**2. Aggression**

#### **2.1 Types of aggression**

Albeit some difficulty to differentiate between aggressive acts that are reactive and defensive and those that are intentionally destructive, yet psycho-socialists have defined aggression as a forceful physical or symbolic action that can be motivated (instrumental or proactive, and affective or reactive aggression), or deliberately damaging (aggression), whether directed to other person that does not wish to be harmed, living creature, the environment, or one's self, leading to physical or psychological harm [3]. So depending on the intent of the act, affective, reactive, defensive, or impulsive aggression is characterized, so that tough responses are not intended to harm. The opposite would be the predatory, premeditated, instrumental, proactive, or cognitive aggression when the intention is to hurt someone [4].

Not all aggressive reactions are physical, some can be psychological, verbal, sexual, social, or racial. The type causing actual physical harm is termed "violence" and is the extreme of aggression [5]*.* Nonphysical aggression is the more common to observe, yet the more difficult to track and punish, see examples [6, 7]*.*

In terms of pharmacotherapeutics, we have the treatable secondary or medical aggression, related to psychologic disorders that respond to medications, including antipsychotics and antimanics, and the primary impulsive aggression that is addressed using other specific agents [8], although, in absence of psychopathology, seems resistant to manage [9].

#### **2.2 Epidemiology of aggression**

Two-million people are annually exposed to workplace violence, with 50% of cases falling among healthcare workers, and 7% of fatalities are ascribed to physical harm. Domestic violence affects 10 million people yearly in the United States, with an economic burden of more than 12 billion dollars per year. These estimates are expected to rise over the next 20 years [10].

Lifestyle changes during the coronavirus disease (COVID-19) pandemic, including the distress of getting infected [11], poor sleep quality, a higher prevalence of posttraumatic stress disorder among hospitalized patients [12], and the social isolation

#### *Perspective Chapter: Neurotoxins and Erythrocytes – A Double-headed Arrow DOI: http://dx.doi.org/10.5772/intechopen.108342*

of the recommended lockdown, increasing the incidence of domestic violence and abuse toward children, in case of a violent family member, with limited access to community-based support and assistance [13], provoked depression, anxiety, and suicidal behavior [14]. The evolving stressful life conditions that followed the COVID-19 lockdown triggered violent attitudes and mental health issues, consequent to unemployment, and financial instability, while struggling to satisfy the basic needs of life, being helpless to find new job opportunities, and losing the liberty to have interactive social conversations and relations, concurrent with the compounded feeling of loneliness, uncertainty, and trepidation, considering the "others" potential threats of disease transmission. Neurological symptoms during the pandemic were variable and included suicidal behavior, agitation, paranoid delusions, bizarre behavior, and weird posture [15, 16]. Assumptions were made about the involvement of encephalitis [17, 18] and medications used in the treatment protocol of COVID-19 such as steroids, chloroquine derivatives, and benzodiazepines [19]*.*

#### **2.3 Aggression as related to other medical issues**

Among health problems, pain was the most significant medical issue that can lead to aggression. Reports advocated respiratory distress as a cause of aggression [20]*.*

Neurological disorders can provoke aggression as in some cases of attention deficit and hyperactivity disorder, autism, epilepsy, and Alzheimer's disease (AD) [21].

Psychological issues complicated by secondary aggression include bipolar affective disorder, schizophrenia, major depression, general anxiety disorder, post-traumatic stress disorder, and antisocial personality [22]*.* Substance abuse and/or withdrawal was an undeniable culprit, especially alcohols and hallucinogens [23].

Anemia, one of the most prevalent worldwide [24], was involved in aggressive cases [25–27]*.* Furthermore, iron deficiency can contribute to mood and behavioral disturbances, owing to its crucial role as a co-enzyme for the production and release of neurotransmitters [28]*.*

Iatrogenic aggression can be seen with medications such as dopaminergic agents [29]*,* antidepressants [30]*,* glucocorticoids, testosterone, and androgenic steroids [31].

#### **2.4 Diagnosis and management of aggression**

There is no consensus concerning laboratory or imaging tools to diagnose aggression. But assessments converge on reporting either the consequences or some etiological factors such as substance abuse, toxicological screening, or psychological disorder [10]*.* While most pharmacologic treatments have long converged on controlling the causative factors of aggression, now, addressing the deliberate hostile behavior as an isolated disorder is getting more attention.

Experimental dietary manipulation deterred 2-year aggression in a dog using a diet regimen whose plan was based on hematologic, biochemical, and imaging investigations [32]*.*

Presumably, investigating key mediators of aggression might help control primary aggression, for which psychological assessments failed to find a clue. Researchers suggested neuronal mediators that might lower the aggression threshold, including, but not limited to, dopamine (DA), serotonin (5-HT), gamma-amino butyric acid (GABA) [33, 34]*,* and glutamate (Glu) [35]*.*

### **3. Glutamate**

#### **3.1 Glutamate as brain neurotransmitter**

Glutamate (Glu) is a nonessential and most abundant free amino acid, excitatory neurotransmitter in the brain. It is released through the glutamate-cystine exchange system (xC-system) in exchange of cystine at a 1:1 ratio, also used for the synthesis of the brain antioxidant, glutathione (GSH). Its central existence is not limited to the synapse, but it projects to extra-synaptic sites through ionotropic (iGluRs) and metabotropic glutamate receptors (mGluRs) [36]*.* The ionotropic receptors comprise three types, N-methyl-D-aspartate (NMDA), 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA), and kainate.

To establish a synaptic neurotransmission, glypicans, the synapse-forming proteins secreted by astrocytes, increase the number and activity of postsynaptic AMPA receptors, amplifying the electrical current to open the Mg2+-gated NMDA receptors. In the brain, micromolar levels of glycine, an inhibitory neurotransmitter, are sufficient to saturate NMDA for full functioning [37]*.* The ionotropic receptors are connected to their intracellular second messengers, stargazine, D-serine, and nitric oxide synthase, by postsynaptic density proteins (PSD95) [38]*,* controlled by the immune (glial) cells, astrocytes, and microglia [39]*.*

Glu diffuses binds to mGluRs on the astrocytic surface, triggering the release of the chemokine, CXCL12/stromal cell-derived factor (CXCL12/SDF1) [40], implicated in preclinical models of anxiety [41]*,* urging microglia to release small physiologic quantities of tumor necrosis factor-alpha (TNF-α) [42]*.* By binding to astrocytes, TNF-α regulates Glu clearance, to ensure a well-controlled neuronal excitation, by immune-to-glutamate signaling [43]*.*

The glial cells, microglia, astrocytes, and oligodendrocytes, communicate on a large-scale [44]**,** conveying transsynaptic information along large brain regions [45]*.* The net result would be a presynaptic Glu release propagated and reflected on Glu release and uptake at distant sites [46]*.*

Astrocytes, of the fibrous type, nurture and protect the unmyelinated nodes of Ranvier, while oligodendrocytes exert the same function for myelin sheath and cells [47]*.* While astrocytes of the fibrous type expand the white matter of the brain, astrocytes of the protoplasmic type span the gray matter of the brain, branching multiple times to yield fine processes that encase blood vessels at one end, forming part of the blood–brain barrier (BBB) [48]*,* while surrounding thousands of synapses forming "astrocytic cradles" [47]*,* provided with plenty of Glu transporters, that mediate Glu clearance [38] and keep Glu from spilling over into the extra-synaptic space [49]*.*

Glu is cleared by excitatory aminoacids transporters (EAAT) of the endothelium of cerebral blood vessels as well as by passive diffusion through BBB to the systemic circulation [50, 51]. The EAATs-mediated Glu uptake is impaired during immune activation (**Figure 1**) [52–58].

Interestingly, reducing plasma Glu accelerated its clearance from the brain to the blood. Pharmacologically, this can be accomplished by the administration of inducers of the Glu metabolizing enzymes, serum Glu oxaloacetate (SGOT), and serum Glu pyruvate transaminase (SGPT) [43]*.* Experimentally, this Glu scavenging policy was successful to counteract excitotoxicity in animal model of stroke [59]*.*

*Perspective Chapter: Neurotoxins and Erythrocytes – A Double-headed Arrow DOI: http://dx.doi.org/10.5772/intechopen.108342*

#### **Figure 1.**

*Glutamate clearance and immunomodulators. Glu is taken up by astrocytes, driven by Kir4.Kt, where both Glu and NH4 yield the inert, Gln, by the action of GS. de novo Gln is transported to neurons either, to be re-converted to Glu, or to be transaminated to aspartate, or to be decarboxylated to GABA. Glu, synthesized from Gln, is packaged and stored in synaptic vesicles via VGLUT1–3. Membrane EAATs are synthesized in the endoplasmic reticulum and modified in the Golgi apparatus, before their expression on the surface. Their gene promoters are responsive to NF-κB. This is followed by their internalization either to recycle back to the surface or to be phagocytosed by lysosomes. EATTs are suppressed by TNF-α and IL-1β, rendering them insufficient for Glu clearance.*

#### **3.2 Glutamate and aggression**

An epigenetic mutation in the promoter region of *BEGAIN*, the gene expressing PSD95, involved in Glu receptors signaling, was identified in postmortem specimens of suicidal depressed patients [60]*.* A preclinical model of prenatal viral exposure incriminated in schizophrenia and autism spectrum disorders resulted in reduced PSD95, with overwhelming behavioral chaos [61]*.*

Exposure to stress reduced a specific type of oligodendrocytes, NG+ cells, in laboratory animals [62]*,* that share in glutamatergic and GABAergic synapse formation [63, 64]*,* eventually impairing EAATs, with subsequent brain Glu overload [62]*.*

A hypothalamic hamartoma (a congenital malformation) with excessive glutamic acid decarboxylase (GAD), enzyme involved in the synthesis of GABA from Glu, was accompanied by impulsive aggression, which improved after surgical resection of the deformity [65]*.* Glu has been targeted by various antiepileptic medications, many of which were successfully introduced in psychiatry to control psychopathologic aggression [66]*.*

Experimental animals can be used to model both types of aggression, hyperarousal or defensive, and hypo-arousal or predatory, corresponding to the impulsive and proactive types in humans, respectively. In different species, from fish to humans, Glu was implicated in the hypothalamic elicit of impulsive aggression [67]. Despite the involvement of other neurotransmitters in aggression, such as DA and noradrenaline (NA), yet it seems that they operate through glutamatergic neurons. Preclinical research indicated that Glu might be the leading mediator of aggression, as identified in cats, rats, and hamsters [68, 69]*.* Genetic studies in mice linked the severity of aggressive traits to the Glu ionotropic receptor AMPA3 gene (Gria3) [70]*.* More

astonishing was that in mice subjected to social isolation and depicting aggressive behavior, NMDA subunits were highly expressed in the hippocampus, while downregulated in the prefrontal cortex, the area of judgment and reasoning [71]*.* In human studies, the elevation of Glu in cerebrospinal fluid (CSF) was associated with impulsive aggression as well [1]*.*

Nonetheless, the link between Glu and aggression is still confusing, noting the opposing effects of NMDA antagonists, when at the low dose they aggravate aggression, while at a high dose they soothe aggression [36]*.* Further work is also needed to track discrete Glu circuity in specific brain areas.

#### **4. Blood glutamate and brain glutamate: a double-headed arrow**

In erythrocytes, as in brain, a continuous Glu supply is required to synthesize the antioxidant, GSH, along with cysteine and glycine, by aid of the enzymes, glutamate cysteine ligase (GCL) and GS. As the erythrocytic cell membrane is impermeable to Glu [72]*,* erythrocytes synthesize de novo Glu from either alpha-ketoglutarate using alanine aminotransferase (ALT), and aspartate aminotransferase (AST), or Gln using glutamine aminohydrolase (GA) [73]*.* As the oxidant, hydrogen peroxide (H2O2), traverses readily; in diseases with oxidative stress, erythrocytes capacity to synthesize more GSH is increased, using the endogenous Glu precursors, Gln and/or alphaketoglutarate, which exogenous supply was demonstrated to accelerate this process [74]*.* Recently, GA was proposed as one of the most powerful predictors of COVID-19 prognosis, based on case reports of critically—ill patients, indicating glutaminolysis and shift of glycolysis from anaerobic to aerobic, enriching Gln/Glu metabolic pathways, as was formerly detected in seizure disorders and inflammatory diseases [75]*.*

Immune cells express Glu cognate receptors that regulate their functions. T-lymphocytes exhibit both iGluRs and mGluRs that respond to Glu in a dose-dependent way. In the nanomolar-micromolar range, Glu acts on ionotropic receptors, stimulating T-cells migration, and proliferation. In pathologic conditions, at high millimolar Glu concentration, metabotropic receptors are activated leading to suppression of T-cells proliferation, versus increased inflammatory cytokines release. By acting on mGluRs, Glu induces the apoptosis of memory and naïve B-lymphocytes [76]*.*

In turn, iron deficiency anemia was involved in irreversible fetal brain alterations of excitatory and inhibitory neurotransmitter receptors. In a study [77]*,* using an experimental model of stroke due to intracranial hemorrhage, several blood components modified the AMPA- and NMDA-mediated synaptic responses. While the whole blood inhibited the synaptic activity; diluted blood precipitated a prolonged epileptic NMDA synaptic activation; plasma and part of leukocytes evoked neuronal epileptiform discharges; and fraction of red blood cells, initially, stimulated the receptors, followed by their depression. In cerebral ischemia, brain Glu was found to rise [78], culminating into excitotoxicity [79].

Despite the inability of Glu to penetrate the BBB [80]*,* the brain is not absolutely segregated from the effects of fluctuating blood Glu.

As a positive correlation has been reported between Glu levels in the blood and either CSF [81] or CNS [82], it was not surprising that, in 2018, Madeira et al*.* [83] assayed blood Glu and Gln in patients with recent onset and chronic schizophrenia to find that blood Gln/Glu ratio was increased with recent onset, versus decreased with long-standing disease. This complies with other studies reporting a low blood Glu with the first psychotic episode [84]*,* versus high blood Glu in cases with chronic schizophrenia [85]*.* This peripheral Glu change was previously mirrored in the brain by increased CSF Glu in chronic cases and a high Gln/Glu ratio in CSF of new-onset disorder [81]*.*

In terms of pharmacological approach, typical antipsychotics were associated with lower blood Gln/Glu ratio than with atypical medications of the same category [83]*.* The inconsistent link between blood and brain Glu could be related to the altered eating behavior induced by either the atypical antipsychotics [86] and/or the disease itself [87]*.*
