Sharma HS, Patnaik R, Patnaik S, Mohanty S, Sharma A, Vannemreddy P. Antibodies to serotonin attenuate closed head injury induced blood-brain barrier disruption and brain pathology. In: Annals of the New York Academy of Sciences. 2007. 1122:295-312

[61] Sharma HS, Westman J, Nyberg F. Pathophysiology of brain edema and cell changes following hyperthermic brain injury. Progress in Brain Research. 1998. 115:351-412

[62] Sharma HS, Westman J, Nyberg F, Cervos-Navarro J, Dey PK. Role of serotonin and prostaglandins in brain edema induced by heat stress. An experimental study in the young rat. Acta Neurochir Suppl (Wien). 1994; 60:65-70.

[63] Sharma HS, Olsson Y, Nyberg F, Dey PK. Prostaglandins modulate alterations of microvascular permeability, blood flow, edema and serotonin levels following spinal cord injury: An experimental study in the rat. Neuroscience. 1993; 443-449

[64] Wroblewska B, Ueki Y, Mršulja BB, Djuričić BM, Spatz M. Serotonin Receptors in Ischemic Brain Edema. Brain Edema. 1985;178-84.

[65] Maruki C, Merkel N, Rausch WD, Spatz M. Brain Monoamines in Cerebral Ischemic Edema, the Effect of Gamma-Hydroxy-Butyrate. In: Recent Progress in the Study and Therapy of Brain Edema. 1984.

[66] Mršulja BB, Djuričić BM, Cvejić V, Mićić D V. Pharmacological Approach to Postischemic Brain Edema in Gerbils. In:

## *Role of 5-HT in Cerebral Edema after Traumatic Brain Injury DOI: http://dx.doi.org/10.5772/intechopen.96460*

Recent Progress in the Study and Therapy of Brain Edema. 1984.

[67] Mršulja BB, Mršulja BJ, Spatz M, Klatzo I. Monoamines in Cerebral Ischemia in Relation to Brain Edema. Dyn Brain Edema. 1976;187-92.

[68] Iyengar R, Birnbaumer L. Agonistspecific desensitization: molecular locus and possible mechanism. Adv Cyclic Nucleotide Res. 1981;14:93-100.

[69] Marion DW, Darby J, Yonas H. Acute regional cerebral blood flow changes caused by severe head injuries. J Neurosurg. 1991; 74(3):407-14

[70] Zauner A, Bullock R, Kuta AJ, Woodward J, Young HF. Glutamate Release and Cerebral Blood Flow after Severe Human Head Injury. Acta Neurochir Suppl. 1996; 67:40-4

[71] Bouma GJ, Muizelaar JP, Choi SC, Newlon PG, Young HF. Cerebral circulation and metabolism after severe traumatic brain injury: The elusive role of ischemia. J Neurosurg. 1991; 75(5):685-93

[72] Benveniste H, Drejer J, Schousboe A, Diemer NH. Elevation of the Extracellular Concentrations of Glutamate and Aspartate in Rat Hippocampus During Transient Cerebral Ischemia Monitored by Intracerebral Microdialysis. J Neurochem. 1984; 43(5):1369-74

[73] Hagberg H, Andersson P, Lacarewicz J, Jacobson I, Butcher S, Sandberg M. Extracellular Adenosine, Inosine, Hypoxanthine, and Xanthine in Relation to Tissue Nucleotides and Purines in Rat Striatum During Transient Ischemia. J Neurochem. 1987; 49(1):227-31

[74] Globus MY-., Busto R, Dietrich WD, Martinez E, Valdes I, Ginsberg MD. Effect of Ischemia on the In Vivo Release of Striatal Dopamine, Glutamate, and γ-Aminobutyric Acid Studied by

Intracerebral Microdialysis. J Neurochem. 1988; 51(5):1455-64

[75] Sarna GS, Obrenovitch TP, Matsumoto T, Symon L, Curzon G. Effect of Transient Cerebral Ischaemia and Cardiac Arrest on Brain Extracellular Dopamine and Serotonin as Determined by In Vivo Dialysis in the Rat. J Neurochem. 1990; 55(3):937-40

[76] Jørgensen MB, Diemer NH. Selective neuron loss after cerebral ischemia in the rat: Possible role of transmitter glutamate. Acta Neurol Scand. 1982; 66(5):536-46

[77] Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron. 1988. 1(8):623-34

[78] Beck SG, Clarke WP, Goldfarb J. Spiperone differentiates multiple 5-hydroxytryptamine responses in rat hippocampal slices in vitro. Eur J Pharmacol. 1985; 116(1-2):195-7

[79] Andrade R, Malenka RC, Nicoll RA. A G protein couples serotonin and GABAB receptors to the same channels in hippocampus. Science (80- ). 1986; 234(4781):1261-5

[80] Colino A, Halliwell J V. Differential modulation of three separate K-conductances in hippocampal ca1 neurons by serotonin. Nature. 1988; 328(6125):73-7

[81] Basse-Tomusk A, Rebec G V. Ipsapirone depresses neuronal activity in the dorsal raphe nucleus and the hippocampal formation. Eur J Pharmacol. 1986; 130(1-2):141-3

[82] Davies MF, Deisz RA, Prince DA, Peroutka SJ. Two distinct effects of 5-hydroxytryptamine on single cortical neurons. Brain Res. 1987; 2):347-52

[83] Jorge RE, Robinson RG, Moser D, Tateno A, Crespo-Facorro B, Arndt *S. Major* Depression Following Traumatic Brain Injury. Arch Gen Psychiatry. 2004; 61(1):42-50

[84] Bombardier CH, Fann JR, Temkin NR, Esselman PC, Barber J, Dikmen SS. Rates of major depressive disorder and clinical outcomes following traumatic brain injury. JAMA - J Am Med Assoc. 2010; 303(19): 1938-45

[85] Koponen S, Taiminen T, Portin R, Himanen L, Isoniemi H, Heinonen H, et al. Axis I and II psychiatric disorders after traumatic brain injury: A 30-year follow-up study. Am J Psychiatry. 2002; 159(8):1315-21

[86] Koponen S, Taiminen T, Hiekkanen H, Tenovuo O. Axis I and II psychiatric disorders in patients with traumatic brain injury: A 12-month follow-up study. Brain Inj. 2011; 25(11):1029-34

[87] Markianos M, Seretis A, Kotsou A, Christopoulos M. CSF neurotransmitter metabolites in comatose head injury patients during changes in their clinical state. Acta Neurochir (Wien). 1996; 138(1):57-9

[88] Tsuiki K, Yamamoto YL, Diksic M. Effect of Acute Fluoxetine Treatment on the Brain Serotonin Synthesis as Measured by the α-Methyl-l-Tryptophan Autoradiographic Method. J Neurochem. 1995; 65(1):250-6

[89] Tsuiki K, Takada A, Nagahiro S, Grdiša M, Diksic M, Pappius HM. Synthesis of Serotonin in Traumatized Rat Brain. J Neurochem. 1995; 64(3):1319-25

[90] Kline AE, Yu J, Horváth E, Marion DW, Dixon CE. The selective 5-HT1A receptor agonist repinotan HCl attenuates histopathology and spatial learning deficits following traumatic brain injury in rats. Neuroscience. 2001; 106(3):547-55.

[91] Schneier FR, Campeas R, Carcamo J, Glass A, Lewis-Fernandez R, Neria Y, et al. COMBINED MIRTAZAPINE and SSRI TREATMENT of PTSD: A PLACEBO-CONTROLLED TRIAL. Depress Anxiety. 2015; 32(8): 570-579

[92] Mostert JP, Koch MW, Heerings M, Heersema DJ, De Keyser J. Therapeutic potential of fluoxetine in neurological disorders. CNS Neuroscience and Therapeutics. 2008. 14(2):153-164

[93] Iaccarino MA, Bhatnagar S, Zafonte R. Rehabilitation after traumatic brain injury. In: Handbook of Clinical Neurology. 2015. 127:411-22

[94] Meythaler JM, Depalma L, Devivo MJ, Guin-Renfroe S, Novack TA. Sertraline to improve arousal and alertness in severe traumatic brain injury secondary to motor vehicle crashes. Brain Inj. 2001; 15(4):321-31

[95] Teng CJ, Bhalerao S, Lee Z, Farber J, Morris H, Foran T, et al. The use of bupropion in the treatment of restlessness after a traumatic brain injury. Brain Inj. 2001; 15(5):463-7

## **Chapter 8**

## Serotonin Pathway in Neuroimmune Network

*Giada Mondanelli and Claudia Volpi*

## **Abstract**

Once considered merely as a neurotransmitter, serotonin (5-HT) now enjoys a renewed reputation as an interlocutor in the dense and continuous dialogue between neuroendocrine and immune systems. In the last decades, a role has been depicted for serotonin and its derivatives as modulators of several immunological events, due to the expression of specific receptors or enzymes controlling 5-HT metabolism in diverse immune cell types. A growing body of evidence suggests that the effects of molecules belonging to the 5-HT pathways on the neuroimmune communication may be relevant in the clinical outcome of autoimmune/inflammatory pathologies of the central nervous system (CNS), such as multiple sclerosis, but also in Alzheimer's disease, or in mood disorders and major depression. Moreover, since the predominance of 5-HT is produced by enterochromaffin cells of the gastrointestinal tract, where 5-HT and its derivatives are important mucosal signalling molecules giving rise to the so-called "brain-gut axis", alterations in brain-gut communication are also involved in the pathogenesis and pathophysiology of several psychiatric and neurologic disorders. Here we illustrate how functional interactions between immune and neuronal cells are crucial to orchestrate tissue homeostasis and integrity, and the role of serotonin pathway components as pillars of the neuroimmune system.

**Keywords:** neuroimmune system, tryptophan metabolism, serotonin, N-acetylserotonin, melatonin, indoleamine 2,3-dioxygenase

## **1. Introduction**

It's now widely accepted that the immune system and neuroendocrine system function in close association of each other, to such an extent that it's possible to refer to them as "neuroimmune system" [1]. The interactions that take place within the neuroimmune system involve the production and use of immune factors, as well as neuroendocrine mediators, in a role-playing game where it's impossible to trace the belonging of specific molecules exclusively in one of the two systems. The constant dialogue between the participants to the neuroimmune communication in the CNS and in the periphery not only allows the fine tuning of the immune response, but also the synaptic plasticity, and alterations in the propagation of neuroimmune messages may account for several immune-mediated and psychiatric diseases.

Here we examine the role of serotonin and its derivatives in the neuroimmune communication and we highlight the importance of an appropriate balance between the production of tryptophan metabolites for the maintenance of the neuroimmune

homeostasis. Moreover, we give a perspective on how the regulation of the metabolic pathways leading to different tryptophan metabolites, including serotonin and derived molecules, could represent a significant pharmacological target for the treatment of various CNS diseases.

## **2. Serotonin pathway in the neuroimmune system: an overview**

Under physiological conditions, the majority of Tryptophan (Trp) is degraded along the kynurenine pathway (KP) and only about 1% is metabolized into serotonin (5-HT) in the so-called methoxyindoles pathway (**Figure 1**). This metabolic route begins with the transformation of Trp into 5-hydroxytryptophan and then into serotonin through two consecutive reactions catalyzed by the enzymes tryptophan hydroxylase (TPH) and 5-hydroxytryptophan decarboxylase (AADC). Subsequently, the rate-limiting enzyme arylalkylamine N-acetyltransferase (AANAT) promotes the acetylation of serotonin into N-acetylserotonin (NAS), which, in turn, serves as a substrate for the hydroxyindole-O-methyl transferase (HIOMT or acetylserotonin O-methyltransferase, ASMT) to generate melatonin. Then, melatonin can be cleaved by indoleamine 2,3-dioxygenase 1 (IDO1) in a nonspecific reaction and transformed into N-acetyl-N-formyl-5-methoxykynurenamine (AFMK). Additional enzymatic or oxidative pathways other than IDO1 are responsible for the generation of AFMK from the common precursor. Specifically, AFMK can arise from reaction of melatonin with hydroxyl radical and the subsequent interaction of the new-born melatonyl species with superoxide anion [2]. Moreover,

#### **Figure 1.**

*Tryptophan metabolism along the kynurenine, serotonin and indole pathways. The majority of tryptophan is converted into kynurenine, whereas only about 1% is metabolized into serotonin. A small amount of tryptophan is used by the gut microbiota to produce indole derivatives. AADC, aromatic amino acid decarboxylase; AANAT, arylalkylamine N-acetyltransferase; ALDH, aldehyde dehydrogenase; AFMK, acetyl-N-formyl-5-methoxykynurenamine; ArAT, acromatic amino acid aminotransferase; ASMT, N-acetylserotonin O-methyltransferase; 3-HAA, 3-hydroxyanthranilic acid; 3-HK, 3-hydroxykynurenine; 5-HTTP, 5-hydroxytryptophan; IA, indoleacrylic acid; IAA, indoleacetic acid; Iald, indole-3-aldehyde; IAAld, indole-3-acetaldehyde; IAM, indole-3-acetamide; IDO1, indoleamine 2–3-dioxygenase 1; ILA, indolelactic acid; INMT, indolethylamine-N-methyltransferase; IPA, indole-3-propionic acid; IPYA, Indole-3-pyruvate; KAT, kynurenine aminotransferase; KMO, kynurenine-3-monooxygenase; KYNU, kynureninase; MAO, monoamine oxidase; NAD+, nicotinamide adenine dinucleotide; NAS, Nacetylserotonin; TDO2, tryptophan 2,3-dioxygenase; TMO, tryptophan 2-monooxygenase; TPH, tryptophan hydroxylase.*

### *Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

melatonin can yield to AFMK either by directly scavenging hydrogen peroxide or serving as a substrate of neutrophils' myeloperoxidase [3, 4].

Serotonin is a double life metabolite acting as neurotransmitter and peripheral hormone [5]. As a matter of fact, about 5% of the total serotonin is synthesized by serotoninergic neurons and operates within the CNS, while the majority of human body's serotonin is produced by enterochromaffin cells (EC) located in the gastrointestinal tract (GI). A significant amount of gut serotonin is released in the bloodstream where it is rapidly absorbed and stored by platelets and, to a lesser extent, by immune cells [6]. Although both TPH and AADC are necessary for the production of serotonin, TPH is the rate-limiting enzyme, as demonstrated by its weak affinity for any other amino acid and by the reduced serotonin levels upon pharmacologic or genetic ablation of the enzyme [7]. TPH exists into two isoforms that mainly differ in terms of cellular localization, i.e. TPH1- expressed by EC cells - and TPH2, found in central neurones [8].

The balance between the biosynthesis and the metabolism affects the bioavailability of serotonin. Indeed, besides the main branch of methoxyindoles pathway that yields to AFMK as end product, three additional catabolic reactions are responsible for the biotransformation of serotonin into metabolites mainly excreted with the urine [9]. In particular, through the catalysis mediated by IDO1, monoamine oxidases (MAO) or indolethylamine-N-methyltransferase (INMT), serotonin is converted into formyl-5-hydroxykynurenamine, 5-hydroxyindoleacetic acid and N-methylserotonin, respectively. Although rapidly metabolized, serotonin can be taken up by serotonin reuptake transporters (SERT) expressed in the CNS, platelets, GI and peripheral vasculature; once in the cytosol, the metabolite is immediately packaged into vesicles by vesicular monoamine transporter (VMAT) that prevents further degradation by mitochondrial MAO. Calcium-dependent exocytosis, such as that triggered during an inflammatory response or vascular injury, is responsible for the release of serotonin from the storing vesicles.

As an archetype of chronobiological hormone, melatonin is mainly produced by the pineal gland in response to circadian rhythm, i.e. the concentration of melatonin rises in the darkness and decreases in the daytime [10]. Along with melatonin, pineal NAS levels are higher at night than during the day, as opposed to pineal serotonin whose concentration peaks with the lightering. The rhythmic rotation between daily and nightly profiles of pineal indoles is controlled by the circadian clock located in the suprachiasmatic nuclei of the hypothalamus [11]. In homeostatic conditions during the darkness, the norepinephrine-mediated activation of adrenergic receptors results in an increase of cytosolic calcium and cAMP, which activate the protein kinase A (PKA) with the consequent phosphorylation of the cAMP response element binding protein (CREB). Phosphorylated CREB migrates into the nucleus and induces the transcription of *Aanat* gene, thus fuelling the synthesis of NAS and melatonin. Moreover, PKA phosphorylates AANAT, protecting the enzyme from the proteasomal degradation.

This central clock not only ensures the adaptation of living organisms to the cyclic and seasonal environmental changes, but also allows the efficient handling of immune responses [12]. If on one hand, pineal melatonin can regulate the immune responses and rhythmically vary the immune system's components, on the other hand signals sent by immune cells can be perceived by pineal gland as feedback for the regulation of melatonin production [13, 14]. This back and forward switch in melatonin biosynthesis, namely immune-pineal axis, is considered the cornerstone of the neuroendocrine-immune network that allows the communication between immune, nervous and endocrine systems [15].

Pathogen-associated molecular patterns (PAMPs, such as bacterial lipopolysaccharide and viral double stranded RNA) as well as danger-associated molecular

patterns (DAMPs; including tissue debris and amyloid β peptide) trigger the shift between pineal and extra-pineal melatonin synthesis. By interacting with their cognate receptors, PAMPs and DAMPs promote the nuclear translocation of the transcription factor nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB), which binds to the promoter of target genes coding for pro-inflammatory mediators as well as of anti-inflammatory factors involved in the later recovery phase. *Aanat* is one of the genes whose transcription is regulated by NF-κB either positively or negatively, depending on cellular microenvironment. Specific NF-κB dimers allow the activation of the immune system in synch with the relocation of melatonin production from the pineal gland to the activated immune cells and vice versa. In the pinealocytes, the homodimer p50/p50 inhibits *Aanat* transcription, while in macrophages the heterodimer RelA/c-Rel induces Aanat gene expression and thus fuels the local melatonin production [16]. Whilst macrophages-derived melatonin promotes their migration to damaged tissue and enhances their phagocytic capacity, it is the indole metabolite itself that directly ends the process through the inhibition of NF-κB activity [17, 18]. The blockage of NF-κB re-establishes the homeostatic conditions and shifts the synthesis of melatonin from immune cells to pinealocytes. Moreover, during the recovery phase, melatonin is assisted by the adrenal cortex hormones (namely corticosteroids) in reducing the nuclear content of pineal p50/p50 homodimer, leading to an increase of *Aanat* transcription and thus more feed for melatonin synthesis [19].

## **3. Serotonin and its metabolites in immune cells**

In the guise of both neurotransmitter and hormone, serotonin contributes to the regulation of several physiologic processes, such as central and peripheral functions, including sleep, mood and appetite as well as heart functionality, intestinal mobility and vascular tone among the most relevant. Accumulating evidences suggest that non-neuronal serotonin is also endowed with immunoregulatory properties. As a matter of fact, several immune cells possess the machinery to synthesize, store, respond to and take serotonin up from the microenvironment [20]. Changes in serotonin levels have been reported in patients with chronic inflammation and autoimmune dysfunctions, including multiple sclerosis (MS), rheumatoid arthritis and inflammatory bowel disease [21]. Drugs that modulate serotonin signalling, such as the selective serotonin reuptake inhibitors (SSRIs), appear to affect peripheral immunity. By blocking the reuptake of serotonin, SSRIs have found a place as anti-depressant in the clinical practice and only recently their ability to influence T lymphocytes proliferation, apoptosis and cytokines' production has emerged [22].

## **3.1 Serotonin receptors expression in cells of the innate immune system**

In mammals, seven families of serotonin receptor (5-HTRs) have been identified (**Table 1**) [23]. All 5-HTRs belong to the G-protein coupled receptor (GPCR) superfamily, with the exception of 5-HT3R, which is a ligand-gated ion channel permeable to calcium, sodium and potassium, whose activation leads to a rapid depolarization of the plasma membrane. The members of the GPCR-like serotonin receptors activate an intracellular signaling cascade that involves Adenylyl cyclase (AC) and phospholipase C (PLC) as effector systems [23]. 5-HT1R and 5-HT5R are negatively coupled with AC and thus their activation results in a reduced cAMP. Conversely, 5-HTRs 4, 6 and 7 are positively associated with AC with the consequent raise of cAMP levels. Upon serotonin binding, 5-HT2R signals through


*Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

#### **Table 1.**

*Molecular targets of serotonin and metabolites thereof, and their expression on immune cells.*

PLC-mediated release of inositol triphosphate and diacylglycerol, which increases intracellular calcium levels.

By virtue of the ubiquitous expression of the 5-HTRs and the different intracellular pathways activated, the biology of serotonin appears to be somewhat intricate and this accounts for its pleiotropic functions. 5-HTRs have been identified on murine and human innate immune cells, including neutrophils, monocytes, macrophages, dendritic cells (DCs), mast cells and natural killer cells [24]. The modulatory effects of serotonin on DCs depends on their maturity state, as 5-HTRs are differentially located on mature (mainly expressing 5-HT4R and 5-HT7R) and immature (expressing 5-HT1BR and 5-HT2BR) cells [25]. The overall literature agrees on the role of serotonin in modulating migration, morphology and cytokines' production by human and murine DCs. Through the activation of 5-HT4R and 5-HT7R, indeed, the monoamine affects the differentiation capacity of human monocytes to DCs, and increases the release of the anti-inflammatory cytokine IL-10, meanwhile the engagement of 5-HT7R results in increased expression of C-C chemokine receptor type 7 (CCR7), an important receptor involved in DCs migration [25, 26].

Although the expression of several 5-HTRs has been described in both human macrophages (5-HT1AR, 5-HT2AR, 5-HT2BR, 5-HT3R and 5-HT7R) and monocytes (5-HT2AR, 5-HT3R, 5-HT4R and 5-HT7R) at transcriptional level, only specific

subtypes have been confirmed by molecular and functional studies. Indeed, through 5-HT1AR, serotonin can induce the secretion of pro-inflammatory cytokines by peritoneal macrophages as well as boosts their phagocytic activity. Contrarily, by the engagement of 5-HT2BR and 5HT7R, serotonin promotes the polarization of human macrophages toward the anti-inflammatory phenotype [27]. The 5-HT1AR is the prevailing receptor involved in inducing mast cells adhesion to fibronectin and thus in promoting their recruitment to the inflammatory bed. Unlike to other innate immune cells, mast cells express TPH1 enzyme, thus they are able to deplete Trp from the microenvironment and de novo synthesise serotonin [28]. Thanks to the presence of SERT, mast cells, macrophages and DCs are able to take serotonin up, store it in vesicles and subsequently release it in a calciumdependent manner, in response to danger signals and inflammatory stimuli.

## **3.2 Serotonin receptors expression in cells of the adaptive immune system**

Serotonin can shape the course of not only innate, but also adaptive immune responses, as demonstrated by its co-stimulatory role in the immunological synapse between DCs and T lymphocytes. By activating the 5-HT2BR expressed on inflammatory monocyte-derived DCs (moDCs), serotonin alters their cytokines' profile and thus interferes with the differentiation of moDCs primed-CD4<sup>+</sup> T cells toward the inflammatory Th1 and Th17 lymphocytes [29]. Besides indirectly affecting the activation of T cells, serotonin can activate the 5-HTRs expressed on T and B cells and thus directly influence their phenotype and functions. Pioneering studies have proposed that the stimulation of 5-HT1AR and 5-HT3R promotes T cells proliferation, while the blockage of 5-HT1BR with a specific antagonist decreases the cytokines' production by T lymphocytes and their cell-mediated immunity [30]. In naive-T cells, signalling through the 5-HT7R induces the phosphorylation of the kinase ERK1/2 and activates the transcription factor NF-κB, converging in IL-2 synthesis and T-cell proliferation [31].

In addition to 5-HTRs, T cells express the high affinity transporter SERT, whose modulation with the selective inhibitors (SSRIs) suppresses T cells proliferation and induces apoptosis [32]. Moreover, T lymphocytes possess all the machinery to store, produce and degrade serotonin, suggesting an autocrine and paracrine role of the monoamine in modulating T cells proliferation and function [33]. As in platelets, the secretory ability of T cells can be affected by intracellular serotonin via a process known as serotonylation, which is the covalent linking of serotonin to glutamine residues of small intracellular GTPases involved in the exocytosis. This process occurs right after the monoamine transport into the cell, involves the enzyme transglutaminase for the creation of glutamyl-amide bonds, and results into a constitutive activation of the G-protein dependent signalling cascade [34].

The complexity of peripheral serotonin has emerged since 1999, i.e. since, when applied to intestinal preparations, opposite effects appeared depending on the conditions [35]. The variety of serotonin functions outside the CNS seems to apply also to the role of the monoamine in the regulation of immune responses. Although numerous investigations have attempted to fill the gaps in such direction, the knowledge in this field remains yet incomplete [20].

### **3.3 Distribution of receptors for serotonin-derived metabolites in immune cells**

Likewise serotonin, melatonin exhibits a functional versatility as it regulates several biologic processes, ranging from sleep and circadian rhythm to oxidative stress, age and immune function [10, 36, 37]. Mechanistically, the physiologic effects of melatonin can be achieved through the binding of membrane and nuclear

## *Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

receptor as well as via receptor-independent pathways; the latter involving the interaction with cytoplasmic and mitochondrial proteins [38]. Three different subtypes of membrane receptor have been identified, i.e. melatonin receptor type 1a (MT1), type 1b (MT2) and type 1c (MT3) (**Table 1**). With the exception of MT3 (which is quinone reductase-2 enzyme), the melatonin membrane receptors belong to the GPCRs superfamily and are distributed in the CNS and, to a less extent, in cardiovascular system, colon, skin and immune cells. MT1 and MT2 are negatively coupled with AC and thus their activation results in a reduced production of cAMP and the consequent failure of PKA activation. The nuclear receptor signalling of melatonin is mediated via the transcription factor retinoid Z receptors and retinoid orphan receptors (RZR/ROR). RZR/ROR is an orphan member of the nuclear receptor superfamily, which encompasses the product of three genes: RORα, RORβ and RORγ. In immunocompetent cells, specific nuclear melatonin-binding sites have been reported, including RORα and RORβ in human lymphocytes, and RORα in both thymus and spleen of mice [39, 40].

Whilst the MT1/MT2 receptors are mainly responsible for the neuronal functions of melatonin, the activation of both nuclear and membrane receptors appears to be primarily involved in the imunomodulatory and anti-tumor effects of the hormone [41]. The exogenous administration of melatonin stimulates monocyte as well as macrophage production in both bone marrow and spleen of mice, by activating MT receptor and increasing the sensitivity of progenitors to stimulants such as IL-4 and GM-CSF [42]. Human monocytes express both membrane and nuclear melatonin receptor, whose activation stimulates the production of the pro-inflammatory cytokines IL-1β, IL-6 and TNF-α, while decreases IL-10 [42]. By engaging MT1/ MT2 receptor, melatonin activates a mitogenic signal that counteracts the spontaneous apoptosis of circulating monocytes. The activity of melatonin with regard to macrophages translates into the inhibition of inducible nitric oxide synthase (iNOS) expression and blockage of COX-2 activity, with the consequent decrease of inflammatory mediators [43].

T lymphocytes express both membrane and nuclear receptors for melatonin, as well as all the machinery required for the synthesis and secretion of the hormone. Thus, is not surprising that melatonin impacts T cell biology, from the differentiation to the functional activation, as demonstrated by the blunted proliferation of splenic lymphocytes in response to mitogenic signal when both the nuclear and the MT1/MT2 receptors are inhibited [44]. Melatonin, by directly interacting with RORα and promoting its degradation, regulates the expression of IL-2 [45]. Meanwhile, through the activation of MT1-dependent signalling pathway restrains the constitutive activity of RORα, thus further stimulating the IL-2 production [46]. Such a redundancy of the membrane and nuclear receptor is at the service of T cell differentiation as well. Although RORγt is the well-known lineage specific transcription factor for Th17 cells, it synergizes with RORα to enhance Th17 differentiation. On one side, melatonin induces the degradation of nuclear RORα, while on the other, by binding MT1, it activates an intracellular signalling cascade that ends with the repression of the Rora and Rorc gene expression [47]. Depending on the immunological context, melatonin differentially controls T cells effector functions, i.e. under immunosuppressive condition, melatonin stimulates the immune system, while it inhibits exacerbated immune responses. For instance, melatonin increases the number of regulatory T cells in both human and murine model of inflammatory/autoimmune diseases, such as systemic lupus erythematosus or MS; meanwhile it reduces the frequency of IFN-γ and IL-17 producing T lymphocytes [48–50].

For many years, NAS was thought to be merely an intermediate product in melatonin biosynthesis. However, a series of non-overlapping activities of NAS as well

as different brain distribution of the metabolite - when compared to melatonin and serotonin - has given a precise biologic identity to this indole derivative. NAS, but not serotonin or melatonin, is an agonist of the tyrosine kinase B (TrkB) receptor of the brain-derived neurotrophic factor (BDNF), whose activation contributes to the antidepressant, cognition-enhancing and anti-apoptotic effect of NAS (**Table 1**) [51, 52]. TrkB receptors are transmembrane proteins with an extracellular BDNF-binding domain and an intracellular tyrosine kinase domain that, once activated, undergoes autophosphorylation and subsequent coupling to intracellular signalling pathways. Through the activation of TrkB, NAS offers neuroprotection in experimental models of neurological injury and MS, which at least in part occurs by the mitigation of apoptosis and autophagic dysfunction [53, 54]. Additionally, NAS-mediated neuroimmune modulatory effects can arise from the allosteric activation of the enzyme IDO1 [55]. The direct binding of NAS to a previously unknown allosteric site on IDO1 enhances the production of the immunoregulatory metabolite L-Kynurenine, which, in turn, by re-educating the immune system, ameliorates the disease symptoms in a mouse model of MS. Moreover, NAS displays a high affinity for the melatonin MT3 receptor, which is a quinone reductase-2 enzyme and through which NAS exerts additional anti-oxidant and anti-depressant effects [56].

The metabolic product of melatonin, i.e. AFMK, is considered a potent tissue protector as it efficiently neutralizes reactive molecules and reduces lipid peroxidation and DNA damage [57]. AFMK acts as a reducing agent able to donate two electrons, in contrast with other physiological antioxidants that donate a single electron to neutralize free radicals. Increased formation of AFMK is associated with inflammatory conditions, as the concentration of this kynuramine increases in the cerebrospinal fluid of patients with meningitis and the human epidermal keratinocytes exposed to UVB radiation [58, 59]. The raised levels of AFMK are consistent with its role as tissue protector and immune modulator. Indeed, AFMK is capable to attenuate the severity of acute pancreatic inflammation, by reducing pancreatic tissue damage and TNF-α serum concentration, and by increasing the activity of anti-oxidant enzymes [60]. Likewise melatonin, AFMK prevents COX-2 and iNOS activation induced by LPS in macrophages, and the production of TNF-α and IL-8 in activated neutrophils, thus exerts anti-inflammatory and immunomodulatory effects [61, 62].

No longer considered as merely neuronal mediators, the methoxyindoles metabolites are now emerging as key modulators of immune responses. Given the intrinsic complexity of the biological systems, the evolution has conserved and specialized the functions of each serotonin derivatives, making them able to work in the same direction or independently.

## **4. Role of serotonin in the gut-brain axis**

Is "*Butterflies in the stomach*", a metaphor or a real experience? From a physiological point of view, butterflies are authentic visceral sensations coming from an unexpected source, which is the *second* brain. Hidden in the walls of the digestive system, this intestinal brain is also known as enteric nervous system (ENS). It's generally thought that the ENS is the original nervous system that developed in the first vertebrates more than 500 million years ago and that has been conserved during the evolution to link digestion with mood and general organism's fitness [63]. The human ENS contains more than 200 million neurons, distributed in many thousands of small ganglia, the great majority of which are found in two plexuses, the myenteric and submucosal plexuses. Its main role is controlling all the digestive process from the swallowing to the nutrient absorption and elimination. It does not

## *Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

seem capable of common thoughts, but it can communicate back and forth with our big brain, creating the otherwise known "gut-brain axis".

The bidirectional communication underlying the gut-brain axis includes the CNS, the autonomic nervous system, the ENS and the hypothalamic pituitary adrenal (HPA) axis. On one side, the autonomic nervous system drives both afferent and efferent signals arisen from the GI and the CNS, respectively. For its part, the HPA axis is activated by environmental stressors and promotes the cortisol release from the adrenal glands. Thus, by means of hormones and neurotransmitters, the brain controls the activity of intestinal effector cells, including epithelial cells, neurons, smooth muscle, enterochromaffin and immune cells. Recently, the gut microbiome has emerged as critical component of the gut-brain axis, handling not only the local intestinal functions, but also the distant CNS activities [64, 65].

Trp and its metabolite serotonin are the main nexus for the gut-brainmicrobiome axis. This link builds on the principles that (*i*) the manipulation of the microbiota composition across lifespan influences the Trp availability, (*ii*) the gut microbes can directly or indirectly affect the Trp metabolism and serotonergic signaling at the level of CNS to modulate behaviour, and (*iii*) serotonin influences the development of both ENS and CNS. Indeed, the gut microbiota can indirectly influence Trp availability by balancing the amino acid metabolism along the serotonin or the kynurenine pathway. Germ-free animals (i.e., microbiota-deficient mice raised in a sterile environment) exhibit a reduced IDO1 activity (as measured by the kyn/Trp ratio) as well as an increased central serotonin turnover, which both normalize following microbiota colonization immediately post-weaning [66, 67]. The gut microbiome can also directly affect the local and circulating Trp availability for the host, as some bacterial strains harbour the enzymes that can either utilize Trp to produce indole-derivatives (such as indole 3-acetic acid and indole-3-carboxaldehyde) or synthesize the amino acid on their own [68, 69].

Although mainly formed before the mid-gestation in the foetus, the central neuronal circuitry is continuously subjected to genetic and environmental-mediated modifications until puberty. Serotonin is considered one of the signaling molecule that can regulate the development of CNS, among many other organs, as the lack of brain serotonin results into reduced body growth and improper central circuitry formation [70]. Changes in the serotonergic system occurs across the lifespan and a decreased uptake of the metabolite follows the aging [71]. Although, in the human brain, the levels of serotonin remain fairly stable, the overall serotonin receptors reduce by about 30–50% over the lifespan. Developmental changes of serotonergic system are mirrored by the variation of gut microbiota composition during the lifetime, as the infant gut microbiota tends to reach a stable adult-like configuration in the childhood - while completely changes in elderly subjects - and the early colonization of the GI tract is fundamental for the proper development of the central serotonergic system [66].

Likewise the CNS, the ENS is capable of neurogenesis in post-natal and adult life. Such an intrinsic plasticity is mainly related to the exposure of the ENS to microbial, diet and inflammatory challenges that populate the intestinal lumen. Moreover, the normal process of aging contributes to such variability by increasing the neuronal degeneration and cell death. In mice, the post-natal neurogenesis depends on the activation of 5-HT4Rs, whose expression affects the abundance of ENS neurons, while the differentiation of enteric nerve cells is conditioned by the activation of 5-HT2BR [72, 73]. In addition, stimulation of 5- HT4R inhibits inflammatory reactions, protects enteric neurons from apoptosis and promotes the mobilisation of adult stem cells to form new neurons that may replace damaged or dead ones [72].

By involving neuronal, immune and endocrine mediators, the gut-brain-microbiome axis ensures the gut homeostasis as well as integrates the peripheral intestinal activities with emotions, cognitive functions and immune activation. As a matter of fact, people coping with inflammatory bowel disease or other intestinal issues (such as constipation, diarrhoea and abdominal pain) experience depression and anxiety, as a consequence of danger signals sent by an altered GI to the CNS. Noteworthy, these people receive benefit from antidepressants and mind–body therapies that help in smoothing negative signals coming from the GI tract. It is thus clear that not only the big brain is conscious of the ENS and of the gut microbiome, but the intestine as a whole can influence the perception of the world and alter human behaviour. Therefore, in coming years, physicians will need to expand their drugs pool to treat the "mental illness" of the big brain alongside of the second brain, in order to reach therapeutic profits in both behavioural and gastrointestinal diseases.

## **5. Balancing act between Trp degradation pathways as a pharmacological target for CNS diseases**

Serotonin biosynthesis is strictly related to tryptophan availability; in fact, Trp is metabolized not only along the serotonin pathway (SP), but also the kynurenine pathway (KP). The importance of the maintenance of a homeostatic balance between KP and SP of Trp metabolism is underlined by the hypothesis that, in the CNS, some diseases, such as depression [74], Alzheimer's [75] and Parkinson's [76] are triggered by a shift of this equilibrium towards the KP; however, little is still known between the interplay between the two Trp metabolic pathways.

As mentioned above, the very existence of serotonin in different organs and tissues is strongly conditioned by the expression and enzymatic activity of molecules belonging to the tryptophan-metabolizing family, which includes IDO1, tryptophan 2,3-dioxygenase (TDO) and, according to much of the literature to date, IDO2 [77]. Nevertheless, the role of IDO2 as an enzyme capable of initiating the degradation of Trp along the KP probably derives from the erroneous interpretation of the structural analogy between IDO1 and IDO2; recently, this concept is being progressively revisited, and now the idea is emerging that IDO2 functions are linked to an activity other than the enzymatic one [78], which is almost negligible [79]. Thus, IDO1 and TDO represent the two key players determining the fate of Trp.

Trp depletion by TDO and IDO1 occurs via a mechanism that is well studied and has rather clear consequences: as a matter of fact, the catabolism of Trp to immunosuppressive and neuroactive kynurenines is a key metabolic pathway regulating immune responses and neurotoxicity.

The KP initiated by IDO1 or TDO has two main branches (**Figure 1**). Under physiological conditions, Kyn is preferentially converted into 3-hydroxykynurenine (3HK) and then 3-hydroxyanthranilic acid (3HAA), quinolinic acid (QA), and ultimately NAD+ . Alternatively, Kyn can be converted into kynurenic acid (KynA) by the kynurenine aminotransferase (KAT) enzymes [80].

KynA is generally considered to be neuroprotective; it competitively inhibits ionotropic glutamate receptors at high concentrations, and acts as a negative allosteric modulator at the α7-nicotinic receptor [81]. Moreover, KynA has also been shown to act as an agonist at an orphan G-protein-coupled receptor in neurons and astrocytes, leading to a suppression of several inflammatory pathways [82]. KynA also regulates the immune response through its agonistic effects on the aryl hydrocarbon receptor (AhR), a transcription factor involved in the metabolism of xenobiotics. Numerous compounds have been proposed as putative endogenous AhR ligands, many of which are generated through pathways involved in the metabolism

## *Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

of tryptophan and indole. Among them, besides the already mentioned KynA, Kyn, xanthurenic acid, cinnabarinic acid can also be counted, as well as indole derivatives mainly produced in the gut by microbial metabolism, such as indole-3-acetic acid (IAA), indole-3-aldeyde (IAld) and tryptamine; the activation of AhR by metabolites produced downstream IDO1 or TDO may contribute to the modulation of the immune response both in periphery and CNS [83].

QA is an NMDA receptor agonist that can also inhibit the reuptake of glutamate by astrocytes leading to excitotoxicity, and exerts neurotoxic effects via several different mechanisms, including the generation of reactive oxygen species and the disruption of the blood brain barrier. In astrocytes, QA also potentiates the inflammatory response by inducing the production of proinflammatory mediators; moreover, QA may also activate microglia through NMDA receptors, a pathway that triggers neuronal cell death [81].

The two enzymes leading to the activation of the KP, TDO and IDO1 are localized in different cells and tissues and are used in different physiological processes. Hepatic TDO regulates blood homeostasis of Trp and neuronal TDO influences neurogenesis. TDO-deficient mice show no peculiar phenotypes, but display alterations in neurogenesis and anxiety-related behaviour. Moreover, TDO-deficiency or inhibition is neuroprotective in a murine model of MS, suggesting a role for TDO in the production of byproducts involved in the pathogenesis of neurological autoimmune diseases [84].

IDO1 is expressed in most tissues at low levels, including cells of the central nervous system (CNS) and cells of the immune system, but not in the liver. The activity of IDO1 is more closely related to the modulation of the immune response than to the regulation of dietary levels of Trp, and, as in the case of TDO, is decisive in the production of neuroactive metabolites. The effects of Trp metabolism by IDO1 (or TDO) in immunity are complex, and can be shortly explained by four mechanisms: (i) by means of the so-called "Trp starvation", that is, locally depleting Trp, which deprives tryptophan-dependent cells, such as proliferating T cells, of an essential amino acid; (ii) by the production of bioactive kynurenines; (iii) by regulating immune cell metabolism, for example, by feeding de novo NAD+ biosynthesis; and (iv) by means of a recently discovered signalling activity, through which IDO1 becomes phosphorylated in its immunoreceptor tyrosine-based inhibitory motifs (ITIMs), so to mediate intracellular signalling events in a self-sustaining feedforward loop leading to durable immunoregulatory effects [85]. All these mechanisms are involved on the potential development of neuropsychiatric disorders [83], since, as previously said, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects. Thus, it is not surprising that KP is considered implicated in psychiatric illness in the context of inflammation, such as mood disorders (i.e., major depressive disorder - MDD), psychosis, schizophrenia, as well as in neurodegenerative disorders such as Alzheimer's and Parkinson's disease (all reviewed in [81]) and autoimmune diseases, such as MS.

Many efforts in drug development for neurodegenerative and neuropsychiatric diseases have focused on altering the overall balance of neuroactive KP metabolites production through inhibition of enzymes involved in the formation of either QA or KA, or by means of synthetic molecules mimicking the effects of the endogenous compounds. The first clinical trials for MDD are currently ongoing, assessing the effects of an analogous of KynA, AV-101 (NCT02484456 and NCT03078322). AV-101 is a selective antagonist at the glycine-binding site of the NMDA receptor [86].

Since Trp, Kyn, and 3HK can be transported across the blood brain barrier (BBB), and other KP metabolites possibly share the same feature [81], another potential target is the carrier facilitating the passage through the BBB, that is the large amino acid transporter (LAT1). It has been recently demonstrated that leucine treatment is a feasible method of competitively blocking LAT1 to prevent exogenous Kyn from entering into the brain [87]; on the basis of this observation, a phase 2 clinical trial to test the anti-depressant effects of leucine in individuals with MDD is currently ongoing (NCT03079297). Nevertheless, recent findings suggest that several established treatments for depression also alter KP metabolism, as in case of the electro-convulsive therapy, which significantly increases circulating levels of KynA and KynA/3HK in depressed patients [88]. Another example is represented by Ketamine, used as treatment for MDD in selected population of patients, that was shown to acutely decrease circulating kyn and the Kyn/Trp [89].

However, besides the overt involvement of KP in the pathogenesis of several CNS diseases, how the production of kynurenines and the shift of the Trp metabolism from SP towards KP affect the production of serotonin to date it is not clear, and it's also a subject of intense investigation whether the reduced production of serotonin, and the molecules thereof, is involved in the pathogenesis of certain diseases. In the specific case of MDD, the Trp metabolism is considered to explain the aetiology and pathogenesis of depression. More specifically, the aetiology of MDD seems to rely on the concomitant manifestation of an imbalance between the Kyn pathway induced by IDO1 and the serotonin pathway, the neurotoxic effects of Kyn pathway metabolites and the persistent activation of the KP due to exposure to repeated and consistent stress. A further example of the close connection of neuronal and immune systems, and of the importance of a balance between the two branches of Trp metabolism for the maintenance of a health status, can be represented by depression related to cancer. A simplistic and nowadays outdated vision of the immunological asset of cancer patients proposed that one of the major causes of depression in cancer patients could be related to their apparent immunosuppressive general status; today this perspective is gradually undermined by the awareness that in many types of cancer, chronic inflammation is a common feature. Trp breakdown, and the subsequent reduction of the production of serotonin and metabolites thereof, due to the enhanced activation of enzymes of the KP, seems to be related to the prevalence of depressive disorders in cancer patients, since many patients often show decreased plasma Trp levels and increased kyn concentrations [90]. In line with this hypothesis, and with the identification of IDO1 as an authentic immune checkpoint target for the immunopharmacological treatment of cancer [91], inhibition of IDO1 and/or TDO seems to be a promising strategy for the treatment of cancer-related fatigue and depression, with the aim of restoring the physiological balance between the KP and the SP [92].

Moreover, there is an additional factor to consider: not only the functional activity of IDO1/TDO can push the balance towards a decreased production of serotonin, but also the production of specific serotonin metabolites can, in turn, affect this balance, in favour of a sustained production of kynurenines. This is the case of NAS. As previously mentioned, a consistent part of the antidepressant and neurotrophic actions of NAS is due to its capability to activate the TrkB receptor; nevertheless, very recently, additional exciting mechanisms of action of NAS have been demonstrated, unveiling its role as an immunomodulatory molecule. In fact, NAS and melatonin have potent anti-oxidant, anti-inflammatory and neuroprotective properties in several animal models of neurological injury and disease, including MS [53]. When administered in vivo in a murine model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), melatonin and NAS reduced the loss of mature oligodendrocytes, demyelination and axonal injury, significatively ameliorating the disease symptoms and progression. Both compounds also significantly attenuated iNOS induction and reactive oxygen species (ROS) generation in lipopolysaccharide-activated microglia in culture [53].

## *Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

Moreover, NAS is capable of inducing DCs to acquire an immunosuppressive phenotype, which requires the presence and functional activity of the enzyme IDO1. Very interestingly, NAS has been demonstrated to function as a positive allosteric modulator of the enzyme IDO1 binding a recently identified allosteric site thus increasing the catalytic efficacy, but not the binding affinity of IDO1 toward its substrate Trp [55]. Moreover, the effects of NAS have been demonstrated not only in murine DCs, but also in peripheral blood mononuclear cells from a specific subset of MS patients, that is RR-MS patients, opening the possibility for the identification of an innovative and safe immunomodulating therapy for MS. NAS is the first-identified indole derivative of the SP acting as an endogenous IDO1 positive allosteric modulator (PAM). It is noteworthy that Trp shows an opposite behaviour, acting as an IDO1 negative allosteric modulator (NAM) when present at high concentrations [93]. Therefore, although kynurenines acting as endogenous PAMs for the enzymes of the serotonin pathway have not been identified yet, it is possible to speculate that products downstream of the KP and the SP might guarantee an appropriate equilibrium between the two main metabolic routes of Trp metabolism by allosteric mechanisms. This hypothesis may have important relevance for the design of innovative therapeutic strategies not only for the treatment of inflammatory/autoimmune CNS diseases, such as MS, but also for diseases involving an altered regulation of Trp metabolism. As an example, the therapeutic use of potent orthosteric inhibitors of IDO1 for the cancer immunotherapy could be hampered by the induction of a skewing toward the serotonin pathway and thus an excess production of immunoregulatory NAS. Regarding the possibility of rethinking the therapeutic approach for CNS inflammatory/autoimmune diseases, such as MS, that is immunosuppression, the development of PAMs selective for the IDO1 enzyme and therapeutically active in vivo may provide unprecedented opportunities to develop therapeutic agents with a considerably more limited number of undesirable effects than the conventional immunosuppressive therapy.

A cross-regulation of the two metabolic pathways of Trp degradation is performed not only by NAS, but also by its derivative melatonin. As previously said, melatonin can be used by the enzyme IDO1 as a substrate, giving rise to the production of AFMK, a metabolite endowed with anti-inflammatory properties. The effects of AFMK on expression and functional activity of Trp metabolizing enzymes are still unknown, if there are any. Melatonin not only can be metabolized by IDO1, but is capable of inducing the expression of the IDO1 gene in fibroblasts, melanocytes and in adrenal pheochromocytoma cells. In the latter model, silencing of IDO1 gene triggered the up-regulation of the expression of AANAT gene [94], and the overexpression of IDO1, in turns, led to the down-regulation of AANAT, meaning that, in specific cellular subsets, a strictly interconnection occurs between the two Trp degradation pathways. In the same study, melatonin induced an upregulation of the IDO1 expression, through the JAK-STAT2 signaling pathway, and of its enzymatic activity.

Moreover, melatonin is a competitive inhibitor, whereas serotonin is an allosteric inhibitor of the enzyme TDO [95] and although the biological significance of this effects has not been unveiled, it can be speculated that, in the CNS, inhibition of TDO by two metabolites of the SP could contribute to a shift of the balance of Trp consumption through the SP, depending on microenvironmental factors.

Overall, a huge number of pharmacological interventions for CNS diseases targeting Trp metabolism have been developed or are currently under investigation (reviewed in [96]), ranging from the inhibition of specific enzymes along the KP to the modulation of AhR signalling or administration of KYNA and its derivatives [96]; nevertheless, the interconnections between the major pathways of Trp metabolism remain an open question.

## **6. Concluding remarks**

Bidirectional interactions between the nervous system and immune system, known as the "neuroimmune system", regulate a wide range of physiological and pathological processes [1] and there is a huge literature linking general neuroinflammation to neuropsychiatric disorders, such as depression [97], schizophrenia [98], but also MS [99], Alzheimer's [100] and Parkinson's disease [101]. Specific neuroimmune factors, such as Trp derivatives, have been shown to modulate neuronal activity and complex behavioral processes and to create a functional bridge connecting the neuroendocrine and the immune systems. For this reason, serotonin and its derivatives, and the metabolic processes leading to the production of serotonin rather than kyn, are involved in the pathogenesis of various CNS diseases. Thus, it's easy to imagine how Trp metabolism, and mostly the pursuit of an optimal balance between the two Trp metabolic pathways, may be a promising therapeutic target for a manifold spectrum of CNS pathologies. However, there is need for an in-depth knowledge of the mechanisms leading to one or the other Trp metabolic fate, and it's also necessary to unveil their interconnections to define the appropriate intervention for each specific disease, and to have the ability to precisely act on the targeted metabolite or enzyme.

## **Acknowledgements**

This work was supported by the Italian Ministry of Education, University, and Research (PRIN 20173EAZ2Z; to C.V.) and by the University of Perugia (Fondo Ricerca di Base 2019 RB2019GMON; to G.M.)

## **Conflict of interest**

The authors declare no conflict of interest.

## **List of abbreviations**


*Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*


## **Author details**

Giada Mondanelli and Claudia Volpi\* Department of Medicine and Surgery, University of Perugia, Perugia, Italy

\*Address all correspondence to: claudia.volpi@unipg.it

© 2021 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

## **References**

[1] R. Dantzer, Neuroimmune Interactions: From the Brain to the Immune System and Vice Versa, Physiol Rev. 98 (2018) 477-504. https://doi. org/10.1152/physrev.00039.2016.

[2] R. Hardeland, R.J. Reiter, B. Poeggeler, D.X. Tan, The significance of the metabolism of the neurohormone melatonin: antioxidative protection and formation of bioactive substances, Neurosci Biobehav Rev. 17 (1993) 347-357. https://doi.org/10.1016/ s0149-7634(05)80016-8.

[3] S.O. Silva, V.F. Ximenes, L.H. Catalani, A. Campa, Myeloperoxidasecatalyzed oxidation of melatonin by activated neutrophils, Biochem Biophys Res Commun. 279 (2000) 657-662. https://doi.org/10.1006/bbrc.2000.3993.

[4] D.X. Tan, L.C. Manchester, R.J. Reiter, B.F. Plummer, J. Limson, S.T. Weintraub, W. Qi, Melatonin directly scavenges hydrogen peroxide: a potentially new metabolic pathway of melatonin biotransformation, Free Radic Biol Med. 29 (2000) 1177-1185. https://doi.org/10.1016/ s0891-5849(00)00435-4.

[5] G. Mondanelli, C. Volpi, The double life of serotonin metabolites: in the mood for joining neuronal and immune systems, Curr Opin Immunol. 70 (2020) 1-6. https://doi.org/10.1016/j. coi.2020.11.008.

[6] M. Berger, J.A. Gray, B.L. Roth, The expanded biology of serotonin, Annu Rev Med. 60 (2009) 355-366. https://doi.org/10.1146/annurev. med.60.042307.110802.

[7] L.F. Mohammad-Zadeh, L. Moses, S.M. Gwaltney-Brant, Serotonin: a review, J Vet Pharmacol Ther. 31 (2008) 187-199. https://doi. org/10.1111/j.1365-2885.2008.00944.x. [8] D.J. Walther, M. Bader, A unique central tryptophan hydroxylase isoform, Biochem Pharmacol. 66 (2003) 1673-1680. https://doi.org/10.1016/ s0006-2952(03)00556-2.

[9] C. Jonnakuty, C. Gragnoli, What do we know about serotonin?, J Cell Physiol. 217 (2008) 301-306. https://doi. org/10.1002/jcp.21533.

[10] J. Vriend, R.J. Reiter, Melatonin feedback on clock genes: a theory involving the proteasome, J Pineal Res. 58 (2015) 1-11. https://doi.org/10.1111/ jpi.12189.

[11] D.C. Klein, S.L. Coon, P.H. Roseboom, J.L. Weller, M. Bernard, J.A. Gastel, M. Zatz, P.M. Iuvone, I.R. Rodriguez, V. Bégay, J. Falcón, G.M. Cahill, V.M. Cassone, R. Baler, The melatonin rhythm-generating enzyme: molecular regulation of serotonin N-acetyltransferase in the pineal gland, Recent Prog Horm Res. 52 (1997) 307- 357; discussion 357-358.

[12] C. Scheiermann, Y. Kunisaki, P.S. Frenette, Circadian control of the immune system, Nat Rev Immunol. 13 (2013) 190-198. https://doi.org/10.1038/ nri3386.

[13] A. Carrillo-Vico, P.J. Lardone, N. Alvarez-Sánchez, A. Rodríguez-Rodríguez, J.M. Guerrero, Melatonin: buffering the immune system, Int J Mol Sci. 14 (2013) 8638-8683. https://doi. org/10.3390/ijms14048638.

[14] R.J. Nelson, D.L. Drazen, Melatonin mediates seasonal changes in immune function, Ann N Y Acad Sci. 917 (2000) 404-415. https:// doi.org/10.1111/j.1749-6632.2000. tb05405.x.

[15] R.P. Markus, Z.S. Ferreira, P.A.C.M. Fernandes, E. Cecon, The *Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

immune-pineal axis: a shuttle between endocrine and paracrine melatonin sources, Neuroimmunomodulation. 14 (2007) 126-133. https://doi. org/10.1159/000110635.

[16] R.P. Markus, E. Cecon, M.A. Pires-Lapa, Immune-pineal axis: nuclear factor κB (NF-kB) mediates the shift in the melatonin source from pinealocytes to immune competent cells, Int J Mol Sci. 14 (2013) 10979-10997. https://doi. org/10.3390/ijms140610979.

[17] M. Marçola, S. da Silveira Cruz-Machado, P.A.C.M. Fernandes, A.W.A. Monteiro, R.P. Markus, E.K. Tamura, Endothelial cell adhesiveness is a function of environmental lighting and melatonin level, J Pineal Res. 54 (2013) 162-169. https://doi. org/10.1111/j.1600-079X.2012.01025.x.

[18] J.L. Mauriz, P.S. Collado, C. Veneroso, R.J. Reiter, J. González-Gallego, A review of the molecular aspects of melatonin's antiinflammatory actions: recent insights and new perspectives, J Pineal Res. 54 (2013) 1-14. https://doi. org/10.1111/j.1600-079X.2012.01014.x.

[19] Z.S. Ferreira, P.A.C.M. Fernandes, D. Duma, J. Assreuy, M.C.W. Avellar, R.P. Markus, Corticosterone modulates noradrenaline-induced melatonin synthesis through inhibition of nuclear factor kappa B, J Pineal Res. 38 (2005) 182-188. https://doi. org/10.1111/j.1600-079X.2004.00191.x.

[20] N. Herr, C. Bode, D. Duerschmied, The Effects of Serotonin in Immune Cells, Front Cardiovasc Med. 4 (2017) 48. https://doi.org/10.3389/ fcvm.2017.00048.

[21] M. Wan, L. Ding, D. Wang, J. Han, P. Gao, Serotonin: A Potent Immune Cell Modulator in Autoimmune Diseases, Front Immunol. 11 (2020) 186. https:// doi.org/10.3389/fimmu.2020.00186.

[22] V. Gobin, K. Van Steendam, D. Denys, D. Deforce, Selective serotonin reuptake inhibitors as a novel class of immunosuppressants, Int Immunopharmacol. 20 (2014) 148-156. https://doi.org/10.1016/j. intimp.2014.02.030.

[23] M. Filip, M. Bader, Overview on 5-HT receptors and their role in physiology and pathology of the central nervous system, Pharmacol Rep. 61 (2009) 761-777. https://doi.org/10.1016/ s1734-1140(09)70132-x.

[24] N.L. Baganz, R.D. Blakely, A dialogue between the immune system and brain, spoken in the language of serotonin, ACS Chem Neurosci. 4 (2013) 48-63. https://doi.org/10.1021/ cn300186b.

[25] M. Idzko, E. Panther, C. Stratz, T. Müller, H. Bayer, G. Zissel, T. Dürk, S. Sorichter, F. Di Virgilio, M. Geissler, B. Fiebich, Y. Herouy, P. Elsner, J. Norgauer, D. Ferrari, The serotoninergic receptors of human dendritic cells: identification and coupling to cytokine release, J Immunol. 172 (2004) 6011- 6019. https://doi.org/10.4049/ jimmunol.172.10.6011.

[26] K. Holst, D. Guseva, S. Schindler, M. Sixt, A. Braun, H. Chopra, O. Pabst, E. Ponimaskin, The serotonin receptor 5-HT₇R regulates the morphology and migratory properties of dendritic cells, J Cell Sci. 128 (2015) 2866-2880. https:// doi.org/10.1242/jcs.167999.

[27] M. de las Casas-Engel, A. Domínguez-Soto, E. Sierra-Filardi, R. Bragado, C. Nieto, A. Puig-Kroger, R. Samaniego, M. Loza, M.T. Corcuera, F. Gómez-Aguado, M. Bustos, P. Sánchez-Mateos, A.L. Corbí, Serotonin skews human macrophage polarization through HTR2B and HTR7, J Immunol. 190 (2013) 2301-2310. https://doi. org/10.4049/jimmunol.1201133.

[28] N.M. Kushnir-Sukhov, J.M. Brown, Y. Wu, A. Kirshenbaum, D.D. Metcalfe, Human mast cells are capable of serotonin synthesis and release, J Allergy Clin Immunol. 119 (2007) 498-499. https://doi.org/10.1016/j. jaci.2006.09.003.

[29] A. Szabo, P. Gogolak, G. Koncz, Z. Foldvari, K. Pazmandi, N. Miltner, S. Poliska, A. Bacsi, S. Djurovic, E. Rajnavolgyi, Immunomodulatory capacity of the serotonin receptor 5-HT2B in a subset of human dendritic cells, Sci Rep. 8 (2018) 1765. https://doi. org/10.1038/s41598-018-20173-y.

[30] J. Yin, R.H. Albert, A.P. Tretiakova, B.A. Jameson, 5-HT(1B) receptors play a prominent role in the proliferation of T-lymphocytes, J Neuroimmunol. 181 (2006) 68-81. https://doi.org/10.1016/j. jneuroim.2006.08.004.

[31] M. León-Ponte, G.P. Ahern, P.J. O'Connell, Serotonin provides an accessory signal to enhance T-cell activation by signaling through the 5-HT7 receptor, Blood. 109 (2007) 3139-3146. https://doi.org/10.1182/ blood-2006-10-052787.

[32] F. Fazzino, C. Montes, M. Urbina, I. Carreira, L. Lima, Serotonin transporter is differentially localized in subpopulations of lymphocytes of major depression patients. Effect of fluoxetine on proliferation, J Neuroimmunol. 196 (2008) 173-180. https://doi. org/10.1016/j.jneuroim.2008.03.012.

[33] Y. Chen, M. Leon-Ponte, S.C. Pingle, P.J. O'Connell, G.P. Ahern, T lymphocytes possess the machinery for 5-HT synthesis, storage, degradation and release, Acta Physiol (Oxf). 213 (2015) 860-867. https://doi.org/10.1111/ apha.12470.

[34] D.J. Walther, J.-U. Peter, S. Winter, M. Höltje, N. Paulmann, M. Grohmann, J. Vowinckel, V. Alamo-Bethencourt, C.S. Wilhelm, G. Ahnert-Hilger, M.

Bader, Serotonylation of small GTPases is a signal transduction pathway that triggers platelet alpha-granule release, Cell. 115 (2003) 851-862. https://doi. org/10.1016/s0092-8674(03)01014-6.

[35] M.D. Gershon, Review article: roles played by 5-hydroxytryptamine in the physiology of the bowel, Aliment Pharmacol Ther. 13 Suppl 2 (1999) 15-30.

[36] E. Miller, A. Morel, L. Saso, J. Saluk, Melatonin Redox Activity. Its Potential Clinical Application in Neurodegenerative Disorders, Curr Top Med Chem. (2014).

[37] L.H. Opie, S. Lecour, Melatonin has multiorgan effects, Eur Heart J Cardiovasc Pharmacother. 2 (2016) 258-265. https://doi.org/10.1093/ ehjcvp/pvv037.

[38] R.J. Reiter, D.X. Tan, L.C. Manchester, M. Pilar Terron, L.J. Flores, S. Koppisepi, Medical implications of melatonin: receptor-mediated and receptor-independent actions, Adv Med Sci. 52 (2007) 11-28.

[39] A. Carrillo-Vico, A. García-Pergañeda, L. Naji, J.R. Calvo, M.P. Romero, J.M. Guerrero, Expression of membrane and nuclear melatonin receptor mRNA and protein in the mouse immune system, Cell Mol Life Sci. 60 (2003) 2272-2278. https://doi. org/10.1007/s00018-003-3207-4.

[40] S. García-Mauriño, D. Pozo, J.R. Calvo, J.M. Guerrero, Correlation between nuclear melatonin receptor expression and enhanced cytokine production in human lymphocytic and monocytic cell lines, J Pineal Res. 29 (2000) 129-137. https://doi. org/10.1034/j.1600-079x.2000.290301.x.

[41] J.A. García, H. Volt, C. Venegas, C. Doerrier, G. Escames, L.C. López, D. Acuña-Castroviejo, Disruption of the NF-κB/NLRP3 connection by

*Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

melatonin requires retinoid-related orphan receptor-α and blocks the septic response in mice, FASEB J. 29 (2015) 3863-3875. https://doi.org/10.1096/ fj.15-273656.

[42] J.R. Calvo, C. González-Yanes, M.D. Maldonado, The role of melatonin in the cells of the innate immunity: a review, J Pineal Res. 55 (2013) 103-120. https:// doi.org/10.1111/jpi.12075.

[43] W.-G. Deng, S.-T. Tang, H.-P. Tseng, K.K. Wu, Melatonin suppresses macrophage cyclooxygenase-2 and inducible nitric oxide synthase expression by inhibiting p52 acetylation and binding, Blood. 108 (2006) 518-524. https://doi.org/10.1182/ blood-2005-09-3691.

[44] D.L. Drazen, D. Bilu, S.D. Bilbo, R.J. Nelson, Melatonin enhancement of splenocyte proliferation is attenuated by luzindole, a melatonin receptor antagonist, Am J Physiol Regul Integr Comp Physiol. 280 (2001) R1476–R1482. https://doi.org/10.1152/ ajpregu.2001.280.5.R1476.

[45] P.J. Lardone, J.M. Guerrero, J.M. Fernández-Santos, A. Rubio, I. Martín-Lacave, A. Carrillo-Vico, Melatonin synthesized by T lymphocytes as a ligand of the retinoic acid-related orphan receptor, J Pineal Res. 51 (2011) 454-462. https://doi. org/10.1111/j.1600-079X.2011.00909.x.

[46] P.J. Lardone, A. Carrillo-Vico, P. Molinero, A. Rubio, J.M. Guerrero, A novel interplay between membrane and nuclear melatonin receptors in human lymphocytes: significance in IL-2 production, Cell Mol Life Sci. 66 (2009) 516-525. https://doi.org/10.1007/ s00018-008-8601-5.

[47] X. Yu, D. Rollins, K.A. Ruhn, J.J. Stubblefield, C.B. Green, M. Kashiwada, P.B. Rothman, J.S. Takahashi, L.V. Hooper, TH17 cell differentiation is regulated by the circadian clock,

Science. 342 (2013) 727-730. https://doi. org/10.1126/science.1243884.

[48] N. Álvarez-Sánchez, I. Cruz-Chamorro, A. López-González, J.C. Utrilla, J.M. Fernández-Santos, A. Martínez-López, P.J. Lardone, J.M. Guerrero, A. Carrillo-Vico, Melatonin controls experimental autoimmune encephalomyelitis by altering the T effector/regulatory balance, Brain Behav Immun. 50 (2015) 101-114. https://doi. org/10.1016/j.bbi.2015.06.021.

[49] M.F. Farez, I.D. Mascanfroni, S.P. Méndez-Huergo, A. Yeste, G. Murugaiyan, L.P. Garo, M.E. Balbuena Aguirre, B. Patel, M.C. Ysrraelit, C. Zhu, V.K. Kuchroo, G.A. Rabinovich, F.J. Quintana, J. Correale, Melatonin Contributes to the Seasonality of Multiple Sclerosis Relapses, Cell. 162 (2015) 1338-1352. https://doi. org/10.1016/j.cell.2015.08.025.

[50] P. Medrano-Campillo, H. Sarmiento-Soto, N. Álvarez-Sánchez, A.I. Álvarez-Ríos, J.M. Guerrero, I. Rodríguez-Prieto, M.J. Castillo-Palma, P.J. Lardone, A. Carrillo-Vico, Evaluation of the immunomodulatory effect of melatonin on the T-cell response in peripheral blood from systemic lupus erythematosus patients, J Pineal Res. 58 (2015) 219-226. https:// doi.org/10.1111/jpi.12208.

[51] G. Tosini, K. Ye, P.M. Iuvone, N-acetylserotonin: neuroprotection, neurogenesis, and the sleepy brain, Neuroscientist. 18 (2012) 645-653. https://doi. org/10.1177/1073858412446634.

[52] S. Bachurin, G. Oxenkrug, N. Lermontova, A. Afanasiev, B. Beznosko, G. Vankin, E. Shevtzova, T. Mukhina, T. Serkova, N-acetylserotonin, melatonin and their derivatives improve cognition and protect against beta-amyloidinduced neurotoxicity, Ann N Y Acad Sci. 890 (1999) 155-166. https://doi. org/10.1111/j.1749-6632.1999.tb07990.x.

[53] J. Wen, P.S. Ariyannur, R. Ribeiro, M. Tanaka, J.R. Moffett, B.F. Kirmani, A.M.A. Namboodiri, Y. Zhang, Efficacy of N-Acetylserotonin and Melatonin in the EAE Model of Multiple Sclerosis, J Neuroimmune Pharmacol. 11 (2016) 763-773. https://doi.org/10.1007/ s11481-016-9702-9.

[54] J.-M. Yoo, B.D. Lee, D.-E. Sok, J.Y. Ma, M.R. Kim, Neuroprotective action of N-acetyl serotonin in oxidative stress-induced apoptosis through the activation of both TrkB/CREB/BDNF pathway and Akt/Nrf2/Antioxidant enzyme in neuronal cells, Redox Biol. 11 (2017) 592-599. https://doi. org/10.1016/j.redox.2016.12.034.

[55] G. Mondanelli, A. Coletti, F.A. Greco, M.T. Pallotta, C. Orabona, A. Iacono, M.L. Belladonna, E. Albini, E. Panfili, F. Fallarino, M. Gargaro, G. Manni, D. Matino, A. Carvalho, C. Cunha, P. Maciel, M. Di Filippo, L. Gaetani, R. Bianchi, C. Vacca, I.M. Iamandii, E. Proietti, F. Boscia, L. Annunziato, M. Peppelenbosch, P. Puccetti, P. Calabresi, A. Macchiarulo, L. Santambrogio, C. Volpi, U. Grohmann, Positive allosteric modulation of indoleamine 2,3-dioxygenase 1 restrains neuroinflammation, Proc. Natl. Acad. Sci. U.S.A. 117 (2020) 3848-3857. https:// doi.org/10.1073/pnas.1918215117.

[56] J.A. Boutin, E. Marcheteau, P. Hennig, N. Moulharat, S. Berger, P. Delagrange, J.-P. Bouchet, G. Ferry, MT3/QR2 melatonin binding site does not use melatonin as a substrate or a co-substrate, J Pineal Res. 45 (2008) 524-531. https://doi. org/10.1111/j.1600-079X.2008.00631.x.

[57] A. Galano, D.X. Tan, R.J. Reiter, On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK, J Pineal Res. 54 (2013) 245-257. https://doi.org/10.1111/jpi.12010.

[58] S. de O. Silva, V.F. Ximenes, J.A. Livramento, L.H. Catalani, A. Campa, High concentrations of the melatonin metabolite, N1-acetyl-N2-formyl-5 methoxykynuramine, in cerebrospinal fluid of patients with meningitis: a possible immunomodulatory mechanism, J Pineal Res. 39 (2005) 302-306. https://doi. org/10.1111/j.1600-079X.2005.00247.x.

[59] Z. Janjetovic, Z.P. Nahmias, S. Hanna, S.G. Jarrett, T.-K. Kim, R.J. Reiter, A.T. Slominski, Melatonin and its metabolites ameliorate ultraviolet B-induced damage in human epidermal keratinocytes, J Pineal Res. 57 (2014) 90-102. https://doi.org/10.1111/ jpi.12146.

[60] J. Jaworek, J. Szklarczyk, J. Bonior, M. Kot, M. Goralska, P. Pierzchalski, R.J. Reiter, U. Czech, R. Tomaszewska, Melatonin metabolite, N(1)-acetyl-N(1)-formyl-5-methoxykynuramine (AFMK), attenuates acute pancreatitis in the rat: in vivo and in vitro studies, J Physiol Pharmacol. 67 (2016) 411-421.

[61] J.C. Mayo, R.M. Sainz, D.-X. Tan, R. Hardeland, J. Leon, C. Rodriguez, R.J. Reiter, Anti-inflammatory actions of melatonin and its metabolites, N1-acetyl-N2-formyl-5 methoxykynuramine (AFMK) and N1-acetyl-5-methoxykynuramine (AMK), in macrophages, J Neuroimmunol. 165 (2005) 139- 149. https://doi.org/10.1016/j. jneuroim.2005.05.002.

[62] S.O. Silva, M.R. Rodrigues, V.F. Ximenes, A.E.B. Bueno-da-Silva, G.P. Amarante-Mendes, A. Campa, Neutrophils as a specific target for melatonin and kynuramines: effects on cytokine release, J Neuroimmunol. 156 (2004) 146-152. https://doi. org/10.1016/j.jneuroim.2004.07.015.

[63] M. Rao, M.D. Gershon, The bowel and beyond: the enteric nervous system in neurological disorders, Nat Rev Gastroenterol Hepatol. 13 (2016)

*Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

517-528. https://doi.org/10.1038/ nrgastro.2016.107.

[64] S.M. Collins, M. Surette, P. Bercik, The interplay between the intestinal microbiota and the brain, Nat Rev Microbiol. 10 (2012) 735-742. https:// doi.org/10.1038/nrmicro2876.

[65] S. Grenham, G. Clarke, J.F. Cryan, T.G. Dinan, Brain-gut-microbe communication in health and disease, Front Physiol. 2 (2011) 94. https://doi. org/10.3389/fphys.2011.00094.

[66] G. Clarke, S. Grenham, P. Scully, P. Fitzgerald, R.D. Moloney, F. Shanahan, T.G. Dinan, J.F. Cryan, The microbiome-gut-brain axis during early life regulates the hippocampal serotonergic system in a sex-dependent manner, Mol Psychiatry. 18 (2013) 666-673. https://doi.org/10.1038/ mp.2012.77.

[67] R. Diaz Heijtz, S. Wang, F. Anuar, Y. Qian, B. Björkholm, A. Samuelsson, M.L. Hibberd, H. Forssberg, S. Pettersson, Normal gut microbiota modulates brain development and behavior, Proc Natl Acad Sci U S A. 108 (2011) 3047-3052. https://doi. org/10.1073/pnas.1010529108.

[68] J.-H. Lee, J. Lee, Indole as an intercellular signal in microbial communities, FEMS Microbiol Rev. 34 (2010) 426-444. https://doi. org/10.1111/j.1574-6976.2009.00204.x.

[69] S. Raboni, S. Bettati, A. Mozzarelli, Tryptophan synthase: a mine for enzymologists, Cell Mol Life Sci. 66 (2009) 2391-2403. https://doi. org/10.1007/s00018-009-0028-0.

[70] S. Migliarini, G. Pacini, B. Pelosi, G. Lunardi, M. Pasqualetti, Lack of brain serotonin affects postnatal development and serotonergic neuronal circuitry formation, Mol Psychiatry. 18 (2013) 1106-1118. https://doi.org/10.1038/ mp.2012.128.

[71] L.C. Murrin, J.D. Sanders, D.B. Bylund, Comparison of the maturation of the adrenergic and serotonergic neurotransmitter systems in the brain: implications for differential drug effects on juveniles and adults, Biochem Pharmacol. 73 (2007) 1225-1236. https://doi.org/10.1016/j. bcp.2007.01.028.

[72] M.-T. Liu, Y.-H. Kuan, J. Wang, R. Hen, M.D. Gershon, 5-HT4 receptormediated neuroprotection and neurogenesis in the enteric nervous system of adult mice, J Neurosci. 29 (2009) 9683-9699. https://doi. org/10.1523/JNEUROSCI.1145-09.2009.

[73] E. Fiorica-Howells, L. Maroteaux, M.D. Gershon, Serotonin and the 5-HT(2B) receptor in the development of enteric neurons, J Neurosci. 20 (2000) 294-305.

[74] G. Oxenkrug, Serotonin-kynurenine hypothesis of depression: historical overview and recent developments, Curr Drug Targets. 14 (2013) 514-521. https://doi.org/10.2174/1389450111 314050002.

[75] W. Wu, J.A. Nicolazzo, L. Wen, R. Chung, R. Stankovic, S.S. Bao, C.K. Lim, B.J. Brew, K.M. Cullen, G.J. Guillemin, Expression of tryptophan 2,3-dioxygenase and production of kynurenine pathway metabolites in triple transgenic mice and human Alzheimer's disease brain, PLoS One. 8 (2013) e59749. https://doi.org/10.1371/ journal.pone.0059749.

[76] P. Perez-Pardo, Y. Grobben, N. Willemsen-Seegers, M. Hartog, M. Tutone, M. Muller, Y. Adolfs, R.J. Pasterkamp, D. Vu-Pham, A.M. van Doornmalen, F. van Cauter, J. de Wit, J.G. Sterrenburg, J.C.M. Uitdehaag, J. de Man, R.C. Buijsman, G.J.R. Zaman, A.D. Kraneveld, Pharmacological validation of TDO as a target for Parkinson's disease, FEBS J. (2021). https://doi. org/10.1111/febs.15721.

[77] A.A. Fatokun, N.H. Hunt, H.J. Ball, Indoleamine 2,3-dioxygenase 2 (IDO2) and the kynurenine pathway: characteristics and potential roles in health and disease, Amino Acids. 45 (2013) 1319-1329. https://doi. org/10.1007/s00726-013-1602-1.

[78] A. Fiore, P.J. Murray, Tryptophan and indole metabolism in immune regulation, Curr Opin Immunol. 70 (2021) 7-14. https://doi.org/10.1016/j. coi.2020.12.001.

[79] L.M.F. Merlo, L. Mandik-Nayak, IDO2: A Pathogenic Mediator of Inflammatory Autoimmunity, Clin Med Insights Pathol. 9 (2016) 21-28. https:// doi.org/10.4137/CPath.S39930.

[80] I. Cervenka, L.Z. Agudelo, J.L. Ruas, Kynurenines: Tryptophan's metabolites in exercise, inflammation, and mental health, Science. 357 (2017). https://doi.org/10.1126/science. aaf9794.

[81] J. Savitz, The kynurenine pathway: a finger in every pie, Mol Psychiatry. 25 (2020) 131-147. https://doi.org/10.1038/ s41380-019-0414-4.

[82] E. Wirthgen, A. Hoeflich, A. Rebl, J. Günther, Kynurenic Acid: The Janus-Faced Role of an Immunomodulatory Tryptophan Metabolite and Its Link to Pathological Conditions, Front Immunol. 8 (2017) 1957. https://doi. org/10.3389/fimmu.2017.01957.

[83] M. Platten, E.A.A. Nollen, U.F. Röhrig, F. Fallarino, C.A. Opitz, Tryptophan metabolism as a common therapeutic target in cancer, neurodegeneration and beyond, Nat Rev Drug Discov. 18 (2019) 379-401. https:// doi.org/10.1038/s41573-019-0016-5.

[84] T.V. Lanz, S.K. Williams, A. Stojic, S. Iwantscheff, J.K. Sonner, C. Grabitz, S. Becker, L.-I. Böhler, S.R. Mohapatra, F. Sahm, G. Küblbeck,

T. Nakamura, H. Funakoshi, C.A. Opitz, W. Wick, R. Diem, M. Platten, Tryptophan-2,3-Dioxygenase (TDO) deficiency is associated with subclinical neuroprotection in a mouse model of multiple sclerosis, Sci Rep. 7 (2017) 41271. https://doi.org/10.1038/ srep41271.

[85] G. Mondanelli, R. Bianchi, M.T. Pallotta, C. Orabona, E. Albini, A. Iacono, M.L. Belladonna, C. Vacca, F. Fallarino, A. Macchiarulo, S. Ugel, V. Bronte, F. Gevi, L. Zolla, A. Verhaar, M. Peppelenbosch, E.M.C. Mazza, S. Bicciato, Y. Laouar, L. Santambrogio, P. Puccetti, C. Volpi, U. Grohmann, A Relay Pathway between Arginine and Tryptophan Metabolism Confers Immunosuppressive Properties on Dendritic Cells, Immunity. 46 (2017) 233-244. https://doi.org/10.1016/j. immuni.2017.01.005.

[86] S.T. Wilkinson, G. Sanacora, A new generation of antidepressants: an update on the pharmaceutical pipeline for novel and rapid-acting therapeutics in mood disorders based on glutamate/GABA neurotransmitter systems, Drug Discov Today. 24 (2019) 606-615. https://doi.org/10.1016/j. drudis.2018.11.007.

[87] A.K. Walker, E.E. Wing, W.A. Banks, R. Dantzer, Leucine competes with kynurenine for bloodto-brain transport and prevents lipopolysaccharide-induced depressionlike behavior in mice, Mol Psychiatry. 24 (2019) 1523-1532. https://doi. org/10.1038/s41380-018-0076-7.

[88] S. Guloksuz, B. Arts, S. Walter, M. Drukker, L. Rodriguez, A.-M. Myint, M.J. Schwarz, R. Ponds, J. van Os, G. Kenis, B.P.F. Rutten, The impact of electroconvulsive therapy on the tryptophan-kynurenine metabolic pathway, Brain Behav Immun. 48 (2015) 48-52. https://doi.org/10.1016/j. bbi.2015.02.029.

*Serotonin Pathway in Neuroimmune Network DOI: http://dx.doi.org/10.5772/intechopen.96733*

[89] R. Moaddel, M. Shardell, M. Khadeer, J. Lovett, B. Kadriu, S. Ravichandran, P.J. Morris, P. Yuan, C.J. Thomas, T.D. Gould, L. Ferrucci, C.A. Zarate, Plasma metabolomic profiling of a ketamine and placebo crossover trial of major depressive disorder and healthy control subjects, Psychopharmacology (Berl). 235 (2018) 3017-3030. https:// doi.org/10.1007/s00213-018-4992-7.

[90] L. Lanser, P. Kink, E.M. Egger, W. Willenbacher, D. Fuchs, G. Weiss, K. Kurz, Inflammation-Induced Tryptophan Breakdown is Related With Anemia, Fatigue, and Depression in Cancer, Front Immunol. 11 (2020) 249. https://doi.org/10.3389/ fimmu.2020.00249.

[91] B.J. Van den Eynde, N. van Baren, J.-F. Baurain, Is There a Clinical Future for IDO1 Inhibitors After the Failure of Epacadostat in Melanoma?, Annual Review of Cancer Biology. 4 (2020) 241-256. https://doi.org/10.1146/ annurev-cancerbio-030419-033635.

[92] L. Sforzini, M.A. Nettis, V. Mondelli, C.M. Pariante, Inflammation in cancer and depression: a starring role for the kynurenine pathway, Psychopharmacology (Berl). 236 (2019) 2997-3011. https://doi.org/10.1007/ s00213-019-05200-8.

[93] A. Lewis-Ballester, S. Karkashon, D. Batabyal, T.L. Poulos, S.-R. Yeh, Inhibition Mechanisms of Human Indoleamine 2,3 Dioxygenase 1, J Am Chem Soc. 140 (2018) 8518-8525. https://doi.org/10.1021/jacs.8b03691.

[94] Y. Li, N. Hu, D. Yang, G. Oxenkrug, Q. Yang, Regulating the balance between the kynurenine and serotonin pathways of tryptophan metabolism, FEBS J. 284 (2017) 948-966. https://doi.org/10.1111/ febs.14026.

[95] H.A. Walsh, S. Daya, Inhibition of hepatic tryptophan-2,3-dioxygenase:

superior potency of melatonin over serotonin, J Pineal Res. 23 (1997) 20-23. https://doi.org/10.1111/j.1600- 079x.1997.tb00330.x.

[96] M. Modoux, N. Rolhion, S. Mani, H. Sokol, Tryptophan Metabolism as a Pharmacological Target, Trends Pharmacol Sci. 42 (2021) 60-73. https:// doi.org/10.1016/j.tips.2020.11.006.

[97] E.S. Wohleb, T. Franklin, M. Iwata, R.S. Duman, Integrating neuroimmune systems in the neurobiology of depression, Nat Rev Neurosci. 17 (2016) 497-511. https://doi.org/10.1038/ nrn.2016.69.

[98] F.M. das G. Corsi-Zuelli, F. Brognara, G.F. da S. Quirino, C.H. Hiroki, R.S. Fais, C.M. Del-Ben, L. Ulloa, H.C. Salgado, A. Kanashiro, C.M. Loureiro, Neuroimmune Interactions in Schizophrenia: Focus on Vagus Nerve Stimulation and Activation of the Alpha-7 Nicotinic Acetylcholine Receptor, Front Immunol. 8 (2017) 618. https://doi.org/10.3389/ fimmu.2017.00618.

[99] I. Bjelobaba, D. Savic, I. Lavrnja, Multiple Sclerosis and Neuroinflammation: The Overview of Current and Prospective Therapies, Curr Pharm Des. 23 (2017) 693-730. https://doi.org/10.2174/13816128226661 61214153108.

[100] M.T. Heneka, M.J. Carson, J. El Khoury, G.E. Landreth, F. Brosseron, D.L. Feinstein, A.H. Jacobs, T. Wyss-Coray, J. Vitorica, R.M. Ransohoff, K. Herrup, S.A. Frautschy, B. Finsen, G.C. Brown, A. Verkhratsky, K. Yamanaka, J. Koistinaho, E. Latz, A. Halle, G.C. Petzold, T. Town, D. Morgan, M.L. Shinohara, V.H. Perry, C. Holmes, N.G. Bazan, D.J. Brooks, S. Hunot, B. Joseph, N. Deigendesch, O. Garaschuk, E. Boddeke, C.A. Dinarello, J.C. Breitner, G.M. Cole, D.T. Golenbock, M.P. Kummer, Neuroinflammation in

Alzheimer's disease, Lancet Neurol. 14 (2015) 388-405. https://doi.org/10.1016/ S1474-4422(15)70016-5.

[101] Q. Wang, Y. Liu, J. Zhou, Neuroinflammation in Parkinson's disease and its potential as therapeutic target, Transl Neurodegener. 4 (2015) 19. https://doi.org/10.1186/ s40035-015-0042-0.

## *Edited by Berend Olivier*

Serotonin is an ancient neurotransmitter system involved in various systems and functions in the body and plays an important role in health and disease. The present volume illustrates the broadness of the involvement of serotonergic activity in many processes, focusing particularly on disorders of the brain, including depression, stress and fear, Alzheimer's disease, aggression, sexual behavior, and neuro-immune disorders. Chapters illustrate techniques and methods used to study the complex role of the serotonergic system in all kinds of processes, present new hypotheses for several brain disorders like sleep and depression, and use mathematical modeling as a tool to advance knowledge of the extremely complex brain and body processes.

Published in London, UK © 2022 IntechOpen © xrender / iStock

Serotonin and the CNS - New Developments in Pharmacology and Therapeutics

Serotonin and the CNS

New Developments in Pharmacology

and Therapeutics

*Edited by Berend Olivier*