Next Article in Journal
Current Status and Future Perspectives of Genomics Research in the Rust Fungi
Next Article in Special Issue
Saffron Extract Attenuates Anxiogenic Effect and Improves Cognitive Behavior in an Adult Zebrafish Model of Traumatic Brain Injury
Previous Article in Journal
Metal Ion Periplasmic-Binding Protein YfeA of Glaesserella parasuis Induces the Secretion of Pro-Inflammatory Cytokines of Macrophages via MAPK and NF-κB Signaling through TLR2 and TLR4
Previous Article in Special Issue
Characterization of Calpain and Caspase-6-Generated Glial Fibrillary Acidic Protein Breakdown Products Following Traumatic Brain Injury and Astroglial Cell Injury
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 23
Issue 17
10.3390/ijms23179628
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

by
Benjamin F. Gruenbaum
1,†,
Alexander Zlotnik
2,†,
Ilya Fleidervish
3,
Amit Frenkel
2 and
Matthew Boyko
2,*
1
Department of Anesthesiology and Perioperative Medicine, Mayo Clinic, Jacksonville, FL 32224, USA
2
Department of Anesthesiology and Critical Care, Soroka University Medical Center, Ben-Gurion of the Negev, Beer-Sheva 84105, Israel
3
Department of Physiology and Cell Biology, Faculty of Health Sciences and Zlotowski Center for Neuroscience, Ben-Gurion University of the Negev, Beer-Sheva 84105, Israel
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2022, 23(17), 9628; https://doi.org/10.3390/ijms23179628
Submission received: 26 July 2022 / Revised: 17 August 2022 / Accepted: 22 August 2022 / Published: 25 August 2022
(This article belongs to the Special Issue Neuropathology and Cellular Mechanisms in Traumatic Brain Injury)
Browse Figure
Versions Notes

Abstract

:
Traumatic brain injury (TBI) is associated with significant cognitive and psychiatric conditions. Neuropsychiatric symptoms can persist for years following brain injury, causing major disruptions in patients’ lives. In this review, we examine the role of glutamate as an aftereffect of TBI that contributes to the development of neuropsychiatric conditions. We hypothesize that TBI causes long-term blood–brain barrier (BBB) dysfunction lasting many years and even decades. We propose that dysfunction in the BBB is the central factor that modulates increased glutamate after TBI and ultimately leads to neurodegenerative processes and subsequent manifestation of neuropsychiatric conditions. Here, we have identified factors that determine the upper and lower levels of glutamate concentration in the brain after TBI. Furthermore, we consider treatments of disruptions to BBB integrity, including repairing the BBB and controlling excess glutamate, as potential therapeutic modalities for the treatment of acute and chronic neuropsychiatric conditions and symptoms. By specifically focusing on the BBB, we hypothesize that restoring BBB integrity will alleviate neurotoxicity and related neurological sequelae.

1. Introduction

Traumatic brain injury (TBI) has long-term cognitive and psychiatric effects, including depression, anxiety, and aggression. While the condition’s psychiatric symptoms may at first be attributable to the emotional burdens of TBI-related physical disability, it has been established that neuropsychiatric symptoms, such as memory and cognitive impairment, anxiety, depression, social withdrawal, or aggression [1,2,3], can persist for decades [4,5] after the initial brain injury. These symptoms can delay rehabilitation and a return to employment [6]. The associated psychiatric symptoms are not correlated with severity of the initial injury or with pain [7,8,9].
An association between TBI and the development of a wide range of neuropsychiatric diseases has been well established [1,2,3,10,11]. A possible explanation for the increase in the incidence of neuropsychiatric illness after TBI lies in the general mechanisms underlying the development of these diseases. However, to date, there is no unified theory that explains this phenomenon. In this review, we hypothesize that long-term dysregulation of glutamate as a result of TBI, modulated by variability in blood–brain barrier (BBB) permeability, causes a process of neurodegeneration, which ultimately leads to the development of neuropsychiatric consequences of TBI. Here, we detail the proposed pathways of the process and provide evidence for this hypothesized relationship.

2. Pharmacological Basis of Dementia, Anxiety, and Mood Disorders: The Role of Glutamate

The relationship between depression, anxiety, dementia, aggression, and glutamate [12,13,14] is well studied and documented in the scientific literature [3,15,16]. Traditionally, anxiety and mood disorders are treated with medications that act primarily on monoamines [17], benzodiazepines [18,19], or cannabidiol [20]; however, there is a burgeoning interest in the role of the major excitatory neurotransmitter glutamate in the etiology and treatment of anxiety [13,21,22,23], mood disorders, and disorders of social behavior and aggression [24]. Medications that attenuate glutamate release or block N-methyl-D-aspartate (NMDA) receptors [21,24,25,26] are used to treat anxiety disorders. Glutamate is the major excitatory neurotransmitter in the brain, essential for long-term potentiation and mediating long-term depression, and provides the molecular and cellular mechanisms of learning [27,28,29]. Poor long-term cognitive evaluation in patients with TBI was correlated with higher levels of brain glutamate recorded one week [30] and one month after the injury [31], confirming the link between glutamate excess and deficits in higher cognitive function. Glutamate excess following loss of neurons and astrocytes is common in stroke, dementia, and neurogenerative diseases, and after injury such as TBI [32,33].

3. TBI and Glutamate Dysregulation

Glutamate is the most abundant free amino acid in the brain [34]. Glutamate concentrations in the plasma and whole blood are 50–100 μM/L and 150–300 μM/L, respectively [12]; in the whole brain, they are 10,000–12,000 μM/kg [35], but they are only 1–10 μM/L in extracellular fluids (ECF) [12]. The gradient between brain cells, blood, and ECF is maintained by facilitative and active transport systems of the BBB [35]. A healthy BBB effectively prevents glutamate from moving between the intraparenchymal and blood compartments [36]. There are a number of mechanisms that cause an increase in brain glutamate associated with TBI: (i) neuronal death [37]; (ii) inflammation [38,39,40,41,42]; (iii) impaired glutamatergic recycling and signaling [43]; (iv) prolonged stress [29]; (v) astrocytic release of adenosine triphosphate (ATP) [44]; and (vi) other sources of elevated intraparenchymal glutamate [36,45]. Above all, however, we find the mechanisms of BBB destruction to be a significant factor in increased brain glutamate and its association with TBI [35].

3.1. The Mechanisms of Increase in Brain Glutamate Is Associated with Neuronal Death

The well-known process of neuronal death, which begins in the first minutes after a traumatic brain injury, can potentially lead to an increase in the glutamate levels in cerebrospinal fluid (CSF) and extracellular fluid (ECF) of the brain to the levels of glutamate in the whole brain, up to 10,000–12,000 µM/kg [12]. However, in practice, such high levels of glutamate in CSF and ECF of the brain do not occur, and glutamate concentrations are usually limited to about 20–50 µM/L [46,47,48,49,50]. The explanation for this phenomenon is that even with the complete destruction of the BBB, concentrations of glutamate in the CSF and ECF of the brain cannot exceed the concentration of plasma glutamate, which is approximately 50–100 µM/L [12]. Plasma effectively clears out excess glutamate, sending it into other organs and even red blood cells. Due to this process, a concentration of glutamate at 100 µM/L, at the upper level of plasma concentration, is the maximum that can be recorded in the CSF and ECF of the brain. Rare exceptions may occur when whole blood is included in CSF collection.
However, the concentration of glutamate can reach 150–300 µM/L at the expense of red blood cells, since whole blood contains higher levels of glutamate. However, in most cases, the functionality of the BBB is not completely lost. Consequently, the concentration of glutamate that appears after partial destruction of the BBB will be lower than the concentration of plasma glutamate (50 µM/L). The concentration of glutamate in the brain, CSF, and ECF depends on the degree of BBB damage as its determining factor.
As established above, the process of neuronal death provides an explanation for elevated levels of glutamate in the ECF and CSF of the brain shortly after TBI (from the first minutes to the first week). The initial impact from TBI leads directly to cell necrosis from the impact, exacerbated by ischemia, hypoxia, axonal shearing, and gliosis [51,52,53]. Neuronal damage occurs with a massive influx of calcium, which subsequently causes over-excitation and additional release of glutamate [54,55]. This process begins immediately, in the first minutes after injury, and is characterized by significant neuronal death followed by the release of glutamate into the ECF. Cell death lasts up to several hours or days [56,57,58,59], depending on the volume of brain destruction and on the size and duration of cerebral edema and penumbra. This process, however, clearly does not fully account for the occurrence of neuropsychiatric consequences after TBI that manifest themselves months, years, and even decades after the head injury.

3.2. The Mechanism of Increase in Brain Glutamate Is Associated with Inflammation [42]

Cell death in TBI patients leads to inflammation in the injured brain (focal brain inflammation), which secondarily causes brain injury through brain edema and neuronal death, even as it binds the damaged limitans and removes cellular debris. However, brain inflammation can also disseminate to other areas of the brain beyond the injured part [42]. Inflammation through glutamate alterations may also be a cause of mood disorders, as patients with mood disorders have been observed to have increased inflammation [38]. Inflammation and alterations in glutamate neurotransmission at the level of the glia increases glutamate and disrupts extrasynaptic signaling. Glutamate diffusion outside the synapse can produce lost synaptic fidelity and specificity of neurotransmission that leads to circuit dysfunction and behavioral pathology [60]. It has also been suggested that inflammation may have an impact on altering behavior of glutamate metabolism, which can cause depressive symptoms such as anhedonia and psychomotor slowing [38].
However, inflammation cannot be the only explanation for psychiatric symptoms following brain injury. If inflammation was closely associated with those symptoms, then conditions with significant neuroinflammation and stress, such as encephalitis, meningitis, and sepsis, would also present with associated neuropsychiatric diseases such as depression, anxiety, aggression, and dementia to a similar degree as after TBI. However, studies show little if any association between those conditions of neuroinflammation and neuropsychiatric disease or show the presence of neuropsychiatric diseases that are secondary to the neuroinflammation itself [61,62].

3.3. The Mechanism of Increases in Brain Glutamate Is Associated with Impaired Glutamatergic Recycling and Signaling

Disruption in brain glutamate impairs glutamatergic recycling and signaling [63]. In neurodegenerative diseases, such as Alzheimer’s disease, the system of glutamate recycling is significantly impaired [43,64].

3.4. The Mechanism of Increase in Brain Glutamate Is Associated with Prolonged Stress

Glutamate neurotransmission, through its mediation of mood function and stress responses in the brain, has a relationship with the physical biochemical connections of stress and depression [29].
The relationship between increased brain glutamate and stress has also been studied. In one study of induced panic in healthy subjects, a significant rise in brain glutamate was observed in the anterior cingulate cortex [65]. Some studies, however, have shown only a slight correlation between increased glutamate and stress [66] or none at all [67].

3.5. The Mechanism of Increase in Brain Glutamate Is Associated with Astrocytic Release of ATP [44]

Astrocytes release ATP, which prompts signaling between neurons and Schwann cells in the peripheral nervous system. When it results from neuronal activity, released ATP can also modulate central synaptic transmission. Glutamate release that occurs during neuronal activity also initiates non-NMDA receptors of astrocytes and ATP release from them, which causes homosynaptic and heterosynaptic suppression. Glutamate, then, may play a role in synaptic modulation [68].

3.6. The Mechanism of Increase in Brain Glutamate Is Associated with Other Sources of Elevated Intraparenchymal Glutamate

The intraparenchymal–blood glutamate concentration gradient is governed by normal baseline levels of glutamate in the blood and in the CSF. The difference between these concentrations is close to 50 μM, a level that creates a normal intraparenchymal concentration gradient. The integrity of the BBB preserves this gradient, and alterations in BBB integrity disrupt it. As a result of a variety of brain diseases, including both acute brain injury and chronic disease, increased glutamate levels in the blood and CSF lead to disruptions in the intraparenchymal–blood concentration gradient via compromised BBB integrity [36]. Thus, there are a number of mechanisms that can cause an increase in glutamate in brain tissue. However, with a healthy BBB and well-functioning brain glutamate active transport systems, the brain is able to quickly clear excess glutamate from the brain into the plasma and maintain physiologically low levels of glutamate.

4. Disruption of the BBB

A critical process that can induce an increase in brain glutamate in the CSF and ECF is a disruption of the BBB. The destruction of the BBB after brain injury is described as biphasic [69]. The peak of the first phase occurs 5 h after the injury [69], and the second phase peaks in rats after 72 h [70,71,72] and in humans on day 3 [73,74,75] after injury. Recent data show that recovery of the integrity of the BBB in rats can take 1–3 months [76] or even up to 10 months [77], and up to many years after the brain injury in humans [78,79,80]. It is known that damage to the BBB impedes thorough clearance of cerebral glutamate from ECF into the bloodstream, in which excitatory amino acid transporters (EAAT) on endothelial cells underlie the mechanisms for modulating the intraparenchymal–blood glutamate concentration gradient [36].
The integrity of the BBB is a natural limiter of the pathological increase in the levels of ECF/CSF glutamate in the phase of neuronal death and plays a key role in setting the upper level of the concentration of ECF/CSF glutamate in the brain after TBI. However, this is only one aspect of the process. It is the integrity of the BBB that also controls the lower level of the brain glutamate level in all phases of both the healthy and the affected brain after TBI.
In a healthy brain with stable BBB integrity, control of low glutamate levels is maintained by facilitative and active transport systems of the BBB that efficiently remove glutamate from the brain into the blood [81]. When the BBB is destroyed, these systems cannot effectively remove glutamate from the CSF and ECF into the blood and cannot balance its concentration with the blood. Previously, it was believed that the BBB is restored a short time after TBI and after a week its integrity does not significantly differ from those of the control groups without TBI [82]. However, recent data show that disruption of the BBB does not recover within hours, days, or even weeks but continues for many months, years, and even decades after TBI [78,79,80]. Newly developed, highly sensitive methods for determining BBB permeability based on molecular complexes with a molecular size starting from 103 Da [83] register the difference between the control and TBI groups in human and rat populations months and even years after TBI [78,79,80]. These methods are more sensitive and accurate than previous methods to measure BBB permeability, such as with Evans Blue staining, which may explain why a theory of long-term (chronic) glutamate neurotoxicity had not developed until recently [77,78].
Despite a high correlation of sensitivity between nervous tissue and high concentrations of glutamate, studies suggest that a prolonged increase of even 10% of extracellular brain glutamate (considered glutamate neurotoxicity) may induce neurodegenerative processes [12].
Other processes described above are well documented in the scientific literature and can also increase glutamate levels both locally in brain tissue and in CSF. However, it is the degree of integrity of the BBB that is the key factor controlling the range of glutamate concentration in both healthy and damaged brains. Thus, for the first time, we hypothesize that it is the integrity of the BBB that is the key factor that modulates glutamate in CSF and ECF after brain damage and specifically after TBI, which, via high levels of glutamate, causes neurodegenerative processes which ultimately lead to mental disorders (Figure 1).

5. Glutamate Neurotoxicity and Its Association with Neurodegeneration

There is well-established evidence that shows a relationship between glutamate neurotoxicity and neurodegeneration [29]. Glutamate excitotoxicity describes the process of excessive glutamate causing neuronal degeneration and dysfunction, resulting in neurotoxicity [29,84,85]. Its role in mood disorders has informed recent research into new therapeutic modalities, with drugs that target glutamatergic systems proposed as anti-depressants and related therapies [86,87,88].
Increased extracellular glutamate can prompt excitotoxicity, via overaction of ionotropic glutamate receptors, after acute brain insults such as ischemic stroke, cerebral ischemia, TBI, hypoglycemia, and epilepsy [85,89,90,91,92,93,94]. In addition to these acute conditions, a process of chronic glutamate neurotoxicity has also been suggested as a factor in many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer’s disease, and Huntington’s disease [92]. In these cases, it is possible that chronic excitotoxicity occurs in diseases where nerve cell death occurs over a longer period of time, in which neurons exposed to glutamate at higher-than-normal levels can gradually lead to cell death or impaired neuroplasticity [92]. We hypothesize that therapeutic modalities for these diseases may work by specifically restoring glutamatergic homeostasis through stimulating glutamate uptake and releasing extracellular glutamate. The process of glutamate neurotoxicity leading to neurodegeneration leads to new possibilities for treatments for acute and chronic neurological diseases that target the glutamatergic system.

6. New Treatment Strategies for Neuropsychiatric Consequences of TBI Associated with the Hypothesis of Impaired BBB Permeability and Brain–Blood Glutamate Equilibrium

Immediately following TBI, the concentration of cerebral glutamate increases, then decreases. However, it does not reduce to normal levels; excess levels can persist for months or years [74,75]. As noted above, an excess of glutamate in CSF and ECF over time causes neurodegenerative processes that ultimately lead to the development of neuropsychiatric pathology (Figure 1). Modulating excess glutamate, therefore, is a critical factor in limiting the spread of brain damage. According to our hypothesis, BBB permeability is a key factor controlling the upper and lower levels of CSF and ECF glutamate. Therefore, we propose two promising strategies to reduce the level of brain glutamate. The first strategy involves the treatment and reconstruction of the BBB. The goal of the second strategy is to reduce CSF and ECF glutamate levels by lowering plasma glutamate levels.

6.1. Treatment Aimed at Recovery of the Integrity of the BBB [95,96]

Treatments to restore BBB function and integrity consist of several approaches (Table 1) [95]. However, some treatments solely aimed at restoring the BBB have not been shown to be effective in treating neurodegenerative diseases [97,98]. Thus, this approach alone may be inadequate in treating symptoms of BBB dysfunction.

6.2. Reducing Post-Injury Glutamate Excess Based on Manipulation of Brain–Blood Glutamate Equilibrium

Excess brain glutamate can also be modulated by changing the brain–blood glutamate equilibrium and sending excess glutamate from the brain’s interstitial fluid (ISF) into the body’s circulatory system [99]. Glutamate transporters on the endothelial cells of brain capillaries enable extrusion of glutamate from ISF [37,100]. Synaptic glutamate receptors are not directly stimulated or impeded through this process, allowing mechanisms of learning to continue.
Treatments shown in a rat model to lessen the early neuroanatomical and neurological detriments caused by TBI include administration of the enzymes glutamic oxaloacetic transaminase (GOT), serum glutamic pyruvic transaminase (GPT), and their co-substrates oxaloacetic acid (OxAc) and pyruvate, which reduces excess brain glutamate by altering the balance between blood and brain glutamate [101,102,103]. This reduction in glutamate is referred to as blood glutamate scavenging (BGS).
It has been shown that low levels of GOT and GPT are associated with poor neurological outcomes following stroke, whereas high GOT and GPT levels correlate with a better neurological outcome [104,105]. The enzymes GOT and GPT use glutamate as a substrate and pyridoxal phosphate as a cofactor to reversibly convert glutamate into the inactive metabolite 2-ketoglutarate.
This process prompts blood glutamate levels to fall below basal levels, causing a much steeper gradient of glutamate levels between the ISF or CSF and blood. To attain an equilibrium again, glutamate is moved from the brain to the blood, thus reducing the high level of glutamate in the brain. As long as glutamate stays at a low level in the blood, this brain-to-blood efflux will continue. To maintain the proper functionality of GOT and GPT to convert glutamate into 2-ketoglutarate, their respective substrates OxAc and pyruvate must be administered at doses at least double their Km values. The conversion of glutamate to 2-ketoglutarate is reversible. Thus, upon glutamate transformation via an enzymatic reaction into 2-ketoglutarate, there is an accrual of 2-ketoglutarate which can cause the enzyme to convert 2-ketoglutarate into glutamate. Thus, it is advantageous to break down 2-ketoglutarate fully to ensure the continual metabolism of glutamate. 2-ketoglutarate (with lipoamide) is reversibly metabolized by the enzyme 2-ketoglutarate dehydrogenase to S-succinyldihydrolipoamide and carbon dioxide [74]. The increased concentration gradient between blood and brain glutamate accelerates the efflux of glutamate from brain to plasma, thereby minimizing excitotoxicity caused by excess brain glutamate.
OxAc and pyruvate infusions reduce the severity of neurological deficits and symptoms of depression in rats after stroke [106] and traumatic injury in the brain [46]. The therapeutic effect of pyruvate on aggression and anxiety symptoms in a rat model of TBI has been observed in our laboratory (data yet to be published). The efflux of glutamate with pyruvate or OxAc is blocked by adding exogenous glutamate, demonstrating the dependence of the scavenging method on lowering blood glutamate [37,103]. GOT and GPT likely enhance the efflux of glutamate from the brain and blocking the function of GOT and GPT exacerbated the behavioral and morphological deficits following ischemia [107].
OxAC, pyruvate, GPT, and GOT have been proposed as treatments for TBI and stroke [46,106,108,109,110]. The safety of OxAc and pyruvate has been shown in elderly patients [111,112,113,114,115,116,117,118,119,120], and its potential in alleviating symptoms of anxiety, depression, suicidal ideation, and aggression in women with PMS was suggested in a clinical trial [121].
Table
Table 1. Treatments to restore blood–brain barrier function and integrity.
Table 1. Treatments to restore blood–brain barrier function and integrity.
InterventionDescription
Targeting paracellular permeability Targeting junction molecules (adherens junctions, tight junctions), or their regulators (microRNA, transcription factor) in order to limit or reverse paracellular permeability [95,122]. Examples include chelerythrine chloride [123].
Targeting transcellular permeabilityInhibition of transcytosis in brain endothelial cells, important to maintain neurological function and BBB integrity [95,124,125].
Restoring efflux transporter activityRestoring efflux transporter activity, such as ATP-binding cassette (ABC) transporters [95,126], important for clearing neurotoxins from the brain.
Repair of the neurovascular unitReestablishing normal function of the neurovascular unit (neurons, astrocytes, endothelial cells, pericytes, and the basal lamina), by restoring microvascular bed cerebral blood flow, limiting neuronal death, and promoting neurogenesis and angiogenesis [127]. Examples include bone-marrow-derived mesenchymal stem cells (MSCs) [128], pericytes [129,130], endothelial progenitor cells (EPCs) [131], neural and vascular progenitor cells [132,133], bone-marrow-derived macrophages [134], and vascular endothelial growth factor (VEGF) [135].
Targeting inflammationTargeting inflammation and downstream sequalae to restore the BBB. Examples include COX-2 inhibition [136], AQP4 inhibition [123], docosahexaenoic acid (DHA) [137], inhibition of Na-K-Cl cotransporter [138], and bone marrow mononuclear cells (MNCs) [139,140].
Matrix metalloproteinases (MMP)Limiting pathologically elevated MMP expression elevated after brain insult [127]. Examples include progesterone [141], TGF- β1 [142], exendin-4 [143], melatonin [144], regulatory T cells [145], EP1 antagonists [146], and minocycline [147].

7. Other Factors That Play a Role in the Pathophysiology of TBI

Although we propose in this paper that a disruption to BBB integrity is associated with neurological deterioration, other factors may also play a role. These factors include age at the time of injury, hormonal status, medical history, and environmental factors with an impact on general stress [148]. While a discussion of these other factors is beyond the scope of this manuscript, we anticipate future research will provide more information on the possibility of multifactorial pathophysiology of neuropsychological symptoms of brain injury.

8. Conclusions

There are several mechanisms that potentially influence an increase in brain glutamate associated with TBI: (i) neuronal death; (ii) destruction of the BBB; (iii) inflammation; (iv) impaired glutamatergic recycling and signaling; (v) prolonged stress; (vi) astrocytic release of ATP; and (vii) other sources of elevated intraparenchymal glutamate. These mechanisms start in the first minutes after brain injury and continue for many years and even decades after TBI.
Regardless of how much glutamate is released into the CSF and ECF compartment via the above mechanisms, BBB disruption is one component that determines the maximum levels of CSF and brain ECF glutamate. The degree of disruption of BBB integrity controls the glutamate range in both healthy and TBI brains based on two parameters: BBB permeability and the ability of facilitative and active transport systems to remove glutamate into the bloodstream.
Thus, we novelly hypothesize that it is the integrity of the BBB that is the key factor in the context of the control of glutamate in CSF and ECF after brain damage. Specifically, this occurs after TBI, in which neurotoxicity involving high levels of glutamate causes neurodegenerative processes which ultimately lead to mental disorders. Consequently, targeting reparation of BBB integrity through controlling increased glutamate may together have a significant impact on neuropsychological symptoms of acute and chronic brain conditions. We anticipate that future research will explore the role of the BBB as a central location for the development of neuropsychiatric consequences of TBI.

Author Contributions

All authors contributed to the conceptualization, investigation, writing, reviewing, and editing of this manuscript. All authors have read and agreed to the published version of the manuscript.

Funding

This research was partly supported by the ISRAEL SCIENCE FOUNDATION (grant No. 1490/15) awarded to Matthew Boyko and Alexander Zlotnik.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Jorge, R.E.; Arciniegas, D.B. Mood disorders after TBI. Psychiatr. Clin. N. Am. 2014, 37, 13–29. [Google Scholar] [CrossRef] [PubMed]
  2. Rauen, K.; Reichelt, L.; Probst, P.; Schapers, B.; Muller, F.; Jahn, K.; Plesnila, N. Quality of life up to 10 years after traumatic brain injury: A cross-sectional analysis. Health Qual. Life Outcomes 2020, 18, 166. [Google Scholar] [CrossRef] [PubMed]
  3. Tateno, A.; Jorge, R.E.; Robinson, R.G. Clinical correlates of aggressive behavior after traumatic brain injury. J. Neuropsychiatry Clin. Neurosci. 2003, 15, 155–160. [Google Scholar] [CrossRef]
  4. Hoofien, D.; Gilboa, A.; Vakil, E.; Donovick, P.J. Traumatic brain injury (TBI) 10–20 years later: A comprehensive outcome study of psychiatric symptomatology, cognitive abilities and psychosocial functioning. Brain Inj. 2001, 15, 189–209. [Google Scholar] [CrossRef] [PubMed]
  5. Koponen, S.; Taiminen, T.; Portin, R.; Himanen, L.; Isoniemi, H.; Heinonen, H.; Hinkka, S.; Tenovuo, O. Axis I and II psychiatric disorders after traumatic brain injury: A 30-year follow-up study. Am. J. Psychiatry 2002, 159, 1315–1321. [Google Scholar] [CrossRef]
  6. Rivara, F.P.; Koepsell, T.D.; Wang, J.; Temkin, N.; Dorsch, A.; Vavilala, M.S.; Durbin, D.; Jaffe, K.M. Disability 3, 12, and 24 months after traumatic brain injury among children and adolescents. Pediatrics 2011, 128, e1129–e1138. [Google Scholar] [CrossRef]
  7. Fehily, B.; Bartlett, C.A.; Lydiard, S.; Archer, M.; Milbourn, H.; Majimbi, M.; Hemmi, J.M.; Dunlop, S.A.; Yates, N.J.; Fitzgerald, M. Differential responses to increasing numbers of mild traumatic brain injury in a rodent closed-head injury model. J. Neurochem. 2019, 149, 660–678. [Google Scholar] [CrossRef]
  8. Orlovska, S.; Pedersen, M.S.; Benros, M.E.; Mortensen, P.B.; Agerbo, E.; Nordentoft, M. Head injury as risk factor for psychiatric disorders: A nationwide register-based follow-up study of 113,906 persons with head injury. Am. J. Psychiatry 2014, 171, 463–469. [Google Scholar] [CrossRef]
  9. Jorge, R.E.; Robinson, R.G.; Starkstein, S.E.; Arndt, S.V.; Forrester, A.W.; Geisler, F.H. Secondary mania following traumatic brain injury. Am. J. Psychiatry 1993, 150, 916–921. [Google Scholar] [CrossRef]
  10. McAllister, T.W. Neurobehavioral sequelae of traumatic brain injury: Evaluation and management. World Psychiatry 2008, 7, 3–10. [Google Scholar] [CrossRef] [Green Version]
  11. Hicks, A.J.; Clay, F.J.; Hopwood, M.; James, A.C.; Jayaram, M.; Perry, L.A.; Batty, R.; Ponsford, J.L. The Efficacy and Harms of Pharmacological Interventions for Aggression after Traumatic Brain Injury—Systematic Review. Front. Neurol. 2019, 10, 1169. [Google Scholar] [CrossRef] [PubMed]
  12. Gruenbaum, B.F.; 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. [Google Scholar] [CrossRef] [PubMed]
  13. Nasir, M.; Trujillo, D.; Levine, J.; Dwyer, J.B.; Rupp, Z.W.; Bloch, M.H. Glutamate systems in DSM-5 anxiety disorders: Their role and a review of glutamate and GABA psychopharmacology. Front. Psychiatry 2020, 11, 548505. [Google Scholar] [CrossRef] [PubMed]
  14. Benussi, A.; Alberici, A.; Buratti, E.; Ghidoni, R.; Gardoni, F.; Di Luca, M.; Padovani, A.; Borroni, B. Toward a glutamate hypothesis of frontotemporal dementia. Front. Neurosci. 2019, 13, 304. [Google Scholar] [CrossRef] [PubMed]
  15. Domitrovic Spudic, S.; Nikolac Perkovic, M.; Uzun, S.; Nedic Erjavec, G.; Kozumplik, O.; Svob Strac, D.; Mimica, N.; Pivac, N. Reduced plasma BDNF concentration and cognitive decline in veterans with PTSD. Psychiatry Res. 2022, 316, 114772. [Google Scholar] [CrossRef]
  16. Spinhoven, P.; Penninx, B.W.; van Hemert, A.M.; de Rooij, M.; Elzinga, B.M. Comorbidity of PTSD in anxiety and depressive disorders: Prevalence and shared risk factors. Child Abuse Negl. 2014, 38, 1320–1330. [Google Scholar] [CrossRef]
  17. Edition, F. Diagnostic and statistical manual of mental disorders. Am. Psychiatr. Assoc. 2013, 21, 591–643. [Google Scholar]
  18. Marks, D.M.; Park, M.H.; Ham, B.J.; Han, C.; Patkar, A.A.; Masand, P.S.; Pae, C.U. Paroxetine: Safety and tolerability issues. Expert Opin. Drug Saf. 2008, 7, 783–794. [Google Scholar] [CrossRef]
  19. Chouinard, G.; Annable, L.; Fontaine, R.; Solyom, L. Alprazolam in the treatment of generalized anxiety and panic disorders: A double-blind placebo-controlled study. Psychopharmacology 1982, 77, 229–233. [Google Scholar] [CrossRef]
  20. Blessing, E.M.; Steenkamp, M.M.; Manzanares, J.; Marmar, C.R. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics 2015, 12, 825–836. [Google Scholar] [CrossRef]
  21. Amiel, J.M.; Mathew, S.J. Glutamate and anxiety disorders. Curr. Psychiatry Rep. 2007, 9, 278–283. [Google Scholar] [CrossRef] [PubMed]
  22. Popoli, M.; Yan, Z.; McEwen, B.S.; Sanacora, G. The stressed synapse: The impact of stress and glucocorticoids on glutamate transmission. Nat. Rev. Neurosci. 2011, 13, 22–37. [Google Scholar] [CrossRef]
  23. Sanacora, G.; Zarate, C.A.; Krystal, J.H.; Manji, H.K. Targeting the glutamatergic system to develop novel, improved therapeutics for mood disorders. Nat. Rev. Drug Discov. 2008, 7, 426–437. [Google Scholar] [CrossRef]
  24. Zoicas, I.; Kornhuber, J. The role of the N-methyl-D-aspartate receptors in social behavior in rodents. Int. J. Mol. Sci. 2019, 20, 5599. [Google Scholar] [CrossRef] [PubMed]
  25. Bergink, V.; Van Megen, H.J.; Westenberg, H.G. Glutamate and anxiety. Eur. Neuropsychopharmacol. 2004, 14, 175–183. [Google Scholar] [CrossRef]
  26. Cortese, B.M.; Phan, K.L. The role of glutamate in anxiety and related disorders. CNS Spectr. 2005, 10, 820–830. [Google Scholar] [CrossRef] [PubMed]
  27. Maren, S. Synapse-Specific Encoding of Fear Memory in the Amygdala. Neuron 2017, 95, 988–990. [Google Scholar] [CrossRef]
  28. Pare, D. Presynaptic induction and expression of NMDA-dependent LTP. Trends Neurosci. 2004, 27, 440–441. [Google Scholar] [CrossRef]
  29. McGrath, T.; Baskerville, R.; Rogero, M.; Castell, L. Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases. Nutrients 2022, 14, 917. [Google Scholar] [CrossRef]
  30. Shutter, L.; Tong, K.A.; Holshouser, B.A. Proton MRS in acute traumatic brain injury: Role for glutamate/glutamine and choline for outcome prediction. J. Neurotrauma 2004, 21, 1693–1705. [Google Scholar] [CrossRef]
  31. Mao, Y.; Zhuang, Z.; Chen, Y.; Zhang, X.; Shen, Y.; Lin, G.; Wu, R. Imaging of glutamate in acute traumatic brain injury using chemical exchange saturation transfer. Quant. Imaging Med. Surg. 2019, 9, 1652–1663. [Google Scholar] [CrossRef] [PubMed]
  32. Yager, J.Y. Animal Models of Neurodevelopmental Disorders; Springer: Berlin/Heidelberg, Germany, 2015. [Google Scholar]
  33. Muir, K.W. Glutamate-based therapeutic approaches: Clinical trials with NMDA antagonists. Curr. Opin. Pharmacol. 2006, 6, 53–60. [Google Scholar] [CrossRef] [PubMed]
  34. Zhou, Y.; Danbolt, N.C. Glutamate as a neurotransmitter in the healthy brain. J. Neural Transm. 2014, 121, 799–817. [Google Scholar] [CrossRef] [PubMed]
  35. Hawkins, R.A.; Viña, J.R. How glutamate is managed by the blood–brain barrier. Biology 2016, 5, 37. [Google Scholar] [CrossRef]
  36. Bai, W.; Zhou, Y.G. Homeostasis of the Intraparenchymal-Blood Glutamate Concentration Gradient: Maintenance, Imbalance, and Regulation. Front. Mol. Neurosci. 2017, 10, 400. [Google Scholar] [CrossRef]
  37. Teichberg, V.I.; Cohen-Kashi-Malina, K.; Cooper, I.; Zlotnik, A. Homeostasis of glutamate in brain fluids: An accelerated brain-to-blood efflux of excess glutamate is produced by blood glutamate scavenging and offers protection from neuropathologies. Neuroscience 2009, 158, 301–308. [Google Scholar] [CrossRef]
  38. Haroon, E.; Miller, A.H. Inflammation effects on brain glutamate in depression: Mechanistic considerations and treatment implications. In Inflammation-Associated Depression: Evidence, Mechanisms and Implications; Springer: Berlin/Heidelberg, Germany, 2016; pp. 173–198. [Google Scholar]
  39. Haroon, E.; Chen, X.; Li, Z.; Patel, T.; Woolwine, B.J.; Hu, X.P.; Felger, J.C.; Miller, A.H. Increased inflammation and brain glutamate define a subtype of depression with decreased regional homogeneity, impaired network integrity, and anhedonia. Transl. Psychiatry 2018, 8, 189. [Google Scholar] [CrossRef]
  40. King, S.; Jelen, L.A.; Horne, C.M.; Cleare, A.; Pariante, C.M.; Young, A.H.; Stone, J.M. Inflammation, Glutamate, and Cognition in Bipolar Disorder Type II: A Proof of Concept Study. Front. Psychiatry 2019, 10, 66. [Google Scholar] [CrossRef]
  41. Ho, T.C.; Teresi, G.I.; Segarra, J.R.; Ojha, A.; Walker, J.C.; Gu, M.; Spielman, D.M.; Sacchet, M.D.; Jiang, F.; Rosenberg-Hasson, Y.; et al. Higher Levels of Pro-inflammatory Cytokines Are Associated with Higher Levels of Glutamate in the Anterior Cingulate Cortex in Depressed Adolescents. Front. Psychiatry 2021, 12, 642976. [Google Scholar] [CrossRef]
  42. Shi, K.; Zhang, J.; Dong, J.-f.; Shi, F.-D. Dissemination of brain inflammation in traumatic brain injury. Cell. Mol. Immunol. 2019, 16, 523–530. [Google Scholar] [CrossRef]
  43. Gasiorowska, A.; Wydrych, M.; Drapich, P.; Zadrozny, M.; Steczkowska, M.; Niewiadomski, W.; Niewiadomska, G. The biology and pathobiology of glutamatergic, cholinergic, and dopaminergic signaling in the aging brain. Front. Aging Neurosci. 2021, 391. [Google Scholar] [CrossRef] [PubMed]
  44. Ferrini, F.; De Koninck, Y. Microglia control neuronal network excitability via BDNF signalling. Neural Plast. 2013, 2013, 429815. [Google Scholar] [CrossRef] [PubMed]
  45. Sasaki-Hamada, S.; Sanai, E.; Kanemaru, M.; Kamanaka, G.; Oka, J.-I. Long-term exposure to high glucose induces changes in the expression of AMPA receptor subunits and glutamate transmission in primary cultured cortical neurons. Biochem. Biophys. Res. Commun. 2022, 589, 48–54. [Google Scholar] [CrossRef] [PubMed]
  46. Frank, D.; Gruenbaum, B.F.; Shelef, I.; Severynovska, O.; Gal, R.; Dubilet, M.; Zlotnik, A.; Kofman, O.; Boyko, M. Blood glutamate scavenging with pyruvate as a novel preventative and therapeutic approach for depressive-like behavior following traumatic brain injury in a rat model. Front. Neurosci. 2022, 16, 83247821. [Google Scholar] [CrossRef] [PubMed]
  47. Folkersma, H.; Foster Dingley, J.C.; van Berckel, B.N.; Rozemuller, A.; Boellaard, R.; Huisman, M.C.; Lammertsma, A.A.; Vandertop, W.P.; Molthoff, C.F. Increased cerebral (R)-[11C] PK11195 uptake and glutamate release in a rat model of traumatic brain injury: A longitudinal pilot study. J. Neuroinflamm. 2011, 8, 67. [Google Scholar] [CrossRef]
  48. Stefani, M.A.; Modkovski, R.; Hansel, G.; Zimmer, E.R.; Kopczynski, A.; Muller, A.P.; Strogulski, N.R.; Rodolphi, M.S.; Carteri, R.K.; Schmidt, A.P. Elevated glutamate and lactate predict brain death after severe head trauma. Ann. Clin. Transl. Neurol. 2017, 4, 392–402. [Google Scholar] [CrossRef]
  49. Zhang, D.; Xiao, M.; Wang, L.; Jia, W. Blood-based glutamate scavengers reverse traumatic brain injury-induced synaptic plasticity disruption by decreasing glutamate level in hippocampus interstitial fluid, but not cerebral spinal fluid, in vivo. Neurotox. Res. 2019, 35, 360–372. [Google Scholar] [CrossRef]
  50. Dai, S.-S.; Zhou, Y.-G.; Li, W.; An, J.-H.; Li, P.; Yang, N.; Chen, X.-Y.; Xiong, R.-P.; Liu, P.; Zhao, Y. Local glutamate level dictates adenosine A2A receptor regulation of neuroinflammation and traumatic brain injury. J. Neurosci. 2010, 30, 5802–5810. [Google Scholar] [CrossRef]
  51. McConeghy, K.W.; Hatton, J.; Hughes, L.; Cook, A.M. A review of neuroprotection pharmacology and therapies in patients with acute traumatic brain injury. CNS Drugs 2012, 26, 613–636. [Google Scholar] [CrossRef]
  52. Krishna, G.; Bromberg, C.; Connell, E.C.; Mian, E.; Hu, C.; Lifshitz, J.; Adelson, P.D.; Thomas, T.C. Traumatic Brain Injury-Induced Sex-Dependent Changes in Late-Onset Sensory Hypersensitivity and Glutamate Neurotransmission. Front. Neurol. 2020, 11, 749. [Google Scholar] [CrossRef]
  53. Selwyn, R.; Hockenbury, N.; Jaiswal, S.; Mathur, S.; Armstrong, R.C.; Byrnes, K.R. Mild traumatic brain injury results in depressed cerebral glucose uptake: An (18)FDG PET study. J. Neurotrauma 2013, 30, 1943–1953. [Google Scholar] [CrossRef] [PubMed]
  54. Dorsett, C.R.; McGuire, J.L.; Niedzielko, T.L.; DePasquale, E.A.; Meller, J.; Floyd, C.L.; McCullumsmith, R.E. Traumatic Brain Injury Induces Alterations in Cortical Glutamate Uptake without a Reduction in Glutamate Transporter-1 Protein Expression. J. Neurotrauma 2017, 34, 220–234. [Google Scholar] [CrossRef] [PubMed]
  55. O’Neil, D.A.; Nicholas, M.A.; Lajud, N.; Kline, A.E.; Bondi, C.O. Preclinical Models of Traumatic Brain Injury: Emerging Role of Glutamate in the Pathophysiology of Depression. Front. Pharmacol. 2018, 9, 579. [Google Scholar] [CrossRef] [PubMed]
  56. Vornov, J.J.; Wozniak, K.; Lu, M.; Jackson, P.; Tsukamoto, T.; Wang, E.; Slusher, B. Blockade of NAALADase: A novel neuroprotective strategy based on limiting glutamate and elevating NAAG. Ann. N. Y. Acad. Sci. 1999, 890, 400–405. [Google Scholar] [CrossRef] [PubMed]
  57. Lin, J.-Y.; Chung, S.-Y.; Lin, M.-C.; Cheng, F.-C. Effects of magnesium sulfate on energy metabolites and glutamate in the cortex during focal cerebral ischemia and reperfusion in the gerbil monitored by a dual-probe microdialysis technique. Life Sci. 2002, 71, 803–811. [Google Scholar] [CrossRef]
  58. Han, J.-l.; Blank, T.; Schwab, S.; Kollmar, R. Corrigendum to “Inhibited glutamate release by granulocyte-colony stimulating factor after experimental stroke”[Neurosci. Lett. 432 (2008) 167–169]. Neurosci. Lett. 2009, 3, 258. [Google Scholar] [CrossRef]
  59. Hurtado, O.; De Cristobal, J.; Sanchez, V.; Lizasoain, I.; Cardenas, A.; Pereira, M.P.; Colado, M.I.; Leza, J.C.; Lorenzo, P.; Moro, M.A. Inhibition of glutamate release by delaying ATP fall accounts for neuroprotective effects of antioxidants in experimental stroke. FASEB J. 2003, 17, 2082–2084. [Google Scholar] [CrossRef]
  60. Haroon, E.; Miller, A.H.; Sanacora, G. Inflammation, Glutamate, and Glia: A Trio of Trouble in Mood Disorders. Neuropsychopharmacology 2017, 42, 193–215. [Google Scholar] [CrossRef]
  61. Hodgson, C.L.; Higgins, A.M.; Bailey, M.; Barrett, J.; Bellomo, R.; Cooper, D.J.; Gabbe, B.J.; Iwashyna, T.; Linke, N.; Myles, P.S.; et al. Comparison of 6-month outcomes of sepsis versus non-sepsis critically ill patients receiving mechanical ventilation. Crit. Care 2022, 26, 174. [Google Scholar] [CrossRef]
  62. Quinn, C.M.; Kasibante, J.; Namudde, A.; Bangdiwala, A.S.; Kabahubya, M.; Nakasujja, N.; Lofgren, S.; Elliott, A.; Boulware, D.R.; Meya, D.B.; et al. Neurocognitive outcomes of tuberculous meningitis in a primarily HIV-positive Ugandan cohort. Wellcome Open Res. 2021, 6, 208. [Google Scholar] [CrossRef]
  63. Andersen, J.V.; Markussen, K.H.; Jakobsen, E.; Schousboe, A.; Waagepetersen, H.S.; Rosenberg, P.A.; Aldana, B.I. Glutamate metabolism and recycling at the excitatory synapse in health and neurodegeneration. Neuropharmacology 2021, 196, 108719. [Google Scholar] [CrossRef]
  64. Zhong, C.; Talmage, D.A.; Role, L.W. Nicotine elicits prolonged calcium signaling along ventral hippocampal axons. PLoS ONE 2013, 8, e82719. [Google Scholar] [CrossRef] [PubMed]
  65. Zwanzger, P.; Zavorotnyy, M.; Gencheva, E.; Diemer, J.; Kugel, H.; Heindel, W.; Ruland, T.; Ohrmann, P.; Arolt, V.; Domschke, K.; et al. Acute shift in glutamate concentrations following experimentally induced panic with cholecystokinin tetrapeptide—A 3T-MRS study in healthy subjects. Neuropsychopharmacology 2013, 38, 1648–1654. [Google Scholar] [CrossRef] [PubMed]
  66. Houtepen, L.C.; Schur, R.R.; Wijnen, J.P.; Boer, V.O.; Boks, M.P.; Kahn, R.S.; Joels, M.; Klomp, D.W.; Vinkers, C.H. Acute stress effects on GABA and glutamate levels in the prefrontal cortex: A 7T (1)H magnetic resonance spectroscopy study. Neuroimage Clin. 2017, 14, 195–200. [Google Scholar] [CrossRef] [PubMed]
  67. Hasler, G.; van der Veen, J.W.; Grillon, C.; Drevets, W.C.; Shen, J. Effect of acute psychological stress on prefrontal GABA concentration determined by proton magnetic resonance spectroscopy. Am. J. Psychiatry 2010, 167, 1226–1231. [Google Scholar] [CrossRef]
  68. Zhang, J.M.; Wang, H.K.; Ye, C.Q.; Ge, W.; Chen, Y.; Jiang, Z.L.; Wu, C.P.; Poo, M.M.; Duan, S. ATP released by astrocytes mediates glutamatergic activity-dependent heterosynaptic suppression. Neuron 2003, 40, 971–982. [Google Scholar] [CrossRef]
  69. Chodobski, A.; Zink, B.J.; Szmydynger-Chodobska, J. Blood–brain barrier pathophysiology in traumatic brain injury. Transl. Stroke Res. 2011, 2, 492–516. [Google Scholar] [CrossRef]
  70. Toyota, S.; Graf, R.; Valentino, M.; Yoshimine, T.; Heiss, W.D. Malignant infarction in cats after prolonged middle cerebral artery occlusion: Glutamate elevation related to decrease of cerebral perfusion pressure. Stroke 2002, 33, 1383–1391. [Google Scholar] [CrossRef]
  71. Hone, E.; Hu, H.; Sprowls, S.; Farooqi, I.; Grasmick, K.; Lockman, P.; Simpkins, J.; Ren, X. Biphasic blood-brain barrier openings after stroke. Neurol. Disord. Stroke Int. 2018, 11. [Google Scholar] [CrossRef]
  72. Başkaya, M.K.; Rao, A.M.; Doğan, A.; Donaldson, D.; Dempsey, R.J. The biphasic opening of the blood–brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neurosci. Lett. 1997, 226, 33–36. [Google Scholar] [CrossRef]
  73. Chamoun, R.; Suki, D.; Gopinath, S.P.; Goodman, J.C.; Robertson, C. Role of extracellular glutamate measured by cerebral microdialysis in severe traumatic brain injury. J. Neurosurg. 2010, 113, 564–570. [Google Scholar] [CrossRef]
  74. Bullock, R.; Zauner, A.; Woodward, J.J.; Myseros, J.; Choi, S.C.; Ward, J.D.; Marmarou, A.; Young, H.F. Factors affecting excitatory amino acid release following severe human head injury. J. Neurosurg. 1998, 89, 507–518. [Google Scholar] [CrossRef]
  75. Vespa, P.; Prins, M.; Ronne-Engstrom, E.; Caron, M.; Shalmon, E.; Hovda, D.A.; Martin, N.A.; Becker, D.P. Increase in extracellular glutamate caused by reduced cerebral perfusion pressure and seizures after human traumatic brain injury: A microdialysis study. J. Neurosurg. 1998, 89, 971–982. [Google Scholar] [CrossRef]
  76. Yu, M.; Wang, M.; Yang, D.; Wei, X.; Li, W. Dynamics of blood brain barrier permeability and tissue microstructure following controlled cortical impact injury in rat: A dynamic contrast-enhanced magnetic resonance imaging and diffusion kurtosis imaging study. Magn. Reson. Imaging 2019, 62, 1–9. [Google Scholar] [CrossRef]
  77. van Vliet, E.A.; Ndode-Ekane, X.E.; Lehto, L.J.; Gorter, J.A.; Andrade, P.; Aronica, E.; Grohn, O.; Pitkanen, A. Long-lasting blood-brain barrier dysfunction and neuroinflammation after traumatic brain injury. Neurobiol. Dis. 2020, 145, 105080. [Google Scholar] [CrossRef]
  78. Hay, J.R.; Johnson, V.E.; Young, A.M.; Smith, D.H.; Stewart, W. Blood-Brain Barrier Disruption Is an Early Event that May Persist for Many Years after Traumatic Brain Injury in Humans. J. Neuropathol. Exp. Neurol. 2015, 74, 1147–1157. [Google Scholar] [CrossRef]
  79. Cash, A.; Theus, M.H. Mechanisms of blood–brain barrier dysfunction in traumatic brain injury. Int. J. Mol. Sci. 2020, 21, 3344. [Google Scholar] [CrossRef]
  80. Wu, Y.; Wu, H.; Guo, X.; Pluimer, B.; Zhao, Z. Blood–brain barrier dysfunction in mild traumatic brain injury: Evidence from preclinical murine models. Front. Physiol. 2020, 11, 1030. [Google Scholar] [CrossRef]
  81. Hawkins, R.A. The blood-brain barrier and glutamate. Am. J. Clin. Nutr. 2009, 90, 867S–874S. [Google Scholar] [CrossRef]
  82. Kobeissy, F.; Dixon, C.E.; Hayes, R.L.; Mondello, S. Injury Models of the Central Nervous System; Springer: Berlin/Heidelberg, Germany, 1940. [Google Scholar]
  83. Okada, T.; Suzuki, H.; Travis, Z.D.; Zhang, J.H. The stroke-induced blood-brain barrier disruption: Current progress of inspection technique, mechanism, and therapeutic target. Curr. Neuropharmacol. 2020, 18, 1187–1212. [Google Scholar]
  84. Lau, A.; Tymianski, M. Glutamate receptors, neurotoxicity and neurodegeneration. Pflügers Arch.-Eur. J. Physiol. 2010, 460, 525–542. [Google Scholar] [CrossRef]
  85. Al-Nasser, M.N.; Mellor, I.R.; Carter, W.G. Is L-Glutamate Toxic to Neurons and Thereby Contributes to Neuronal Loss and Neurodegeneration? A Systematic Review. Brain Sci. 2022, 12, 577. [Google Scholar] [CrossRef]
  86. Borbely, E.; Simon, M.; Fuchs, E.; Wiborg, O.; Czeh, B.; Helyes, Z. Novel drug developmental strategies for treatment-resistant depression. Br. J. Pharmacol. 2022, 179, 1146–1186. [Google Scholar] [CrossRef]
  87. Berman, R.M.; Cappiello, A.; Anand, A.; Oren, D.A.; Heninger, G.R.; Charney, D.S.; Krystal, J.H. Antidepressant effects of ketamine in depressed patients. Biol. Psychiatry 2000, 47, 351–354. [Google Scholar] [CrossRef]
  88. Blaylock, R.L.; Faria, M. New concepts in the development of schizophrenia, autism spectrum disorders, and degenerative brain diseases based on chronic inflammation: A working hypothesis from continued advances in neuroscience research. Surg. Neurol. Int. 2021, 12, 556. [Google Scholar]
  89. Belov Kirdajova, D.; Kriska, J.; Tureckova, J.; Anderova, M. Ischemia-triggered glutamate excitotoxicity from the perspective of glial cells. Front. Cell. Neurosci. 2020, 14, 51. [Google Scholar] [CrossRef]
  90. Simões, A.P.; Silva, C.G.; Marques, J.M.; Pochmann, D.; Porciúncula, L.O.; Ferreira, S.; Oses, J.P.; Beleza, R.O.; Real, J.I.; Köfalvi, A. Glutamate-induced and NMDA receptor-mediated neurodegeneration entails P2Y1 receptor activation. Cell Death Dis. 2018, 9, 297. [Google Scholar] [CrossRef]
  91. Kumar, A.; Singh, R.L.; Babu, G.N. Cell death mechanisms in the early stages of acute glutamate neurotoxicity. Neurosci. Res. 2010, 66, 271–278. [Google Scholar] [CrossRef]
  92. Lewerenz, J.; Maher, P. Chronic glutamate toxicity in neurodegenerative diseases—What is the evidence? Front. Neurosci. 2015, 9, 469. [Google Scholar] [CrossRef]
  93. Meldrum, B.S. The role of glutamate in epilepsy and other CNS disorders. Neurology 1994, 44, S14–S23. [Google Scholar]
  94. Meldrum, B.; Garthwaite, J. Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol. Sci. 1990, 11, 379–387. [Google Scholar] [CrossRef]
  95. Li, J.; Zheng, M.; Shimoni, O.; Banks, W.A.; Bush, A.I.; Gamble, J.R.; Shi, B. Development of novel therapeutics targeting the blood–brain barrier: From barrier to carrier. Adv. Sci. 2021, 8, 2101090. [Google Scholar] [CrossRef]
  96. Barar, J.; Rafi, M.A.; Pourseif, M.M.; Omidi, Y. Blood-brain barrier transport machineries and targeted therapy of brain diseases. BioImpacts BI 2016, 6, 225. [Google Scholar] [CrossRef] [PubMed]
  97. Howard, R.; Zubko, O.; Bradley, R.; Harper, E.; Pank, L.; O’brien, J.; Fox, C.; Tabet, N.; Livingston, G.; Bentham, P. Minocycline at 2 different dosages vs placebo for patients with mild Alzheimer disease: A randomized clinical trial. JAMA Neurol. 2020, 77, 164–174. [Google Scholar] [CrossRef] [PubMed]
  98. Liu, P.P.; Xie, Y.; Meng, X.Y.; Kang, J.S. History and progress of hypotheses and clinical trials for Alzheimer’s disease. Signal Transduct Target Ther. 2019, 4, 29. [Google Scholar] [CrossRef] [PubMed]
  99. Castillo, J.; Loza, M.I.; Mirelman, D.; Brea, J.; Blanco, M.; Sobrino, T.; Campos, F. A novel mechanism of neuroprotection: Blood glutamate grabber. J. Cereb. Blood Flow Metab. 2016, 36, 292–301. [Google Scholar] [CrossRef]
  100. Cederberg, H.H.; Uhd, N.C.; Brodin, B. Glutamate efflux at the blood-brain barrier: Cellular mechanisms and potential clinical relevance. Arch. Med. Res. 2014, 45, 639–645. [Google Scholar] [CrossRef]
  101. Li, Y.; Hou, X.; Qi, Q.; Wang, L.; Luo, L.; Yang, S.; Zhang, Y.; Miao, Z.; Zhang, Y.; Wang, F.; et al. Scavenging of blood glutamate for enhancing brain-to-blood glutamate efflux. Mol. Med. Rep. 2014, 9, 305–310. [Google Scholar] [CrossRef]
  102. Zlotnik, A.; Gurevich, B.; Cherniavsky, E.; Tkachov, S.; Matuzani-Ruban, A.; Leon, A.; Shapira, Y.; Teichberg, V.I. The contribution of the blood glutamate scavenging activity of pyruvate to its neuroprotective properties in a rat model of closed head injury. Neurochem. Res. 2008, 33, 1044–1050. [Google Scholar] [CrossRef]
  103. Boyko, M.; Melamed, I.; Gruenbaum, B.F.; Gruenbaum, S.E.; Ohayon, S.; Leibowitz, A.; Brotfain, E.; Shapira, Y.; Zlotnik, A. The effect of blood glutamate scavengers oxaloacetate and pyruvate on neurological outcome in a rat model of subarachnoid hemorrhage. Neurotherapeutics 2012, 9, 649–657. [Google Scholar] [CrossRef]
  104. Perez-Mato, M.; Ramos-Cabrer, P.; Sobrino, T.; Blanco, M.; Ruban, A.; Mirelman, D.; Menendez, P.; Castillo, J.; Campos, F. Human recombinant glutamate oxaloacetate transaminase 1 (GOT1) supplemented with oxaloacetate induces a protective effect after cerebral ischemia. Cell Death Dis. 2014, 5, e992. [Google Scholar] [CrossRef] [PubMed]
  105. Campos, F.; Sobrino, T.; Ramos-Cabrer, P.; Castellanos, M.; Blanco, M.; Rodriguez-Yanez, M.; Serena, J.; Leira, R.; Castillo, J. High blood glutamate oxaloacetate transaminase levels are associated with good functional outcome in acute ischemic stroke. J. Cereb. Blood Flow Metab. 2011, 31, 1387–1393. [Google Scholar] [CrossRef] [PubMed]
  106. Frank, D.; Kuts, R.; Tsenter, P.; Gruenbaum, B.F.; Grinshpun, Y.; Zvenigorodsky, V.; Shelef, I.; Natanel, D.; Brotfain, E.; Zlotnik, A. The effect of pyruvate on the development and progression of post-stroke depression: A new therapeutic approach. Neuropharmacology 2019, 155, 173–184. [Google Scholar] [CrossRef] [PubMed]
  107. Dopico-Lopez, A.; Perez-Mato, M.; da Silva-Candal, A.; Iglesias-Rey, R.; Rabinkov, A.; Bugallo-Casal, A.; Sobrino, T.; Mirelman, D.; Castillo, J.; Campos, F. Inhibition of endogenous blood glutamate oxaloacetate transaminase enhances the ischemic damage. Transl. Res. 2021, 230, 68–81. [Google Scholar] [CrossRef] [PubMed]
  108. Boyko, M.; Zlotnik, A.; Gruenbaum, B.F.; Gruenbaum, S.E.; Ohayon, S.; Kuts, R.; Melamed, I.; Regev, A.; Shapira, Y.; Teichberg, V.I. Pyruvate’s blood glutamate scavenging activity contributes to the spectrum of its neuroprotective mechanisms in a rat model of stroke. Eur. J. Neurosci. 2011, 34, 1432–1441. [Google Scholar] [CrossRef] [PubMed]
  109. Khanna, S.; Briggs, Z.; Rink, C. Inducible glutamate oxaloacetate transaminase as a therapeutic target against ischemic stroke. Antioxid. Redox Signal. 2015, 22, 175–186. [Google Scholar] [CrossRef]
  110. Campos, F.; Sobrino, T.; Ramos-Cabrer, P.; Argibay, B.; Agulla, J.; Pérez-Mato, M.; Rodríguez-González, R.; Brea, D.; Castillo, J. Neuroprotection by glutamate oxaloacetate transaminase in ischemic stroke: An experimental study. J. Cereb. Blood Flow Metab. 2011, 31, 1378–1386. [Google Scholar] [CrossRef] [PubMed]
  111. Swerdlow, R.; Lyons, K.; Khosla, S.; Nashatizadeh, M.; Pahwa, R. A pilot Study of oxaloacetate 100 mg capsules in Parkinson’s disease patients. J. Parkinsons Dis. Alzheimers Dis. 2016, 3, 4. [Google Scholar]
  112. Swerdlow, R.H.; Bothwell, R.; Hutfles, L.; Burns, J.M.; Reed, G.A. Tolerability and pharmacokinetics of oxaloacetate 100 mg capsules in Alzheimer’s subjects. BBA Clin. 2016, 5, 120–123. [Google Scholar] [CrossRef]
  113. Koh-Banerjee, P.K.; Ferreira, M.P.; Greenwood, M.; Bowden, R.G.; Cowan, P.N.; Almada, A.; Kreider, R.B. Effects of calcium pyruvate supplementation during training on body composition, exercise capacity, and metabolic responses to exercise. Nutrition 2005, 21, 312–319. [Google Scholar] [CrossRef]
  114. Stone, M.H.; Sanborn, K.; Smith, L.L.; O’Bryant, H.S.; Hoke, T.; Utter, A.C.; Johnson, R.L.; Boros, R.; Hruby, J.; Pierce, K.C. Effects of in-season (5 weeks) creatine and pyruvate supplementation on anaerobic performance and body composition in American football players. Int. J. Sport Nutr. Exerc. Metab. 1999, 9, 146–165. [Google Scholar] [CrossRef] [PubMed]
  115. Stanko, R.T.; Reynolds, H.R.; Lonchar, K.D.; Arch, J.E. Plasma lipid concentrations in hyperlipidemic patients consuming a high-fat diet supplemented with pyruvate for 6 wk. Am. J. Clin. Nutr. 1992, 56, 950–954. [Google Scholar] [CrossRef]
  116. Morrison, M.A.; Spriet, L.L.; Dyck, D.J. Pyruvate ingestion for 7 days does not improve aerobic performance in well-trained individuals. J. Appl. Physiol. 2000, 89, 549–556. [Google Scholar] [CrossRef] [PubMed]
  117. Stanko, R.T.; Reynolds, H.R.; Hoyson, R.; Janosky, J.E.; Wolf, R. Pyruvate supplementation of a low-cholesterol, low-fat diet: Effects on plasma lipid concentrations and body composition in hyperlipidemic patients. Am. J. Clin. Nutr. 1994, 59, 423–427. [Google Scholar] [CrossRef] [PubMed]
  118. Ostojic, S.M.; Ahmetovic, Z. The effect of 4 weeks treatment with a 2-gram daily dose of pyruvate on body composition in healthy trained men. Int. J. Vitam. Nutr. Res. 2009, 79, 173–179. [Google Scholar] [CrossRef] [PubMed]
  119. Jäger, R.; Metzger, J.; Lautmann, K.; Shushakov, V.; Purpura, M.; Geiss, K.-R.; Maassen, N. The effects of creatine pyruvate and creatine citrate on performance during high intensity exercise. J. Int. Soc. Sports Nutr. 2008, 5, 4. [Google Scholar] [CrossRef] [PubMed]
  120. Kalman, D.; Colker, C.M.; Wilets, I.; Roufs, J.B.; Antonio, J. The effects of pyruvate supplementation on body composition in overweight individuals. Nutrition 1999, 15, 337–340. [Google Scholar] [CrossRef]
  121. Tully, L.; Humiston, J.; Cash, A. Oxaloacetate reduces emotional symptoms in premenstrual syndrome (PMS): Results of a placebo-controlled, cross-over clinical trial. Obstet. Gynecol. Sci. 2020, 63, 195–204. [Google Scholar] [CrossRef]
  122. Chakraborty, C.; Sharma, A.R.; Sharma, G.; Bhattacharya, M.; Lee, S.-S. MicroRNAs: Possible regulatory molecular switch controlling the BBB microenvironment. Mol. Ther.-Nucleic Acids 2020, 19, 933–936. [Google Scholar] [CrossRef]
  123. Zhu, M.-x.; Lu, C.; Xia, C.-m.; Qiao, Z.-w.; Zhu, D.-n. Simvastatin pretreatment protects cerebrum from neuronal injury by decreasing the expressions of phosphor-CaMK II and AQP4 in ischemic stroke rats. J. Mol. Neurosci. 2014, 54, 591–601. [Google Scholar] [CrossRef]
  124. Coureuil, M.; Lécuyer, H.; Bourdoulous, S.; Nassif, X. A journey into the brain: Insight into how bacterial pathogens cross blood–brain barriers. Nat. Rev. Microbiol. 2017, 15, 149–159. [Google Scholar] [CrossRef] [PubMed]
  125. Ben-Zvi, A.; Lacoste, B.; Kur, E.; Andreone, B.J.; Mayshar, Y.; Yan, H.; Gu, C. Mfsd2a is critical for the formation and function of the blood–brain barrier. Nature 2014, 509, 507–511. [Google Scholar] [CrossRef] [PubMed]
  126. Kooij, G.; Van Horssen, J.; Bandaru, V.V.R.; Haughey, N.J.; De Vries, H.E. The role of ATP-binding cassette transporters in neuro-inflammation: Relevance for bioactive lipids. Front. Pharmacol. 2012, 3, 74. [Google Scholar] [CrossRef] [PubMed]
  127. Zhang, W.; Zhu, L.; An, C.; Wang, R.; Yang, L.; Yu, W.; Li, P.; Gao, Y. The blood brain barrier in cerebral ischemic injury—Disruption and repair. Brain Hemorrhages 2020, 1, 34–53. [Google Scholar] [CrossRef]
  128. Cui, X.; Chopp, M.; Zacharek, A.; Roberts, C.; Lu, M.; Savant-Bhonsale, S.; Chen, J. Chemokine, vascular and therapeutic effects of combination Simvastatin and BMSC treatment of stroke. Neurobiol. Dis. 2009, 36, 35–41. [Google Scholar] [CrossRef] [Green Version]
  129. Dore-Duffy, P. Pericytes: Pluripotent cells of the blood brain barrier. Curr. Pharm. Des. 2008, 14, 1581–1593. [Google Scholar] [CrossRef]
  130. Liu, S.; Agalliu, D.; Yu, C.; Fisher, M. The role of pericytes in blood-brain barrier function and stroke. Curr. Pharm. Des. 2012, 18, 3653–3662. [Google Scholar] [CrossRef]
  131. Hayakawa, K.; Pham, L.-D.D.; Katusic, Z.S.; Arai, K.; Lo, E.H. Astrocytic high-mobility group box 1 promotes endothelial progenitor cell-mediated neurovascular remodeling during stroke recovery. Proc. Natl. Acad. Sci. USA 2012, 109, 7505–7510. [Google Scholar] [CrossRef]
  132. Li, J.; Tang, Y.; Wang, Y.; Tang, R.; Jiang, W.; Yang, G.-Y.; Gao, W.-Q. Neurovascular recovery via cotransplanted neural and vascular progenitors leads to improved functional restoration after ischemic stroke in rats. Stem Cell Rep. 2014, 3, 101–114. [Google Scholar] [CrossRef]
  133. Tang, Y.; Wang, J.; Lin, X.; Wang, L.; Shao, B.; Jin, K.; Wang, Y.; Yang, G.-Y. Neural stem cell protects aged rat brain from ischemia–reperfusion injury through neurogenesis and angiogenesis. J. Cereb. Blood Flow Metab. 2014, 34, 1138–1147. [Google Scholar] [CrossRef]
  134. Gliem, M.; Mausberg, A.K.; Lee, J.I.; Simiantonakis, I.; van Rooijen, N.; Hartung, H.P.; Jander, S. Macrophages prevent hemorrhagic infarct transformation in murine stroke models. Ann. Neurol. 2012, 71, 743–752. [Google Scholar] [CrossRef] [PubMed]
  135. Li, S.-f.; Sun, Y.-b.; Meng, Q.-h.; Li, S.-r.; Yao, W.-c.; Hu, G.-j.; Li, Z.-j.; Wang, R.-z. Recombinant adeno-associated virus serotype 1-vascular endothelial growth factor promotes neurogenesis and neuromigration in the subventricular zone and rescues neuronal function in ischemic rats. Neurosurgery 2009, 65, 771–779. [Google Scholar] [CrossRef]
  136. Candelario-Jalil, E. Nimesulide as a promising neuroprotectant in brain ischemia: New experimental evidences. Pharmacol. Res. 2008, 57, 266–273. [Google Scholar] [CrossRef] [PubMed]
  137. Hong, S.-H.; Khoutorova, L.; Bazan, N.G.; Belayev, L. Docosahexaenoic acid improves behavior and attenuates blood–brain barrier injury induced by focal cerebral ischemia in rats. Exp. Transl. Stroke Med. 2015, 7, 3. [Google Scholar] [CrossRef] [PubMed]
  138. Yan, Y.; Dempsey, R.J.; Flemmer, A.; Forbush, B.; Sun, D. Inhibition of Na+–K+–Cl− cotransporter during focal cerebral ischemia decreases edema and neuronal damage. Brain Res. 2003, 961, 22–31. [Google Scholar] [CrossRef]
  139. Brenneman, M.; Sharma, S.; Harting, M.; Strong, R.; Cox, C.S., Jr.; Aronowski, J.; Grotta, J.C.; Savitz, S.I. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. J. Cereb. Blood Flow Metab. 2010, 30, 140–149. [Google Scholar] [CrossRef]
  140. Friedrich, M.A.; Martins, M.P.; Araújo, M.D.; Klamt, C.; Vedolin, L.; Garicochea, B.; Raupp, E.F.; Ammar, J.S.E.; Machado, D.C.; Da Costa, J.C. Intra-arterial infusion of autologous bone marrow mononuclear cells in patients with moderate to severe middle cerebral artery acute ischemic stroke. Cell Transplant. 2012, 21, 13–21. [Google Scholar] [CrossRef]
  141. Won, S.; Lee, J.H.; Wali, B.; Stein, D.G.; Sayeed, I. Progesterone attenuates hemorrhagic transformation after delayed tPA treatment in an experimental model of stroke in rats: Involvement of the VEGF–MMP pathway. J. Cereb. Blood Flow Metab. 2014, 34, 72–80. [Google Scholar] [CrossRef]
  142. Cai, Y.; Liu, X.; Chen, W.; Wang, Z.; Xu, G.; Zeng, Y.; Ma, Y. TGF-β1 prevents blood–brain barrier damage and hemorrhagic transformation after thrombolysis in rats. Exp. Neurol. 2015, 266, 120–126. [Google Scholar] [CrossRef]
  143. Kuroki, T.; Tanaka, R.; Shimada, Y.; Yamashiro, K.; Ueno, Y.; Shimura, H.; Urabe, T.; Hattori, N. Exendin-4 inhibits matrix metalloproteinase-9 activation and reduces infarct growth after focal cerebral ischemia in hyperglycemic mice. Stroke 2016, 47, 1328–1335. [Google Scholar] [CrossRef]
  144. Sarkar, S.; Mukherjee, A.; Das, N.; Swarnakar, S. Protective roles of nanomelatonin in cerebral ischemia-reperfusion of aged brain: Matrixmetalloproteinases as regulators. Exp. Gerontol. 2017, 92, 13–22. [Google Scholar] [CrossRef] [PubMed]
  145. Li, P.; Gan, Y.; Sun, B.L.; Zhang, F.; Lu, B.; Gao, Y.; Liang, W.; Thomson, A.W.; Chen, J.; Hu, X. Adoptive regulatory T-cell therapy protects against cerebral ischemia. Ann. Neurol. 2013, 74, 458–471. [Google Scholar] [CrossRef] [PubMed]
  146. Frankowski, J.C.; DeMars, K.M.; Ahmad, A.S.; Hawkins, K.E.; Yang, C.; Leclerc, J.L.; Doré, S.; Candelario-Jalil, E. Detrimental role of the EP1 prostanoid receptor in blood-brain barrier damage following experimental ischemic stroke. Sci. Rep. 2015, 5, 17956. [Google Scholar] [CrossRef] [PubMed]
  147. Machado, L.S.; Kozak, A.; Ergul, A.; Hess, D.C.; Borlongan, C.V.; Fagan, S.C. Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci. 2006, 7, 1–7. [Google Scholar] [CrossRef] [PubMed]
  148. Izzy, S.; Chen, P.M.; Tahir, Z.; Grashow, R.; Radmanesh, F.; Cote, D.J.; Yahya, T.; Dhand, A.; Taylor, H.; Shih, S.L. Association of traumatic brain injury with the risk of developing chronic cardiovascular, endocrine, neurological, and psychiatric disorders. JAMA Netw. Open 2022, 5, e229478. [Google Scholar] [CrossRef]
Ijms 23 09628 g001 550
Figure 1. Role of the blood–brain barrier in the mechanism of post-traumatic brain injury neuropsychiatric consequences.
Figure 1. Role of the blood–brain barrier in the mechanism of post-traumatic brain injury neuropsychiatric consequences.
Ijms 23 09628 g001
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Gruenbaum, B.F.; Zlotnik, A.; Fleidervish, I.; Frenkel, A.; Boyko, M. Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies. Int. J. Mol. Sci. 2022, 23, 9628. https://doi.org/10.3390/ijms23179628

AMA Style

Gruenbaum BF, Zlotnik A, Fleidervish I, Frenkel A, Boyko M. Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies. International Journal of Molecular Sciences. 2022; 23(17):9628. https://doi.org/10.3390/ijms23179628

Chicago/Turabian Style

Gruenbaum, Benjamin F., Alexander Zlotnik, Ilya Fleidervish, Amit Frenkel, and Matthew Boyko. 2022. "Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies" International Journal of Molecular Sciences 23, no. 17: 9628. https://doi.org/10.3390/ijms23179628

APA Style

Gruenbaum, B. F., Zlotnik, A., Fleidervish, I., Frenkel, A., & Boyko, M. (2022). Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies. International Journal of Molecular Sciences, 23(17), 9628. https://doi.org/10.3390/ijms23179628

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop