Open access peer-reviewed chapter
Abstract
The prevalence of aggression has become an increasing problem that threatens lives, from suicidal ideation to homicide. Multiple factors contribute to such issue, including genetic, psychological, familial, economic, environmental, dietary habits, endocrine disturbances, psychiatric disorders, and neurological disturbances, making it resistant to control. If key targets can be identified, it might be possible to find a cure. To date, glutamate has been one culprit involved in aggression, instigated by inflammatory mediators and reactive oxygen species. Monosodium glutamate as well as omega-3 and-6 polyunsaturated fatty acids -components of our modern diet- modulate the inflammatory state, hence, affecting brain and blood glutamate, the latter is an essential neurotransmitter sharing in the antioxidant capacity of erythrocytes.Hence, the erythrocytic or blood glutamate assay, along with members of the inflammatory cascade, might be a cost-effective diagnostic and prognostic tool for aggressive behavior, especially feasible for assessing the efficacy of the intervening dietary and/or pharmacological measures to prevent such potentially devastating behavior.
Keywords
- aggression
- glutamate
- monosodium glutamate
- omega-3 fatty acids
- omega-6 fatty acids
1. Introduction
Neurotransmitters in the brain are classified into inhibitory and excitatory. Each single neurotransmitter is a gear in an engine whose release is crucial for the brain's equilibrated machinery to proceed. The overflow of one neurotransmitter draws a cascade of events that disturb this discrete brain signaling, so does its deficiency. Accumulation of glutamate (Glu), the most abundant amino acid excitatory neurotransmitter, has been implicated in many neurological disorders, including aggressive behavior and the tendency to violence [1].
Exposure to ongoing or anticipated threatening events provokes a multitude of instinctive behavioral reactions, that enhance the ability to accommodate, survive, and sustain the stress, whether acute or chronic [2]. Among humans, stress-related behavior might be controlled relative to the magnitude of stress and its foreseen consequences; but in other cases, it might extend far beyond logic thinking and rational control, building up a crescendo aggressive attitude, that, instead of being a reactive physiologic response, becomes an intuitive pathologic one, that, even, needs no impulse to ignite.
Since the brain is not totally segregated from the peripheral system, variations of blood Glu can mirror brain Glu turbulence, hence, blood assays have been suggested to diagnose and follow-up neurological diseases. Assaying blood Glu might offer a noninvasive, cost-effective, and quantitative way to assess aggression for a better control, comparing the potency and efficacy of various interventions that address this issue. Therefore, we can gather and analyze data, derived from blood assays of glutamate and inflammatory markers in cases exhibiting aggressive behaviors, to be invested for future implementation of treatment plans and optimum choice of medications, instead of a trial-and-error policy that wastes the time and delays improvements in which timing would be critical for the patient and his/her family, or surroundings.
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 post-traumatic stress disorder among hospitalized patients [12], and the social isolation 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, 26, 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, 53, 54, 55, 56, 57, 58].
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.
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].
3.2 Glutamate and aggression
An epigenetic mutation in the promoter region of
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 alpha-ketoglutarate, 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].
5. Diet, glutamate, neuroinflammation, and neurotoxicity
5.1 Monosodium glutamate (MSG): a glutamate receptor agonist
Monosodium glutamate (MSG) is the sodium salt of
Despite being generally recognized as safe (GRAS) by the food safety regulatory agencies, animal and human studies continue to raise concerns about its potential toxicity. In 2006, the European Food Safety Association (EFSA) included MSG in the list of food additives for which established acceptable daily intake (ADI) was reassessed to be 30 mg/kg, considering its no-observed adverse effect level (NOAEL) that is 3200 mg/kg.
Focusing on its neurotoxicity, MSG has been alleged of causing stroke, epilepsy, schizophrenia, anxiety, depression, and AD [89], all of which predispose to aggression. This food additive acts on Glu receptors, triggering an array of inflammatory events and oxidative stress [90], especially with chronic consumption of high doses [91]. By binding to hepatic Glu receptors, excess NH4 ions are produced, with the secondary generation of reactive oxygen species (ROS), and eventual hepatotoxicity [92], impairing MSG metabolism, leading to its blood accumulation, and increasing the likelihood of neurotoxicity. Downregulating mGluRs and NMDA receptors was one of the protective mechanisms exerted by curcumin against MSG neurotoxicity [93].
Multiple experiments tracked the behavioral and neurochemical events associated with MSG [94, 95, 96, 97, 98, 99]. Notably, extrapolating animal studies employing the systemic route of administration to human practice may flaw results interpretation, bypassing the usual metabolic breakdown of oral MSG ingested in food [100].
Interestingly, a positive link was detected between MSG and hemoglobin levels [101] and it was found to reduce the percentage of blood lymphocytes as well [102]. Moreover, the oxidative stress during MSG toxicity overwhelmed the Glu-derived antioxidants generated by erythrocytes [103].
5.2 Omega-3 (ω3) versus omega-6 (ω6) long-chain polyunsaturated fatty acids (LC-PUFA)
Polyunsaturated fatty acids (PUFA) are those containing two or more carbon double bonds, classified as omega-3, -6, and -9. Among long-chain polyunsaturated fatty acids (LC-PUFA), omega-3 (ω3), and omega-6 (ω6) can be discriminated. While the literature recommended the addition of ω3 sources in the diet, they advised to limit the consumption of its nonidentical twin, ω6. A debatable issue was to whether focus on the relative ω6 to ω3 consumption, versus determining absolute figures for each [104].
Despite being essential FA, ω6 PUFA have a narrow therapeutic window, requiring a rational dietary consumption to establish physiologic, rather than deleterious effects [105]. The major dietary ω6 is linoleic acid (LA), converted to other ω6 products as γ-linolenic acid and dihomo-γ-linolenic acid, and from which arachidonic acid (AA) is derived, yielding pro-inflammatory molecules and ROS. Rich sources of LA are vegetable oils such as corn, sunflower, soy, and canola oils, while AA is present in meat and eggs mainly [106]. The recommended daily intake of LA in adult men is 17 g/day, to be further reduced for adult women to 12 g/day [107].
On the other side, the major component of ω-3 PUFA is the alpha-linolenic acid (ALA), contained in chia seeds, black walnuts, and soybean oil, and converted in the liver to docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), and decosapentaenoic acid (DPA) [108, 109]
The fatty acid composition of the brain consists of palmitate, AA, an ω6 PUFA, and DHA, as the major ω3 PUFA, other members of the latter group are present, but in very small quantities [114]. The brain depends on the uptake of ω3 PUFA from dietary or liver sources. Once absorbed from diet, ω3 PUFA are transported by lipoproteins and albumin to the blood stream [115]. In adult mice, blood and brain levels of ω3 PUFA (DHA and EPA) were dependent on dietary consumption [116]. Free fatty acid receptor (GPR40), which ligands include several medium and LC-FA, saturated or unsaturated, is ubiquitously expressed in the brain. If ω6 binds to GPR40, neurodegeneration follows. If the ligand is ω3, serum BDNF is increased with eventual synaptogenesis and neurogenesis [117].
Poor nutrition has long been declared as one of the risk factors to antisocial personality disorder in adulthood [118] and increased aggression during childhood and adolescence [119]. A defective supply of DHA from ω3-PUFA, an integral part of astrocytic cell membrane, caused an impaired Glu clearance, with subsequent altered behavior in adulthood [120]. Several human studies adopted ω3 PUFA to hinder aggression [121, 122, 123, 124, 125, 126, 127]. Omega-3 deficiency favors the production of inflammatory cytokines, disturbing Glu homeostasis (Figure 2) [43, 128, 129, 130, 131, 132]. Inflammation was linked to aggressive behavior in lower mammals and humans [133, 134]. There seems to be a bidirectional interaction, so that aggression by itself can precipitate oxidative stress, as was demonstrated in birds subjected to a violent interaction [135].
Figure 2.
Glutamate and neuroinflammatory mediators. Among inflammatory cytokines, tumor necrosis factor-alpha (TNF-α) upregulates 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl) propanoic acid (AMPA) receptors, on the expense of gamma-aminobutyric acid (GABA) downregulation. The rapid rise of TNF-α from micromolar to millimolar levels can lead to sustained nuclear factor-kappa B (NF-Κb) activation and neurotoxicity. A blunted TNF-α is not beneficial either, as by acting through its corresponding receptors (TNFR1 and TNFR2), it supports synaptic transmission by stimulating presynaptic N-methyl-D-aspartate (NMDA) and postsynaptic NMDA and AMPA activities, as well as assisting Glu transporters by regulating membrane trafficking of excitatory amino acid transporters (EAATs) and their recycling to the surface, added to conferring neuroprotection. Interleukin-1 beta (IL-1β), activated by stress, precipitates excitotoxicity by enhancing the postsynaptic NMDA pool and activity, by facilitating tyrosine kinase-mediated NMDA phosphorylation, increasing Ca2+ permeability. Interferon-gamma (IFN-γ), released from T-lymphocytes at high concentrations, can impair the sequestration of Glu by EAAT, induces tryptophan catabolism through activation of IDO, generating Glu-like compounds as quinolinic acid and enhances AMPA-mediated neurotoxicity. Interleukin-6 (IL-6) acts on soluble IL-6 receptor (IL-6R) to abrogate presynaptic Glu release and reduce AMPA and NMDA activities. Cyclo-oxygenase-2 (COX-2) and prostaglandin E2 (PGE2) trigger the release of Ca2+ from intracellular stores, causing reverse efflux of Glu by EAATs, followed by Glu spillover to bind to extra-synaptic NMDA.
Despite studies claiming the benefits of ω3 PUFA in neurological disorders, a lack of consistency remains. Moreover, most studies addressed ω3 PUFA without discrimination between individual constituents. Scarce work investigated ω3 short-chain PUFA claiming their additional neurological benefits [136]
In blood, erythrocytes content of ω3 PUFA is dependent on either exchange with plasma lipoproteins, in the case of EPA, or erythrocytic turnover, in the case of DHA and DPA [137]. Surprisingly, giving EPA supplementation, but not DPA, was reflected at the level of erythrocytes. Other blood components seem to have a special affinity to supplements of different ω3 PUFA members. Blood levels and response to supplementation are subjected to multiple factors, related to genetics, gender, interindividual variability ranging from an 82% decrease to a 5000% increase, and the type of supplement used [138, 139, 140, 141].
Many years ago, low blood ω3 was detectable in impulsive offenders [142]. Blood levels of ω3 were negatively correlated to behavioral indices of aggression [143]. Blood samples were recommended when dealing with ω3 supplementation, being better predictors of aggression, that can discriminate responders from no- or low-responders and can tackle interactions with other nutrients [127]. Recently, a total daily dose of 960 mg DHA and EPA was provided to adult male prisoners in a correctional center as fish oil capsules reduced their aggression, most of them were nonaggressive at baseline [144]. In this trial, non-fasted blood samples were withdrawn, and plasma was separated from packed erythrocytes. Then, erythrocytes were prepared for fatty acid analysis [145]. Individual fatty acid analysis was done, then ω3 index was calculated as the sum of EPA and DHA, to be expressed as the mol percent of total erythrocyte fatty acids [146]. Participants with an index of 6% or higher were unlikely to benefit from the supplements due to a potential ceiling effect [147].
Unfortunately, results correlating blood levels of ω3 PUFA to the brain levels showed inconsistencies, limiting their applicability as surrogate biomarkers for brain disorders, at least for the time being. In fact, ω3 and ω6 PUFA complement to maintain constant levels of unsaturated membrane phospholipids, so that they compensate for each other [148].
6. Blood–brain bridge, rather than barrier
The brain is no more that sealed-off structure from the rest of the body, as detected in mice lacking immune cells and depicting difficulty in social behavior [149]. Instead of crossing the brain, immune cells signal through cytokines, so that knocking out cytokine receptors on the neurons can disturb social behavior in laboratory animals [150]. In turn, the brain areas involved in positive emotions and motivation can alter immune responses in inflammatory and oncogenic disorders [151]. Although, in healthy humans, limiting the amount of Glu that crosses the BBB [152] protects brain Glu levels from fluctuations of blood Glu [99]. Glutamate can breach such restrictive entry by enhancing the blood-brain permeability, while triggering cerebral vasodilatation [153].
In vascular injury of the brain, whether ischemic or hemorrhagic, the concomitant sizeable rise of blood and brain Glu occurs [154]. Such elevations were also noticed in many neurological disorders, including AD, epilepsy, and schizophrenia [155]. Following traumatic brain injury, the rise of brain Glu persists for months or even years thereafter. Such BBB disruption, not only allows blood Glu to reach the brain, but prevents the escape of cerebral Glu to the bloodstream.
In primary hypertension, the increased arterial content of Glu was linked to the higher Glu entry into the brain [156]. Similarly, systemic injection of Glu exacerbated brain damage [157]. Conversely, medications that lower blood Glu can assist Glu efflux from the brain [158]. So, restoring Glu level in both blood and brain to normal levels is required to reestablish the brain–blood Glu homeostasis. In their review, Gruenbaum et al. [159] highlighted the disruption of Glu efflux, breaking the integrity of the BBB, suggesting the feasibility of blood Glu scavengers in the treatment of depression following stroke.
One applied entity is the stress-induced aggression. During an anger attack, blood perfusion is increased, contrasted by cerebral hypoperfusion in between attacks, owing to stress-induce cerebral vasoconstriction [160]. Chronic stress causes disorganized BBB integrity, permitting the influx of mediators from peripheral blood, causing oxidative stress and neuroinflammation [161]. Altering the blood–brain Glu balance can excite excess Glu exit from the brain. To revert aggression and other subsequent psychological issues, oxaloacetate (OxAc) [162], the substrate of the enzyme glutamate-oxaloacetate transaminase 1 (GOT), that consumes Glu to render OxAc, was given to reduce blood Glu level.
7. Tips for erythrocyte glutamate assay in CNS disorders
In the brain, Glu is taken up from the extracellular to the intracellular domain of neurons and astrocytes by bidirectional transport mechanisms that, not only maintains low/high extracellular/intracellular levels, but also acts as a source of extracellular Glu when low [163], through stimulating Glu release [164]. Similarly, the Glu active transport in erythrocytes maintains a high erythrocyte/plasma (E/P) concentration and a low plasma concentration.
In children with migraine, erythrocytic Glu was employed to mirror a centrally enhanced cellular uptake of this amino acid. In this setting, measuring plasma and erythrocytic Glu revealed a significant decrease in plasma, with a higher E/P concentration which was suggested as a reflection to mishandled CNS Glu turnover [165]. In contrast to the pediatric age group, adult migraineurs experienced elevated plasma and platelets Glu when measured during the attack-free periods [166]. Recently, stress, an aggression trigger, was documented to affect blood Glu levels [167].
A blood assay of Glu should be obtained after an overnight fast, to enhance specificity, avoiding misinterpretation due to nutritional factors, unless dietary management is planned. A preferable practice would be to monitor plasma Glu at the fixed time of the day, if multiple testing is needed, as plasma Glu might fluctuate along the day [168]. For better and more accurate interpretation, multiple factors that can modify blood Glu should be kept in mind, apart from nutritional status mentioned earlier, age, gender [169], body temperature [170], and even blood sampling sites seem confounding factors [171].
Normal Glu in plasma and whole blood is 50–100 and 150–300 μmol/l, respectively [59]. In the whole brain, Glu concentration is 12 μmol/g [172]. The free amino acids concentration can be calculated using whole blood and plasma concentrations [173].
The inverse relationship between plasma Glu and nitrogen hemostasis implicates that plasma urea and ammonia nitrogen should be assessed as well.
It is worthwhile to measure more than one inflammatory marker (C-RP, TNF-α, IL6, IFN-γ, and IL-1β) to identify patients who are likely to respond to Glu-targeted therapies, since inflammation seems an incident predisposing to Glu excitotoxicity. This was corroborated when the elevated inflammatory markers in blood predicted the favorable antidepressant response to the noncompetitive NMDA antagonist, ketamine [174]. Also, the administration of the inflammatory cytokine and interferon (IFN)-α induced a high plasma TNF-α [175]. Moreover, the higher plasma CRP level in depressed patients was correlated to a higher brain Glu [176]. As implicated in neuropsychiatric disorders, IL-6 promotes hepatic acute phase proteins, while processing neuroinflammation in the brain [177].
No study tracking the patients’ behavior to neuropsychiatric medications or dietary manipulations has targeted both the blood level of Glu and the inflammatory markers. So, elaborative research work is indispensable to elucidate the benefits of blood assays in prediction and management panels.
8. Conclusions
Glutamate is one of the key mediators involved in aggressive behavior. In neuropsychiatric disorders, blood or erythrocytic Glu level mirrored brain Glu fluctuations. Anemia was demonstrated to affect brain Glu level, meanwhile precipitating aggression. Lowering blood Glu increased Glu clearance from the brain. Dietary manipulation was successful in controlling aggression, as inflammation and oxidative stress have been implicated in altered brain Glu and aggression. Hence, blood or erythrocytic assay of Glu might help the diagnosis and prognosis of aggression, as well as planning corresponding therapeutic strategies ranging from simple dietary manipulation, up to complex pharmacologic treatments. The more advances in the scientific research, knowledge, and testing techniques, the more explicit will be the dynamics of behavioral issues, the more feasible and successful will be the diagnostic, preventive, and therapeutic interventions. Nonetheless, Glu is not the only culprit in aggression, other explored neurotransmitters and inflammatory markers can be assayed and targeted as well, to obtain a panel of laboratory markers and plan several therapeutic alternatives using these mediators, hoping to prevent an outraged ideation from proceeding to a devastating aggression.
Thanks
I would like to thank prof. Dr. Salwa Abdelmoneim Elmessiry for her continued support, who guided me and taught me a lot about scientific research. My deep gratitude to her. Special thanks and appreciations to all my professors and colleagues at Medical Pharmacology Department, Faculty of Medicine, Kasr Al-Ainy, Cairo University, Egypt, for being supportive and encouraging.
References
- 1.
Felthous AR, Nassif J. CNS glutamate in impulsive aggression. In: Pavlovic ZM, editor. Glutamate and Neuropsychiatric Disorders. Current and Emerging Treatments. Cham: Springer International Publishing AG; 2022. pp. 283-312. DOI: 10.1007/978-3-030-87480-3 - 2.
Dallman MF, Pecoraro N, Akana SF, SEI F, Gomez F, Houshyar H, et al. Chronic stress and obesity: A new view of ‘comfort food’. Proceedings of the National Academy of Sciences of the United States of America. 2003; 100 :11696-11701. DOI: 10.1073/pnas.1934666100 - 3.
American Psychological Association (APA) Dictionary of Psychology. Washington DC: American Psychological Association (APA); 2022 - 4.
Bushman BJ, Anderson CA. Is it time to pull the plug on the hostile versus instrumental aggression dichotomy? Psychological Review. 2001; 108 :273-279. DOI: 10.1037/0033-295X.108.1.273 - 5.
Archer JB, Coyne S. The relationship between indirect and physical aggression on television and in real life. Social Development. 2005; 14 :324-338. Faculty Publications. 2353 Available from:https://scholarsarchive.byu.edu/facpub/2353 - 6.
Olafsen RN, Viemero V. Bully/victim problems and coping with stress in school among 10- to 12-year old pupils in Aland, Finland. Aggressive Behavior. 2000; 26 (1):57-65. DOI: 10.1002(SICI)1098-2337(2000)26:1<57::AID-AB5>3.0.CO;2-I - 7.
Hinduja S, Patchin JW. Bullying Beyond the Schoolyard: Preventing and Responding to Cyberbullying. Thousand Oaks, CA: Corwin Press; 2009 ISBN: 1483349934 - 8.
Barratt ES. Measuring and predicting aggression within the context of a personality theory. The Journal of Neuropsychiatry and Clinical Neurosciences. 1991; 3 (2):S35-S39 PMID: 1821220 - 9.
Felthous AR, Barratt ES. Impulsive versus premeditated aggression: Implications for mens rea decisions. Behavioral Sciences & the Law. 2003; 21 :619-630. DOI: 10.1002/bsl.555 - 10.
Huecker MR, King KC, Jordan JA, Smock W. Domestic violence. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022 PMID: 29763066 - 11.
Zhang Z, Zhai A, Yang M, Zhang J, Zhou H, Yang C, et al. Prevalence of depression and anxiety symptoms of high school students in Shandong Province during the COVID-19 epidemic. Frontiers in Psychiatry. 2020; 11 :570096. DOI: 10.3389/fpsyt.2020.570096 - 12.
Vindegaard N, Benros ME. COVID-19 pandemic and mental health consequences: Systematic review of the current evidence. Brain, Behavior, and Immunity. 2020; 89 :531-542. DOI: 10.1016/j.bbi.2020.05.048 - 13.
Usher K, Bhullar N, Darkin J, Gyamfi N, Jackson D. Family violence and COVID19: Increased vulnerability and reduced options for support. International Journal of Mental Health Nursing. 2020; 29 :549-552. DOI: 10.1111/inm.12735 - 14.
Sher L. The impact of the COVID-19 pandemic on suicide rates. QJM. 2020a; 113 (10):707-712. DOI: 10.1093/qjmed/hcaa202 - 15.
Ferrando SJ, Klepacz L, Lynch S, Tavakkoli M, Dornbush R, Baharani R, et al. COVID-19 psychosis: A potential new neuropsychiatric condition triggered by novel coronavirus infection and the inflammatory response? Psychosomatics. 2020; 61 (5):551-555. DOI: 10.1016/j.psym.2020.05.012 - 16.
DeLisi LE. A commentary revisiting the viral hypothesis of schizophrenia: Onset of a schizophreniform disorder subsequent to SARS CoV-2 infection. Psychiatry Research. 2021; 295 :113573. DOI: 10.1016/j.psychres.2020.113573 - 17.
Ariza-Varón M, Beltrán MA, Marín-Medina DS, González AF, Ávila AM. Psychosis associated with suspected SARS-CoV-2 encephalitis with response to steroids: A case report. Infectious Diseases (London). 2022; 54 (2):152-156. DOI: 10.1080/23744235.2021.19773812021 Aug 15;90(4):e23-e26 - 18.
McAlpine LS, Lifland B, Check JR, Angarita GA, Ngo TT, Pleasure SJ, et al. Remission of subacute psychosis in a COVID-19 patient with an antineuronal autoantibody after treatment with intravenous immunoglobulin. Biological Psychiatry. 2021; 90 (4):e23-e26. DOI: 10.1016/j.biopsych.2021.03.033 - 19.
Smith CM, Gilbert EB, Riordan PA, Helmke N, von Isenburg M, Kincaid BR, et al. COVID-19-associated psychosis: A systematic review of case reports. General Hospital Psychiatry. 2021; 73 :84-100. DOI: 10.1016/j.genhosppsych.2021.10.003 - 20.
Saylor KE, Amann BH. Impulsive aggression as a comorbidity of attention-deficit/hyperactivity disorder in children and adolescents. Journal of Child and Adolescent Psychopharmacology. 2016; 26 (1):19-25. DOI: 10.1089/cap.2015.0126 - 21.
Alniak ĺ, Erkıran M, Mutlu E. Substance use is a risk factor for violence behavior in male patients with bipolar disorder. Journal of Affective Disorders. 2016; 193 :89-93. DOI: 10.1016/j.jad.2015.12.059 - 22.
Soreff SM, Gupta V, Wadhwa R, Arif H. Aggression. In: StatPearls [Internet]. Treasure Island, FL: StatPearls Publishing; 2022 PMID: 28846310 - 23.
Kirwan M, Lanni DJ , Warnke A, Pickett SM, Parkhill MR. Emotion regulation moderates the relationship between alcohol consumption and the perpetration of sexual aggression. Violence Against Women. 2019; 25 (9):1053-1073. DOI: 10.1177/1077801218808396 - 24.
Bhutta ZA, Salam RA. Global nutritional epidemiology and trends. Annals of Nutrition & Metabolism. 2012; 61 (Suppl. 1):19-27. DOI: 10.1159/000345167 - 25.
Pol RR, Howard MR. A man with anemia and a change in personality. Blood Work. 2014; 123 (12):1784. DOI: 10.1182/blood-2013-12-544387 - 26.
Robinson SL, Marín C, Oliveros H, Mora-Plazas M, Richards BJ, Lozoff B, et al. Iron deficiency, anemia, and low vitamin B-12 serostatus in middle childhood are associated with behavior problems in adolescent boys: Results from the Bogotá school children cohort. Journal of Nutrition. 2018; 148 (5):760-770. DOI: 10.1093/jn/nxy029 - 27.
Su J, Cui N, Zhou G, Ai Y, Sun G, Zhao SR, et al. Hemoglobin status and externalizing behavioral problems in children. IJERPH . 2016;13 (8):758. DOI: 10.3390/ijerph13080758 - 28.
Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. The Journal of Nutrition. 2011; 141 (4):740S-746S. DOI: 10.3945/jn.110.131169 - 29.
Bruno V, Mancini D, Ghoche R, Arshinoff R, Miyasaki JM. High prevalence of physical and sexual aggression to caregivers in advanced Parkinson's disease. Experience in the palliative care program. Parkinsonism & Related Disorders. 2016; 24 :141-142. DOI: 10.1016/j.parkreldis.2016.01.010 - 30.
Wise J. Antidepressants may double risk of suicide and aggression in children, study finds. BMJ. 2016; 28 (352):i545. DOI: 10.1136/bmj.i545 - 31.
Turner D, Basdekis-Jozsa R, Briken P. Prescription of testosterone-lowering medications for sex offender treatment in German forensic-psychiatric institutions. The Journal of Sexual Medicine. 2013; 10 (2):570-578. DOI: 10.1111/j.1743-6109.2012.02958.x - 32.
Suñol A, Perez-Accino J, Kelley M, Rossi G, Schmitz SS. Successful dietary treatment of aggression and behavioral changes in a dog. Journal of Veterinary Behavior. 2020; 37 :56-60. DOI: 10.1016/j.jveb.2020.04.009 - 33.
de Almeida RMM, Ferrari PF, Parmigiani S, Miczek KA. Escalated aggressive behavior: Dopamine, serotonin, and GABA. European Journal of Pharmacology. 2005; 526 (1-3):51-64. DOI: 10.1016/j.ejphar.2005.10.004 - 34.
Narvaes R, de Almeida RM. Aggressive behavior and three neurotransmitters: Dopamine, GABA, and serotonin—A review of the last 10 years. Psychology & Neuroscience. 2014; 7 (4):601-607. DOI: 10.3922/j.psns.2014.4.20 - 35.
Nordman JC. Anger management: Mechanisms of glutamate recptor-mediated synaptic plasticity underlying animal aggression. The International Journal of Biochemistry & Cell Biology. 2022; 142 :106120. DOI: 10.1016/j.biocel.2021.106120 - 36.
Takahashi A, Miczek K. Neurogenetics of aggressive behavior: Studies in rodents. Current Topis in Behavioral Neurosciences. 2014; 17 :3-44. DOI: 10.1007/7854_2013_263 - 37.
Kew JN, Trube G, Kemp JA. State-dependent NMDA receptor antagonism by Ro 8-4304, a novel NR2B selective, non-competitive, voltage-independent antagonist. British Journal of Pharmacology. 1998; 123 (3):463-472 PubMed ID: 9504387 - 38.
Ma TM, Paul BD, Fu C, Hu S, Zhu H, Blackshaw S, et al. Serine racemase regulated by binding to stargazin and PSD-95: Potential N-methyl-D-aspartate-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (NMDA-AMPA) glutamate neurotransmission cross-talk. The Journal of Biological Chemistry. 2014; 289 :29631-29641. DOI: 10.1074/jbc.M114.571604 - 39.
Torres-Platas SG, Hercher C, Davoli MA, Maussion G, Labonte B, Turecki G, et al. Astrocytic hypertrophy in anterior cingulate white matter of depressed suicides. Neuropsychopharmacology. 2011; 36 (13):2650-2658. DOI: 10.1038/npp.2011.154 - 40.
Liddelow S, Barres B. SnapShot: Astrocytes in health and disease. Cell. 2015; 162 (5):1170-1170.e1. DOI: 10.1016/j.cell.2015.08.029 - 41.
Yang L, Wang M, Guo YY, Sun T, Li YJ, Wang Q , et al. Systemic inflammation induces anxiety disorder through CXCL12/CXCR4 pathway. Brain, Behavior, and Immunity. 2016; 56 :352-362. DOI: 10.1016/j.bbi.2016.03.001 - 42.
Santello M, Volterra A. TNFalpha in synaptic function: Switching gears. Trends in Neurosciences. 2012; 35 :638-647. DOI: 10.1016/j.tins.2012.06.001 - 43.
Haroon E, Miller AH, Sanacora G. Inflammation, glutamate, and glia: A trio of trouble in mood disorders. Neuropsychopharmacology Reviews. 2017; 42 :193-215. DOI: 10.1038/npp.2016.199 - 44.
Kielian T, Esen N. Effects of neuroinflammation on glia-glia gap junctional intercellular communication: A perspective. Neurochemistry International. 2004; 45 :429-436. DOI: 10.1016/j.neuint.2003.09.010 - 45.
Volterra A, Meldolesi J. Astrocytes, from brain glue to communication elements: The revolution continues. Nature Reviews. Neuroscience. 2005; 6 :626-640. DOI: 10.1038/nrn1722 - 46.
Parri HR, Gould TM, Crunelli V. Spontaneous oscillations astrocytic Ca2+ in situ drive NMDAR-mediated neuronal excitation. Nature Neuroscience. 2001; 4 :803-812. DOI: 10.1038/90507 - 47.
Sofroniew MV, Hinters HV. Astrocytes: Biology and pathology. Acta Neuropathologica. 2010; 119 :7-35. DOI: 10.1007/s00401-009-0619-8 - 48.
Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. Structural and functional features of central nervous system lymphatic vessels. Nature. 2015; 523 :337-341. DOI: 10.1038/nature14432 - 49.
Dorsett CR, McGuire JL, DePasquale EA, Gardner AE, Floyd CL, McCullumsmith RE. Glutamate neurotransmission in rodent models of traumatic brain injury. Journal of Neurotrauma. 2017; 34 (2):263-272. DOI: 10.1089/neu.2015.4373 - 50.
Albrecht J, Zielinska M, Norenberg MD. Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal. Biochemical Pharmacology. 2010; 80 :1303-1308. DOI: 10.1016/j.bcp.2010.07.024 - 51.
Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. Journal of Neural Transmission. 2014; 121 :799-817. DOI: 10.1007/s00702-014-1180-8 - 52.
Shan D, Lucas EK, Drummond JB, Haroutunian V, Meador- Woodruff JH, McCullumsmith RE. Abnormal expression of glutamate transporters in temporal lobe areas in elderly patients with schizophrenia. Schizophrenia Research. 2013; 144 :1-8. DOI: 10.1016/j.schres.2012.12.019 - 53.
Zou JY, Crews FT. TNF alpha potentiates glutamate neurotoxicity by inhibiting glutamate uptake in organotypic brain slice cultures: Neuroprotection by NF kappa B inhibition. Brain Research. 2005; 1034 :11-24. DOI: 10.1016/j.brainres.2004.11.014 - 54.
Nakagawa T, Otsubo Y, Yatani Y, Shirakawa H, Kaneko S. Mechanisms of substrate transport-induced clustering of a glial glutamate transporter GLT-1 in astroglial-neuronal cultures. The European Journal of Neuroscience. 2008; 28 :1719-1730. DOI: 10.1111/j.1460-9568.2008.06494.x - 55.
Takahashi K, Foster JB, Lin CL. Glutamate transporter EAAT2: Regulation, function, and potential as a therapeutic target for neurological and psychiatric disease. Cellular and Molecular Life Sciences. 2015; 72 :3489-3506 ISSN: 1420-682X - 56.
Wang F, Smith NA, Xu Q , Goldman S, Peng W, Huang JH, et al. Photolysis of caged Ca2+ but not receptor—mediated Ca2+ signaling triggers astrocytic glutamate release. The Journal of Neuroscience. 2013; 33 :17404-17412. DOI: 10.1523/JNEUROSCI.2178-13.2013 - 57.
Vercellino M, Mirola A, Piacentino C, Votta B, Capello E, Mancardi GL, et al. Altered glutamate reuptake in relapsing-remitting and secondary progressive multiple sclerosis cortex: Correlation with microglia infiltration, demyelination, and neuronal and synaptic damage. Journal of Neuropathology and Experimental Neurology. 2007; 66 :732-739. DOI: 10.1097/nen.0b013e31812571b0 - 58.
Dantzer R, Walker AK. Is there a role for glutamate-mediated excitotoxicity in inflammation-induced depression? Journal of Neural Transmission. 2014; 121 :925-932. DOI: 10.1007/s00702-014-1187-1 - 59.
Leibowitz A, Boyko M, Shapira Y, Zlotnik A. Blood glutamate scavenging: Insight into neuroprotection. International Journal of Molecular Sciences. 2012; 13 :10041-10066. DOI: 10.3390/ijms130810041 - 60.
Nagy C, Suderman M, Yang J, Szyf M, Mechawar N, Ernest C, et al. Astrocytic abnormalities and global DNA methylation patterns in depression and suicide. Molecular Psychiatry. 2015; 20 :320-328. DOI: 10.1038/mp.2014.21 - 61.
Giovanoli S, Weber-Satdlbauer U, Schedlowski M, Meyer U, Engler H. Prenatal immune activation causes hippocampal synaptic deficits in the absence of overt microglia anomalies. Brain, Behavior, and Immunity. 2016; 55 :25-38. DOI: 10.1016/j.bbi.2015.09.015 - 62.
Birey F, Kloc M, Chavali M, Hussein I, Wilson M, Christoffel DJ, et al. Genetic and stress-induced loss of NG2 glia triggers emergence of depressive-like Behaviors through reduced secretion of FGF2. Neuron. 2015; 88 (5):941-956. DOI: 10.1016/j.neuron.2015.10.046 - 63.
Dimou L, Gallo V. NG2-glia and their functions in the central nervous system. Glia. 2015; 63 (8):1429-1451. DOI: 10.1002/glia.22859 - 64.
Steffek AE, McCullumsmith RE, Haroutunian V, Meador-Woodruff JH. Cortical expression of glial fibrillary acidic protein and glutamine synthetase is decreased in schizophrenia. Schizophrenia Research. 2008; 103 :71-82. DOI: 10.1016/j.schres.2008.04.032 - 65.
Kerrigan JF, Parsons A, Tsang C, Simeone K, Coon S, Wu J. Hypothalamic hamartoma: Neuropathology and epileptogenesis. Epilepsia. 2017; 58 (52):22-31. DOI: 10.1111/epi.13752 - 66.
Huband N, Ferriter M, Nathan R, Jones H. Antiepileptics for aggression and associated impulsivity. Cochrane Database of Systematic Reviews. 2010;(2):CD003499. DOI: 10.1002/14651858.CD003499.pub3 - 67.
Haller J. The neurobiology of abnormal manifestations of aggression—A review of hypothalamic mechanisms in cats, rodents, and humans. Brain Research Bulletin. 2013; 93 :97-109. DOI: 10.1016/j.brainresbull.2012.10.003 - 68.
Siegel A, Bhatt S, Bhatt R, Zalcman SS. The neurobiological bases for development of pharmacological treatments of aggressive disorders. Current Neuropharmacology. 2007; 5 :135-147. DOI: 10.2174/157015907780866929 - 69.
Carrillo M, Ricci LA, Melloni RH. Glutamate and the aggression neural circuit in adolescent anabolic steroid-treated Syrian hamsters ( Mesocricetus auratus ). Behavioral Neuroscience. 2011;125 :753-763. DOI: 10.1037/a0025127 - 70.
Brodkin ES, Goforth SA, Keene AH, Fossella JA, Silver LM. Identification of quantitative trait loci that affect aggressive behavior in mice. The Journal of Neuroscience. 2002; 22 (3):1165-1170. DOI: 10.1523/jneurosci.22-03-01165.2002 - 71.
Zhao X, Sun L, Jia H, Meng Q , Wu S, Li N, et al. Isolation rearing induces social and emotional function abnormalities and alters glutamate and neurodevelopment-related gene expression in rats. Progress in Neuro-Psychopharmacology and Biological Psychiatry. 2009; 33 :1173-1177. DOI: 10.1016/j.pnpbp.2009.06.016 - 72.
Niihara Y, Zerez C, Akiyama D, Tanaka K. Increased red cell glutamine availability in sickle cell anemia: Demonstration of increased active transport, affinity, and increased glutamate level in intact red cells. The Journal of Laboratory and Clinical Medicine. 1997; 130 :83-90. DOI: 10.1016/s0022-2143(97)90062-7 - 73.
Ellinger JJ, Lewis IA, Markley JL. Role of aminotransferases in glutamate metabolism of human erythrocytes. Journal of Biomolecular NMR. 2011; 49 :221-229. DOI: 10.1007/s10858-0119481-9 - 74.
Whillier S, Garcia B, Chapman BE, Kuchel PW, Raftos JE. Glutamine and α-ketoglutarate as glutamate sources for glutathione synthesis in human erythrocytes. FEBS Journal. 2011: 278 (17):3152-3163. DOI: 10.1111/j.1742-4658.2011.08241.x - 75.
Reverte L, Yeregui E, Olona M, Gutierrez-Valencia A, Buzon MJ, Marti A, et al. Fetuin-A, inter-alpha-trypsin inhibitor, glutamic acid and ChoE (18:0) are key biomarkers in a panel distinguishing mild from critical coronavirus disease 2019 outcomes. Clinical and Translational Medicine. 2022; 12 (1):e704. DOI: 10.1002/ctm2.704 - 76.
Jovic Z, Veselinovic M, Vasic K, Stankovic-Djordjevic D, Cekic S, Milovanovic M, et al. Monosodium glutamate induces apoptosis in naive and memory human B cells. Bratislavské Lekárske Listy. 2009; 110 (10):636-640 Accession Number: 20017456 - 77.
Mokrushin AA, Pavlinova LI. Effects of the blood components on the AMPA and NMDA synaptic responses in brain slices in the onset of hemorrhagic stroke. General Physiology and Biophysics. 2013; 32 (4):489-504. DOI: 10.4149/gpb_2013038 - 78.
Meldrum BS. Glutamate as a neurotransmitter in the brain: Review of physiology and pathology. Journal of Nutrition. 2000; 130 :1007S-1015S. DOI: 10.1093/jn/130.4.1007S - 79.
Liu J, Ma W, Zang CH, Wang GD, Zhang SJ, Wu HJ, et al. Salidroside inhibits NLRP3 inflammasome activation and apoptosis in microglia induced by cerebral ischemia/reperfusion injury by inhibiting the TLR4/NF-kappaB signaling pathway. Annals of Translational Medicine. 2021; 9 (22):1694. DOI: 10.21037/atm-21-5752 - 80.
Abbott NJ, Patabendige AAK, Dolman DEM, Yousof SR, Begley DJ. Structure and function of the blood-brain barrier. Neurobiology of Disease. 2010; 37 (1):13-25. DOI: 10.1016/j.nbd.2009.07.030 - 81.
Hashimoto K, Engberg G, Shimizu E, Nordin C, LindstrÖm LH, Iyo M. Elevated glutamine/glutamate ratio in cerebrospinal fluid of first episode and drug naïve schizophrenic patients. BMC Psychiatry. 2005; 5 :6. DOI: 10.1186/1471-244X-5-6 - 82.
Hassan TH, Abdelrahman HM, Abdel Fattah NR, El-Masry NM, Hashim HM, El-Gerby KM, et al. Blood and brain glutamate levels in children with autistic disorder. Research in Autism Spectrum Disorder. 2013; 7 :541-548. DOI: 10.1016/j.rasd.2012.12.005 - 83.
Madeira C, Alheira FV, Calcia MA, Silva TCS, Tannos FM, Vargas-Lopes C, et al. Blood levels of glutamate and glutamine in recent onset and chronic schizophrenia. Frontiers in Psychiatry. 2018; 9 :713. DOI: 10.3389/psyt.2018.00713 - 84.
Palomino A, González-Pinto A, Aldama A, González-Gómez C, Mosquera F, González-García G, et al. Decreased levels of plasma glutamate in patients with first-episode schizophrenia and bipolar disorder. Schizophrenia Research. 2007; 95 :174-178. DOI: 10.1016/j.schres.2007.06.012 - 85.
Ivanova SA, Boyko AS, Fedorenko OY, Krotenko NM, Semke AV, Bokhan NA. Glutamate concentration in the serum of patients with schizophrenia. Procedia Chemistry. 2014; 10 :80-85. DOI: 10. 1016/j.proche.2014.10.015 - 86.
Blouin M, Tremblay A, Jalbert ME, Jenables H, Bouchard RH, Roy MA, et al. Adiposity and eating behaviors in patients under second generation antipsychotics. Obesity. 2008; 2008 (16):1780-1787. DOI: 10.1038/oby.2008.277 - 87.
Bushe C, Haddad P, Peveler R, Pendlebury J. The role of lifestyle interventions and weight management in schizophrenia. Journal of Psychopharmacology. 2005; 19 :28-35. DOI: 10.1177/0269881105058682 - 88.
Geha RS, Beiser A, Ren C, Patterson R, Greenberger PA, Grammar LC, et al. Review of alleged reaction to monosodium glutamate and outcome of a multicenter double-blind placebo-controlled study. The Journal of Nutrition. 2000; 130 (4S Suppl):1058S-1062S. DOI: 10.1093/jn/130.4.1058S - 89.
Husarova V, Ostatnikov D. Monosodium glutamate toxic effects and their implications for human intake: A review. JMED Research. 2013; 2013 (2013), Article ID: 608765. DOI: 10.5171/2013.608765 - 90.
Samuels A. The toxicity/safety of processed free glutamic acid (MSG): A study in suppression of information. Accountability in Research. 1999; 6 (4):259-310. DOI: 10.1080/08989629908573933 - 91.
Farombi O, Onyema OO. Monosodium glutamate-induced oxidative damage and genotoxicity in the rat: Modulatory role of vitamin C, vitamin E and quercetin. Human & Experimental Toxicology. 2006; 25 (5):251-259. DOI: 10.1191/0960327106ht621oa - 92.
Tawfik MS, Al-Badr N. Adverse effects of monosodium glutamate on liver and kidney functions in adult rats and potential protective effect of vitamins C and E. Food and Nutrition Sciences. 2012; 3 :651-659. DOI: 10.4236/fns.201235089 - 93.
Khalil RM, Khedr NF. Curcumin protects against monosodium glutamate neurotoxicity and decreasing NMDA2B and mGluR5 expression in rat hippocampus. Neurosignals. 2016; 24 (1):81-87. DOI: 10.1159/000442614 - 94.
Abu-Taweel GM, Zyadah MA, Ajarem JS, Ahmad M. Cognitive and biochemical effects of monosodium glutamate and aspartame, administered individually and in combination in male albino mice. Neurotoxicology and Teratology. 2014; 42 :60-67. DOI: 10.1016/j.ntt.2014.02.001 - 95.
Quines CB, Rosa SG, Da Rocha JT, Gai BM, Bortolatto CF, Duarte MMMF, et al. Monosodium glutamate, a food additive, induces depressive-like and anxiogenic-like behaviors in young rats. Life Sciences. 2014; 107 (1-2):27-31. DOI: 10.1016/j.lfs.2014.04.032 - 96.
Rivera-Cervantes MC, Castaneda-Arellano R, Castro-Torres RD, Gudino-Cabrera G, Feria Y Velasco AI, Camins A, et al. P38 MAPK inhibition protects against glutamate neurotoxicity and modifies NMDA and AMPA receptor subunit expression. Journal of Molecular Neuroscience. 2014; 55 (3):596-608. DOI: 10.1007/s12031-014-0398-0 - 97.
Sadek K, Abouzed T, Nasr S. Lycopene modulates cholinergic dysfunction, Bcl-2/Bax balance, and antioxidant enzymes gene transcripts in monosodium glutamate (E621) induced neurotoxicity in a rat model. Canadian Journal of Physiology and Pharmacology. 2016; 94 (4):394-401. DOI: 10.1139/cjpp-2015-0388 - 98.
Shivasharan BD, Nagakannan P, Thippeswamy BS, Veerapur VP. Protective effect of Calendula officinalis L. flowers against monosodium glutamate induced oxidative stress and excitotoxic brain damage in rats. Indian Journal of Biochemistry & Biophysics. 2014;28 (3):292-298. DOI: 10.1007/s12291-012-0256-1 256 - 99.
Swamy AH, Patel NL, Gadad PC, Koti BC, Patel UM, Thippeswamy AH, et al. Neuroprotective activity of Pongamia pinnata in monosodium glutamate-induced neurotoxicity in rats. Indian Journal of Pharmaceutical Sciences. 2014;75 (6):657-663 PMID: 24591740 - 100.
Zanfirescu A, Ungurianu A, Tsatsakis AM, Nițulescu GM, Kouretas D, Veskoukis A, et al. A review of the alleged health hazards of monosodium glutamate. Comprehensive Reviews in Food Science and Food Safety. 2019; 18 (4):1111-1134. DOI: 10.1111/1541-4337.12448 - 101.
Shi Z, Yuan B, Wittert GA, Pan X, Dai Y, Adams R, et al. Monosodium glutamate intake, dietary patterns and asthma in Chinese adults. PLoS One. 2012; 7 (12):e51567. DOI: 10.1371/journal.pone.0051567 - 102.
Hriscu M, Saulea G, Vidrascu N, Baciu I. Effects of monosodium glutamate on blood neutrophils phagocytic activity and phagocytic response in mice. Romanian Journal of Physiology. 1997; 34 (1-4):95-101 - 103.
Sharma A. Monosodium glutamate-induced oxidative kidney damage and possible mechanisms: A mini-review. Journal of Biomedical Science. 2015; 22 :93. DOI: 10.1186/s12929-015-0192-5 - 104.
Harris WS. The omega-6/omega-3 ratio and cardiovascular disease risk: Uses and abuses. Current Atherosclerosis Reports. 2006; 8 :453-459. DOI: 10.1007/s11883-006-0019-7 - 105.
Yamashima T, Ota T, Mizukoshi E, Nakamura H, Yamamoto Y, Kikuchi M, et al. Intake of ω-6 polyunsaturated fatty acid-rich vegetable oils and risk of lifestyle diseases. Advances in Nutrition. 2020; 11 (6):1489-1509. DOI: 10.1093/advances/nmaa072 - 106.
Harris WS, Mozaffarian D, Rimm E, Kris-Etherton P, Rudel LL, Appel LJ, et al. Omega-6 fatty acids and risk for cardiovascular disease: A science advisory from the American Heart Association nutrition subcommittee of the council on nutrition, physical activity, and metabolism; council on cardiovascular nursing; and council on epidemiology and prevention. Circulation. 2009; 119 (6):902-907. DOI: 10.1161/CIRCULATIONAHA.108.191627 - 107.
Food and Nutrition Board, Institute of Medicine. Dietary Reference Intake for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein and Amino Acid (Micronutrients). National Academy of Sciences, Washington DC; 2002 - 108.
Parker G, Gibson NA, Brotchie H, Heruc G, Rees AM, Hadzi-Pavlovic D. Omega-3 fatty acids and mood disorders. The American Journal of Psychiatry. 2006; 163 (6):969-978. DOI: 10.1176/ajp.2006.163.6.969 - 109.
Dyall SC. Long-chain omega-3 fatty acids and the brain: A review of the independent and shared effects of EPA, DPA and DHA. Frontiers in Aging Neuroscience. 2015; 7 :52. DOI: doi.org/10.3389/fnagi.2015.00052 - 110.
Kaur G et al. Docosapentaenoic acid (22:5n-3): A review of its biological effects. Progress in Lipid Research. 2011; 50 :28-34. DOI: 10.1016/j.plipres.2010.07.004 - 111.
De Caterina R. n-3 fatty acids in cardiovascular disease. The New England Journal of Medicine. 2011; 364 (25):2439-2450. DOI: 10.1056/NEJMra1008153 - 112.
Hussein N, Ah-Sing E, Wilkinson P, Leach C, Griffin BA, Millward DJ. Long-chain conversion of [13C]linoleic acid and alpha-linolenic acid in response to marked changes in their dietary intake in men. Journal of Lipid Research. 2005; 46 (2):269-280. DOI: 10.1194/jlr.M400225-JLR200 - 113.
Kalmijn S, van Boxtel MPJ, Ocké M, Verschuren WMM, Kromhout D, Launer LJ. Dietary intake of fatty acids and fish in relation to cognitive performance at middle age. Neurology. 2004; 62 (2):275-280. DOI: 10.1212/01.wnl.0000103860.75218.a5 - 114.
Brenna JT, Diau G-Y. The influence of dietary docosahexaenoic acid and arachidonic acid on central nervous system polyunsaturated fatty acid composition. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2007; 77 (5-6):247-250. DOI: 10.1016/j.plefa.2007.10.016 - 115.
Rapaport SI, Rao JS, Igarashi M. Brain metabolism of nutritionally essential polyunsaturated fatty acids depends on both the diet and the liver. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2007; 77 :251-261. DOI: 10.1016/j.plefa.2007.10.023 - 116.
Aryal S, Hussain S, Drevon CA, Nagelhus E, Hvalby Ø, Jensen V, et al. Omega-3 fatty acids regulate plasticity in distinct hippocampal glutamatergic synapses. The European Journal of Neuroscience. 2019; 49 :40-50. DOI: 10.111/ejn.14224 - 117.
Yamashima T. Dual effects of the non-esterified fatty acid receptor 'GPR40' for human health. Progress in Lipid Research. 2015; 58 :40-50. DOI: 10.1016/j.plipres.2015.01.002 - 118.
Neugebauer R, Hoek HW, Susser E. Prenatal exposure to wartime famine and development of antisocial personality disorder in early adulthood. JAMA. 1999; 282 (5):455-462. DOI: 10.1001/jama.282.5.455 - 119.
Liu J, Raine A, Venables PH, Mednick SA. Malnutrition at age 3 years and externalizing behavior problems at ages 8, 11, and 17 years. American Journal of Psychiatry. 2004; 161 (11):2005-2013. DOI: 10.1176/appi.ajp.161.11.2005 - 120.
Moreira JD, Knorr L, Ganzella M, Thomazi AP, de Souza CG, de Souza DG, et al. Omega-3 fatty acids deprivation affects ontogeny of glutamatergic synapses in rats: Relevance for behavior alterations. N eurochemistry International . 2010;56 (6-7):753-759. DOI: 10.1016/j.neuint.2010.02.010 - 121.
Hibbeln JR. Seafood consumption and homicide mortality. A cross-national ecological analysis. World Review of Nutrition and Dietetics. 2001; 88 :41-46. DOI: 10.1159/000059747 - 122.
Iribarren C, Markovitz JH, Jacobs DR Jr, Schreiner PJ, Davilgus M, Hibbeln JR. Dietary intake of n-3, n-6 fatty acids and fish: Relationship with hostility in young adults—The CARDIA study. European Journal of Clinical Nutrition. 2004; 58 :24-31. DOI: 10.1038/sj.ejcn.1601739 - 123.
Hibbeln JR, Davis JM, Steer C, Emmett P, Rogers R, Williams C, et al. Maternal seafood consumption in pregnancy and neurodevelopmental outcomes in childhood (ALSPAC study): An observational cohort study. Lancet. 2007; 17 (369):578-585. DOI: 10.1016/S0140-6736(07)60277-3 - 124.
Zaalberg A, Nijman H, Bulten E, Stroosma L, van der Staak C. Effects of nutritional supplements on aggression, rule-breaking, and psychopathology among young adult prisoners. Aggressive Behavior. 2010; 36 (2):117-126. DOI: 10.1002/ab.20335 - 125.
Long S-J, Benton D. Effects of vitamin and mineral supplementation on stress, mild psychiatric symptoms, and mood in nonclinical samples: A meta-analysis. Psychosomatic Medicine. 2013; 75 (2):144-153. DOI: 10.1097/PSY.0b013e31827d5fbd - 126.
Raine A, Portnoy J, Liu J, Mahoomed T, Hibbeln J. Reduction in behavior problems with omega-3 supplementation in children aged 8-16 years: A randomized, double-blind, placebo-controlled, stratified, parallel-group trial. Journal of Child Psychology and Psychiatry. 2015; 56 (5):509-520. DOI: 10.1111/j.jcpp.12314 - 127.
Bègue L, Zaalberg A, Shankland R, Duke A, Jacquet J, Kaliman P, et al. Omega-3 supplements reduce self-reported physical aggression in healthy adults. Psychiatry Research. 2018; 261 :307-311. DOI: 10.1016/j.psychres.2017.12.038 - 128.
Wohleb ES, Franklin T, Iwata M, Duman RS. Integrating neuroimmune systems in the neurobiology of depression. Nature Reviews. Neuroscience. 2016; 17 (8):497-511. DOI: 10.1038/nrn.2016.69 - 129.
Santello M, Volterra A. TNFα in synaptic function: Switching gears. Trends in Neurosciences. 2012; 35 :638-647. DOI: 10.1016/j.tins.2012.06.001 - 130.
Iwata M, Ota KT, Li X-Y, Sakaue F, Li N, Dutheil S, et al. Psychological stress activates the inflammasome via release of adenosine triphosphate and stimulation of the purinergic type 2X7 receptor. Biological Psychiatry. 2016; 80 (1):12-22. DOI: 10.1016/j.biopsych.2015.11.026 - 131.
Kipnis J, Gadani S, Derecki NC. Pro-cognitive properties of T cells. Nature Reviews. Immunology. 2012; 12 (9):663-669. DOI: 10.1038/nri3280 - 132.
Arisi GM. Nervous and immune systems signals and connections: Cytokines in hippocampus physiology and pathology. Epilepsy & Behavior. 2014; 38 :43-47. DOI: 10.1016/j.yebeh.2014.01.017 - 133.
Coccaro EF, Lee R, Fanning JR, Fuchs D, Goiny M, Erhardt S, et al. Tryptophan, kynurenine, and kynurenine metabolites: Relationship to lifetime aggression and inflammatory markers in human subjects. Psychoneuroendocrinology. 2016; 71 :189-196. DOI: 10.1016/j.psyneuen.2016.04.02 - 134.
Gorlova A, Pavlov D, Anthony DC, Ponomarev ED, Sambon M, Proshin A, et al. Thiamine and benfotiamine counteract ultrasound-induced aggression, normalize AMPA receptor expression and plasticity markers, and reduce oxidative stress in mice. Neuropharmacology. 2019; 156 :107543. DOI: 10.1016/j.neuropharm.2019.02.025 - 135.
Mentesana L, Adreani NM. Is aggression costly? Acute aggressive behavior perturbates the oxidative status of a wild bird independently of testosterone and progesterone. Hormones and Behavior. 2021: 128 :104913. 10.1016/j.yhbeh.2020.104913 - 136.
Whelan J. (n-6) and (n-3) polyunsaturated fatty acids and the aging brain: Food for thought. The Journal of Nutrition. 2008; 138 (12):2521-2522. DOI: 10.3945/jn.108.095943 - 137.
Brown AJ, Pang E, Roberts DC. Erythrocyte eicosapentaenoic acid versus docosahexaenoic acid as a marker for fish and fish oil consumption. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 1991; 44 (2):103-106. DOI: 10.1016/0952-3278(91)90191-7 - 138.
Chouinard-Watkins R, Plourde M. Fatty acid metabolism in carriers of apolipoprotein E epsilon 4 allele: Is it contributing to higher risk of cognitive decline and coronary heart disease? Nutrients. 2014; 6 (10):4452-4471. DOI: 10.3390/nu6104452 - 139.
Metherel AH, Armstrong JM, Patterson AC, Stark KD. Assessment of blood measures of n-3 polyunsaturated fatty acids with acute fish oil supplementation and washout in men and women. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2009; 81 (1):23-29. DOI: 10.1016/j.plefa.2009.05.018 - 140.
Nording ML, Yang J, Georgi K, Karbowski CH, German JB, Weiss RH, et al. Individual variation in lipidomic profiles of healthy subjects in response to omega-3 fatty acids. PLoS One. 2013; 8 (10):e76575. DOI: 10.1371/journal.pone.0076575 - 141.
Brenna JT, Salem N Jr, Sinclair AJ, Cunnane SC. Alpha-linolenic acid supplementation and conversion to n-3 long-chain polyunsaturated fatty acids in humans. International Society for the Study of Fatty Acids and Lipids, ISSFAL. Prostaglandins, Leukotrienes, and Essential Fatty Acids. 2009; 80 (2-3):85-91 - 142.
Virkkunen M, Nuutila A, Goodwin FK, Linnoila M. Cerebrospinal fluid monoamine metabolite levels in male arsonists. Archives of General Psychiatry. 1987; 44 (3):241-247. DOI: 10.1001/archpsyc.1987.01800150053007 - 143.
Meyer BJ, Byrne MK, Collier C, Parletta N, Crawford D, Winberg PC, et al. Baseline omega-3 index correlates with aggressive and attention deficit disorder behaviours in adult prisoners. PLoS One. 2015; 10 (3):e0120220. DOI: 10.1371/journal.pone.0120220 - 144.
Cortie CH, Byrne MK, Collier C, Parletta N, Crawford D, Winberg PC, et al. The effect of dietary supplementation on aggressive behaviour in Australian adult male prisoners: A feasibility and pilot study for a randomised, double blind placebo controlled trial. Nutrients. 2020; 12 (9):2617èè. DOI: 10.3390/nu12092617 - 145.
Swierk M, Williams PG, Wilcox J, Russell KG, Meyer BJ. Validation of an Australian electronic food frequency questionnaire to measure polyunsaturated fatty acid intake. Nutrition. 2011; 27 (6):641-646. DOI: 10.1016/j.nut.2010.06.011 - 146.
Harris WS, Von Schacky C. The omega-3 index: A new risk factor for death from coronary heart disease? Preventive Medicine. 2004; 39 (1):212-220. DOI: 10.1016/j.ypmed.2004.02.030 - 147.
Walker RE, Jackson KH, Tintle NL, Shearer GC, Bernasconi A, Masson S, et al. Predicting the effects of supplemental EPA and DHA on the omega-3 index. The American Journal of Clinical Nutrition. 2019; 110 (4):1034-1040. DOI: 10.1093/ajcn/nqz161 - 148.
Garda HA, Bernasconi AM, Brenner RR. Possible compensation of structural and viscotropic properties in hepatic microsomes and erythrocyte membranes of rats with essential fatty acid deficiency. Journal of Lipid Research. 1994; 35 (8):1367-1377 Accession Number: 7989861 - 149.
Pascut D, Pratama MY, Vo NVT, Masadah R, Tiribelli C. The crosstalk between tumor cells and the microenvironment in hepatocellular carcinoma: The role of exosomal microRNAs and their clinical implications. Cancers (Basel). 2020; 12 (4). DOI: 10.3390/cancers12040823 - 150.
Salvador AF, de Lima KA, Kipnis J. Neuromodulation by the immune system: A focus on cytokines. Nature Reviews. Immunology. 2021; 21 (8):526-541. DOI: 10.1038/s41577-021-00508-z - 151.
Koren T, Yifa R, Amer M, Krot M, Boshnak N, Ben-Shaanan TL, et al. Insular cortex neurons encode and retrieve specific immune responses. Cell. 2021; 184 (25):6211. DOI: 10.1016/j.cell.2021.11.021 - 152.
Klin Y, Zlotnik A, Boyko M, Ohayon S, Shapira Y, Teichberg VI. Distribution of radiolabeled l-glutamate and d-aspartate from blood into peripheral tissues in naive rats: Significance for brain neuroprotection. Biochemical and Biophysical Research Communications. 2010; 399 (4):694-698. DOI: 10.1016/j.bbrc.2010.07.144 - 153.
Smith QR. Transport of glutamate and other amino acids at the blood-brain barrier. The Journal of Nutrition. 2000; 130 (4S):1016S-1022S. DOI: 10.1093/jn/130.4.1016S - 154.
Mayhan WG, Didion SP. Effect of chronic alcohol consumption on responses of cerebral arterioles. Alcoholism Clinical and Experimental Research. 1996; 20 (3):538-542. DOI: 10.1111/j.1530-0277.1996.tb01089.x - 155.
Bai W, Zhou Y-G. Homeostasis of the intraparenchymal-blood glutamate concentration gradient: Maintenance, imbalance, and regulation. Frontiers in Molecular Neuroscience. 2017; 10 :400. DOI: 10.3389/fnmol.2017.00400 - 156.
Profaci CP, Munji RN, Pulido RS, Daneman R. The blood-brain barrier in health and disease: Important unanswered questions. The Journal of Experimental Medicine. 2020; 217 (4). DOI: 10.1084/jem.20190062 - 157.
Al-Sarraf H, Philip L. Effect of hypertension on the integrity of blood brain and blood CSF barriers, cerebral blood flow and CSF secretion in the rat. Brain Research. 2003; 975 :179-188. DOI: 10.1016/S0006-8993(03)02632-5 - 158.
Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI. Invest blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. New Drugs. 2012; 30 (6):2226-2235. DOI: 10.1007/s10637-012-9799-5 - 159.
Gruenbaum BF, Zlotnik A, Frenkel A, Fleidervish I, Boyko M. Glutamate efflux across the blood-brain barrier: New perspectives on the relationship between depression and the glutamatergic system. Metabolites. 2022; 12 (459):1-15. DOI: 10.3390/metabo12050459 - 160.
Sugahara H. Physiological rationale of aggressive behavior: A brain blood perfusion hypothesis. Medical Hypotheses. 2001; 57 (6):745-749. DOI: 10.1054/mehy.2001.1479 - 161.
Kealy J, Greene C, Campbell M. Blood-brain barrier regulation in psychiatric disorders. Neuroscience Letters. 2020; 726 :133664. DOI: 10.1016/j.neulet.2018.06.033 - 162.
Tully L, Humiston J, Cash A. Oxaloacetate reduces emotional symptoms in premenstrual syndrome (PMS): results of a placebo-controlled, cross-over clinical trial. Obstetrics & Gynecology Science. 2020; 63 (2):195-204. DOI: 10.5468/ogs.2020.63.2.195 - 163.
Lipton A, Singel DJ, Stamler JS. Neuroprotective and neurodestructive effects of nitric oxide and redox congeners. Annals of the New York Academy of Sciences. 1994; 738 :382-387. DOI: 10.1111/j.1749-6632.1994.tb21826.x - 164.
Szatkowski M, Barbour B, Attwell D. Non-vesicular release of glutamate from glial cells by reversed electrogenic glutamate uptake. Nature. 1990; 348 (6300):443-446. DOI: 10.1038/348443a0 - 165.
D'Eufemia P, Finocciaro R, Lendvai D, Celli M, Viozzi L, Troiani P, et al. Erythrocyte and plasma levels of glutamate and aspartate in children affected by migraine. Cephalalgia. 1997; 6 :652-657. DOI: 10.1046/j.1468-2982.1997.1706652.x - 166.
Cananzi AR, D'Andrea G, Perini F, Zamberlan F, Welch KM. Platelet and plasma levels of glutamate and glutamine in migraine with and without aura. Cephalalgia. 1995; 15 (2):132-135. DOI: 10.1046/j.1468-2982.1995.015002132.x - 167.
Pal MM. Glutamate: The master neurotransmitter and its implications in chronic stress and mood disorders. Frontiers in Human Neuroscience. 2021: 15 :722323. DOI: 10.3389/fnhum.2021.722323 - 168.
Henry-Unaeze HN. Update on food safety of monosodium L-glutamate (MSG). Pathophysiology. 2017; 24 (4):243-249. DOI: 10.1016/j.pathophys.2017.08.001 - 169.
Zlotnik A, Ohayon S, Gruenbaum BF, Gruenbaum SE, Mohar B, Boyko M, et al. Determination of factors affecting glutamate concentrations in the whole blood of healthy human volunteers. Journal of Neurosurgical Anesthesiology. 2011; 23 (1):45-49. DOI: 10.1097/ANA.0b013e3181f82a8f - 170.
Boyko M, Kuts R, Gruenbaum BF, Melamed I, Gruenbaum S, Klein M, et al. The role of hypothermia in the regulation of blood glutamate levels in naive rats. Journal of Neurosurgical Anesthesiology. 2013; 25 (2). DOI: 10.1097/ANA.0b013e31827ee0ac - 171.
Hanigan M, Calvert C, DePeters EJ, Reis BL, Baldwin RL. Whole blood and plasma amino acid uptakes by lactating bovine mammary glands. Journal of Dairy Science; 74 (8):2484-2490. DOI: 10.3168/jds.S0022-0302(91)78425-7 - 172.
Hawkins RA, Viña JR. How glutamate is managed by the blood–brain barrier. Biology. 2016; 5 :37. DOI: 10.3390/biology5040037 - 173.
Hagenfeldt L, Arvidsson A. The distribution of amino acids between plasma and erythrocytes. Clinica Chimica Acta. 1980; 100 (2):133-141. DOI: 10.1016/0009-8981(80)90074-1 - 174.
Hashimoto K. Inflammatory biomarkers as differential predictors of antidepressant response. International Journal of Molecular Sciences. 2015; 16 (4):7796-7801. DOI: 10.3390/ijms16047796 - 175.
Haroon E, Felger JC, Woolwine B, Chen X, Parekh S, James S, et al. Age-related increases in basal ganglia glutamate are associated with TNF-alpha, reduced motivation and decreased psychomotor speed during IFN-alpha treatment: Preliminary findings. Brain Behavior and Immunity. 2014; 46 :17-22. DOI: 10.1016/j.bbi.2014.12.004 - 176.
Haroon E, Fleischer CC, Felger JC, Chen X, Woolwine BJ, Patel T, et al. Conceptual convergence: Increased inflammation is associated with increased basal ganglia glutamate in patients with major depression. Molecular Psychiatry. 2016; 21 (10):1351-1357. DOI: 10.1038/mp.2015.206 - 177.
Miller AH, Raison CL. The role of inflammation in depression: From evolutionary imperative to modern treatment target. Nature Reviews Immunology. 2016; 16 (1):22-34. DOI: 10.1038/nri.2015.5