**Abstract**

The knowledge regarding pathological and treatment resistance mechanisms involved in the pathology of complex brain disorders is far from understood. The neuroinflammation hypothesis of psychiatric, neurological, and neurodegenerative diseases is well-acknowledged. However, this hypothesis is far from understood. Toll-like receptors (TLRs) family is an innate immunity molecule implicated in neuroinflammation in complex brain disorders. This chapter reviews considerable evidence indicating that activation of endotoxins such as lipopolysaccharide is a common factor. Additionally, we report clinical and preclinical studies highlighting the link between lipopolysaccharide, TLRs, and different types of brain disorders. Also, we review the current pharmacological modulations of TLRs. Hoping we would help in filling our knowledge gaps and highlight potential links to tackle new angles in managing complex brain disorders. This chapter's primary goal is to encourage scientists and researchers to conduct future studies characterizing the nature of endotoxin activation of TLRs in complex brain disorders, filling our knowledge gaps, and finding new treatment strategies.

**Keywords:** Brain disorders, Toll-like receptors, TLR4, Endotoxins, lipopolysaccharide

## **1. Introduction**

The complex nature of neurodegenerative and psychiatric diseases stems from pathological interactions, among which inflammation [1]. Neuroinflammation is a crucial mechanism involved in the pathogenesis of psychiatric [2] and neurodegenerative diseases [3]. Accumulating evidence indicating that targeting neuroinflammation is an appealing strategy since that inflammatory-related diseases comorbid with brain disorders [4–7]. In preclinical settings, triggering inflammation by administering of endotoxins and other activators are well-acknowledged animal models [8]. Preclinical studies found that attenuating inflammation reduces phenotypic features associated with psychiatric and neurodegenerative disorders. In line with this, clinical studies suggest that treatment with anti-inflammatory medications affects memory, cognition, and mood [9–11].

Developmental studies have shown that TLRs are essential elements in regulating brain development. Previously, it was reported that both TLR7 and TLR9 are expressed in corticolimbic regions of the developing brain. *In situ* hybridization and PCR studies indicated that TLR7 and TLR9 expression increased significantly in pre and early postnatal stages, whereas the expression reduced as the rodents reached adult developmental stages [12]. Epidemiological reports indicated that exposure to infection at prenatal stages, where the brain and the central nervous system are developing and vulnerable to an unfavorable environment, increases mental illness risk later in life [13, 14]. Inflammatory cytokines involve ubiquitously in modulating different pathways. For instance, it may alter the developing brain epigenetic system, which could be due to excessive glucocorticoids [14]. According to the Danish National Psychiatric Register, prenatal exposure to bacterial infection was linked to schizophrenia. In a set of about 8000 individuals, 1.1% of cases were diagnosed with schizophrenia by their thirties [15]. In line with this, a previous study linked developmental delay and mental retardation to maternal urinary tract infections [16]. On another cohort, the risk of schizophrenia increases in offspring born to mothers diagnosed with reproductive infections during pregnancy [17]. Also, other reports link cytokine-related mechanisms to the pathology of Attention deficit hyperactivity disorder [18, 19]. *In vitro* studies have shown that TLR3, TLR7 and, TLR8 regulate dendritic arborization in an MYD88 dependent signaling. The studies indicated that among these receptors, the TLR8 is the major contributor in regulating dendritic pruning. It further showed that both TLR3 and TLR7 are essential in regulating axonal development. This evidence indicated that the TLR family is vital in modulating proper neuronal development [20].

All these evidences indicate a functional direct link between inflammation and mental illness. This chapter was undertaken to further highlight the association of TLRs, endotoxins, and brain disorders. We also emphasize the diverse role of multiple TLR family members in both nonregenerative and psychiatric diseases. Lastly, we review the pharmacological modulation of TLRs in the context of brain disorders. Aiming this chapter would stimulate future research in characterizing the nature of endotoxin activation of TLRs in complex brain disorders, filling our knowledge gaps, and finding new treatment strategies.

### **2. The role of endotoxins in mediating brain disorders**

In comparison to most bacterial activators of inflammatory cytokines, endotoxins are considered one of the most potent. Mostly, endotoxins are referred to as lipopolysaccharide (LPS) [21]. LPS is a composition of the bacterial cell wall; an elevated level of LPS reaches different biological systems during infections. Administration of LPS to healthy participants induces both the initiation and the transition phases of acute inflammation. Besides, this activation level reaches the transcriptomic level along with the functional and physiological levels [22]. The systemic application of LPS is utilized extensively in pharmacological animal models of brain disorders [23], including Alzheimer's [24], Parkinson's [25], depression [26], and anxiety [27]. This is mainly regarded as the potency in triggering inflammation.

Previous reports indicated that LPS stimulates the aggregations of both amyloid β and tau, a neuropathological feature of Alzheimer's [28]. Treating Tg2576 mice with LPS increases the mRNA level of cytokines in the cortex [29]. In a transgenic animal model of Alzheimer's, the 3xTg-AD mice, administration of LPS trigger pathological changes in microglia populations associated with later on aggregations of hyperphosphorylated tau. Even though the researchers exposed these mice to

**141**

**Table 1.**

*Pharmacological Modulation of Toll-Like Receptors in Brain Disorders*

LPS at early developmental stages, before the detection of pathological features related to Alzheimer's disease. Additionally, they reported that the aggregation of phosphorylated tau was mediated mechanistically through the activation of the cyclin-dependent kinase 5 (cdk5) [30]. Cdk5 is a member of the cyclin-dependent kinases family. Specifically, they are proline-directed serine–threonine kinases group. Functionally, Cdk5 modulates the cell cycle [31, 32], synaptic wiring, neuronal transmission [33], and neuronal development and survival [34]. In accordance with this, a previous report demonstrated that following the stereotaxic introduction of Aβ in mice, the pharmacological inhibition of Cdk5 using roscovitine resulted in reducing inflammatory and oxidative stress mediators at the mRNA level. Indicating that, Cdk5 is a crucial modulator of neuroinflammation associated with molecular phenotypic features of Alzheimer's disease [35]. Lipopolysaccharide alters the blood–brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease [36]. Also, in a transgenic model lacking the NADPH oxidase regulatory gene, the administration of LPS led to molecular and cellular neurodegenerative changes associated with Parkinson's disease [37]. In line with this, the pre-administration with LPS resulted in accelerated aging and Parkinson -related symptoms in a Parkinson's animal model [38]. Describes the main mechanisms involved in the LPS animal models **Table 1**. In a clinical setting, a previous report indicated that depression and marital distress were significantly associated with an increased LPS, LPS binding protein, and soluble CD14, an LPS co-receptor. Indicating that activation and the translocation of bacterial endotoxin are crucial in mediating mood disorders and stress-related diseases [39]. Functional imaging indicated that individuals exposed to endotoxemia had shown elevated levels of alertness [40], and emotional sensitivity toward visual stimuli [41]. Biochemical changes were observed peripherally, such as elevated stress hormones and inflammation [40, 41], and alterations in the sympathetic nerve's activity [42]. In another clinical study, the cognitive capacity of

**Disease model Phenotypic molecular and behavioral features Reference**

level of cytokines in the cortex

• A loss in dopaminergic neurons.

• Modify reactive microglia.

Model of Alzheimer's disease. • The administration of LPS in mice promoted the influx

*Tg2576: Transgenic Tg2576 mice; LPS: lipopolysaccharide; NOX2: NADPH oxidase 2; IL-2: Interleukin 2; IL-6:* 

(IL-6, IL-2,TNF-alpha,IFN-gamma)

symptoms.

• Treating Tg2576 mice with LPS increases the mRNA

• Activation of the cyclin-dependent kinase 5 (cdk5).

• Oxidative stress and Parkinson-related features.

• Resulted in accelerated aging and Parkinson -related

• Alter the peripheral level of inflammatory cytokines

of amyloid beta protein to the brain and reduced their efflux, a unifying feature of Alzheimer's disease.

• Pathological changes in microglia populations. • Aggregations of hyperphosphorylated tau.

[29]

[30]

[37]

[38]

[36]

*DOI: http://dx.doi.org/10.5772/intechopen.97869*

Model of Alzheimer's disease

Model of Alzheimer's disease

LPS administration to a Parkinson's disease animal

Endotoxin-Induced Neuroinflammation Model of Parkinson's Disease.

*Interleukin 6; IFN-gamma: Interferon gamma.*

*Main mechanisms involved in the lipopolysaccharide animal models.*

*(Tg2576 mice)*.

*(3xTg-AD mice)*

model. (NOX2−/−)mice

### *Pharmacological Modulation of Toll-Like Receptors in Brain Disorders DOI: http://dx.doi.org/10.5772/intechopen.97869*

*Therapy Approaches in Neurological Disorders*

Developmental studies have shown that TLRs are essential elements in regulating brain development. Previously, it was reported that both TLR7 and TLR9 are expressed in corticolimbic regions of the developing brain. *In situ* hybridization and PCR studies indicated that TLR7 and TLR9 expression increased significantly in pre and early postnatal stages, whereas the expression reduced as the rodents reached adult developmental stages [12]. Epidemiological reports indicated that exposure to infection at prenatal stages, where the brain and the central nervous system are developing and vulnerable to an unfavorable environment, increases mental illness risk later in life [13, 14]. Inflammatory cytokines involve ubiquitously in modulating different pathways. For instance, it may alter the developing brain epigenetic system, which could be due to excessive glucocorticoids [14]. According to the Danish National Psychiatric Register, prenatal exposure to bacterial infection was linked to schizophrenia. In a set of about 8000 individuals, 1.1% of cases were diagnosed with schizophrenia by their thirties [15]. In line with this, a previous study linked developmental delay and mental retardation to maternal urinary tract infections [16]. On another cohort, the risk of schizophrenia increases in offspring born to mothers diagnosed with reproductive infections during pregnancy [17]. Also, other reports link cytokine-related mechanisms to the pathology of Attention deficit hyperactivity disorder [18, 19]. *In vitro* studies have shown that TLR3, TLR7 and, TLR8 regulate dendritic arborization in an MYD88 dependent signaling. The studies indicated that among these receptors, the TLR8 is the major contributor in regulating dendritic pruning. It further showed that both TLR3 and TLR7 are essential in regulating axonal development. This evidence indicated that the TLR

family is vital in modulating proper neuronal development [20].

knowledge gaps, and finding new treatment strategies.

**2. The role of endotoxins in mediating brain disorders**

All these evidences indicate a functional direct link between inflammation and mental illness. This chapter was undertaken to further highlight the association of TLRs, endotoxins, and brain disorders. We also emphasize the diverse role of multiple TLR family members in both nonregenerative and psychiatric diseases. Lastly, we review the pharmacological modulation of TLRs in the context of brain disorders. Aiming this chapter would stimulate future research in characterizing the nature of endotoxin activation of TLRs in complex brain disorders, filling our

In comparison to most bacterial activators of inflammatory cytokines, endotoxins are considered one of the most potent. Mostly, endotoxins are referred to as lipopolysaccharide (LPS) [21]. LPS is a composition of the bacterial cell wall; an elevated level of LPS reaches different biological systems during infections. Administration of LPS to healthy participants induces both the initiation and the transition phases of acute inflammation. Besides, this activation level reaches the transcriptomic level along with the functional and physiological levels [22]. The systemic application of LPS is utilized extensively in pharmacological animal models of brain disorders [23], including Alzheimer's [24], Parkinson's [25], depression [26], and anxiety [27]. This is mainly regarded as the potency in triggering

Previous reports indicated that LPS stimulates the aggregations of both amyloid β and tau, a neuropathological feature of Alzheimer's [28]. Treating Tg2576 mice with LPS increases the mRNA level of cytokines in the cortex [29]. In a transgenic animal model of Alzheimer's, the 3xTg-AD mice, administration of LPS trigger pathological changes in microglia populations associated with later on aggregations of hyperphosphorylated tau. Even though the researchers exposed these mice to

**140**

inflammation.

LPS at early developmental stages, before the detection of pathological features related to Alzheimer's disease. Additionally, they reported that the aggregation of phosphorylated tau was mediated mechanistically through the activation of the cyclin-dependent kinase 5 (cdk5) [30]. Cdk5 is a member of the cyclin-dependent kinases family. Specifically, they are proline-directed serine–threonine kinases group. Functionally, Cdk5 modulates the cell cycle [31, 32], synaptic wiring, neuronal transmission [33], and neuronal development and survival [34]. In accordance with this, a previous report demonstrated that following the stereotaxic introduction of Aβ in mice, the pharmacological inhibition of Cdk5 using roscovitine resulted in reducing inflammatory and oxidative stress mediators at the mRNA level. Indicating that, Cdk5 is a crucial modulator of neuroinflammation associated with molecular phenotypic features of Alzheimer's disease [35]. Lipopolysaccharide alters the blood–brain barrier transport of amyloid beta protein: a mechanism for inflammation in the progression of Alzheimer's disease [36]. Also, in a transgenic model lacking the NADPH oxidase regulatory gene, the administration of LPS led to molecular and cellular neurodegenerative changes associated with Parkinson's disease [37]. In line with this, the pre-administration with LPS resulted in accelerated aging and Parkinson -related symptoms in a Parkinson's animal model [38]. Describes the main mechanisms involved in the LPS animal models **Table 1**.

In a clinical setting, a previous report indicated that depression and marital distress were significantly associated with an increased LPS, LPS binding protein, and soluble CD14, an LPS co-receptor. Indicating that activation and the translocation of bacterial endotoxin are crucial in mediating mood disorders and stress-related diseases [39]. Functional imaging indicated that individuals exposed to endotoxemia had shown elevated levels of alertness [40], and emotional sensitivity toward visual stimuli [41]. Biochemical changes were observed peripherally, such as elevated stress hormones and inflammation [40, 41], and alterations in the sympathetic nerve's activity [42]. In another clinical study, the cognitive capacity of


### **Table 1.**

*Main mechanisms involved in the lipopolysaccharide animal models.*

healthy participants exposed to endotoxin systemically was examined. The results suggested that the endotoxin-exposed group exhibited a reduction in cognitive function and reduced capability in processing emotional information compared to the placebo group [43]. Suggesting that short-term exposure to systemic endotoxin has a profound impact on higher cognitive tasks. Disrupted sociability [44], and impaired cognitive capacity are hallmarks of psychiatric disorders [45], mainly schizophrenia, and autism [46, 47]. In another report, a battery of socio-behavioral factors was examined and reported to be functionally linked to the systemic administration of LPS. Indicating a mechanistic link between LPS-inflammation and major depressive disorder [48]. In line with this, the administration of a citalopram, a selective serotonin reuptake inhibitor antidepressant agent, leads to a reduction in fatigue and multiple inflammatory cytokines associated with endotoxins activation [49]. In another clinical setting, the level of circulating endotoxins correlates with the severity of neurodegenerative disorders, including Alzheimer's, sporadic amyotrophic lateral sclerosis (sALS) [50].
