Glutamate Transporters and Brain Injury

Epileptogenic seizures, or status epilepticus (SE), leads to excitotoxic injury in hippocampal and limbic neurons in the kainic acid (KA) animal model of temporal lobe epilepsy (TLE). Here, we have further characterized neural activity regulated methylaminoisobutryic acid (MeAIB)/glutamine transport activity in mature rat hippocampal neurons in vitro that is inhibited by riluzole (IC50 = 1μM), an anti-convulsant benzothiazole agent. We screened a library of riluzole derivatives and identified SKA-41 followed by a second screen and synthesized several novel chlorinated aminothiazoles (SKA-377, SKA-378, SKA-379) that are also potent MeAIB transport inhibitors in vitro, and brain penetrant following systemic administration...

Astrocyte-specific glutamate transporter subtype 1 (GLT-1) plays an important role in influencing glutamate excitatory toxicity and preventing the death of excitatory toxic neurons. Although the mammalian target of rapamycin (mTOR)/protein kinase B(Akt)/nuclear factor kappa B signaling cascade is involved in the upregulation of astrocytic GLT-1 in oxygen-glucose deprivation (OGD), it is unclear whether the mTOR/Akt pathway is involved in astrocytic GLT-1 upregulation in OGD and reoxygenation (OGD/R). In this study, we found that the treatment of cultured astrocytes with rapamycin and triciribine led to the decreased astrocytes' protrusions, smaller nuclei, and an increased apoptotic rate...

The inhibition of synaptic glutamate release to maintain glutamate homeostasis contributes to the alleviation of neuronal cell injury, and accumulating evidence suggests that natural products can repress glutamate levels and associated excitotoxicity. In this study, we investigated whether eupatilin, a constituent of Artemisia argyi , affected glutamate release in rat cortical nerve terminals (synaptosomes). Additionally, we evaluated the effect of eupatilin in an animal model of kainic acid (KA) excitotoxicity, particularly on the levels of glutamate and N-methyl-D-aspartate (NMDA) receptor subunits (GluN2A and GluN2B)...

Primary blast injury is caused by the direct impact of an overpressurization wave on the body. Due to limitations of current models, we have developed a novel approach to study primary blast-induced traumatic brain injury. Specifically, we employ a bioengineered 3D brain-like human tissue culture system composed of collagen-infused silk protein donut-like hydrogels embedded with human IPSC-derived neurons, human astrocytes, and a human microglial cell line. We have utilized this system within an advanced blast simulator (ABS) to expose the 3D brain cultures to a blast wave that can be precisely controlled...

Background: Traumatic spinal cord injury (SCI) is a major clinical concern and a life-changing neurological condition with substantial socioeconomic implications. The initial mechanical force applied to the spinal cord at the time of injury is known as the primary injury. After the primary injury, ischemia and hypoxia induce cell death and autolysis, which are associated with the release of a group of inflammatory factors and biologically active substances, such as superoxide dismutase (SOD), malonaldehyde (MDA), lactate dehydrogenase (LDH), and tumor necrosis factor-α (TNF-α)...

Chronic ethanol exposure affects the glutamatergic system in several brain reward regions such as the nucleus accumbens (NAc). Our laboratory has shown that chronic exposure to ethanol reduced the expression of glutamate transporter 1 (GLT-1) and cystine/glutamate exchanger transporter (xCT) and, as a result, increased extracellular glutamate concentrations in the NAc of alcohol preferring (P) rats. Moreover, previous study from our laboratory reported that chronic ethanol intake altered the expression of certain metabotropic glutamate receptors in the brain...

Cerebellar dysfunction is commonly observed following traumatic brain injury (TBI). While direct impact to the cerebellum by TBI is rare, cerebellar pathology may be caused by indirect injury via cortico-cerebellar pathways. To address the hypothesis that degeneration of Purkinje cells (PCs), which constitute the sole output from the cerebellum, is linked to long-range axonal injury and demyelination, we used the central fluid percussion injury (cFPI) model of widespread traumatic axonal injury in mice. Compared to controls, TBI resulted in early PC loss accompanied by alterations in the size of pinceau synapses and levels of non-phosphorylated neurofilament in PCs...

Glutamate acts as the main excitatory neurotransmitter in the brain and plays a vital role in physiological and pathological neuronal functions. In mammals, glutamate can cause detrimental excitotoxic effects under anoxic conditions. In contrast, Trachemys scripta , a freshwater turtle, is one of the most anoxia-tolerant animals, being able to survive up to months without oxygen. Therefore, turtles have been investigated to assess the molecular mechanisms of neuroprotective strategies used by them in anoxic conditions, such as maintaining low levels of glutamate, increasing adenosine and GABA, upregulating heat shock proteins, and downregulating K ATP channels...

Glutamate is the main excitatory neurotransmitter in the human central nervous system, responsible for a wide variety of normal physiological processes. Glutamatergic metabolism and its sequestration are tightly regulated in the normal human brain, and it has been demonstrated that dysregulation of the glutamatergic system can have wide-ranging effects both in acute brain injury and neurodegenerative diseases. The excitatory amino acid transporter 2 (EAAT2) is the dominant glutamatergic transporter in the human brain, responsible for efficient removal of glutamate from the synaptic cleft for recycling within glial cells...

Repetitive seizures, a common phenomenon in diverse neurologic conditions such as epilepsy, can undoubtedly cause neuronal injury and our prior work reveals that ferroptosis is a contributing factor of neuronal damage post seizure. However, there is no drug available in clinical practice for ameliorating seizure-induced neuronal impairment via targeting ferroptosis. Our present work aimed to explore whether D-penicillamine (DPA), an originally approved drug for treating Wilson's disease, inhibited neuronal ferroptosis and alleviated seizure-associated brain damage...

Background: The dried roots of the Astragalus propinquus Schischkin (RAP) plant, as a traditional Chinese medicine, has been widely used to treat stroke, cerebral ischemia, qi deficiency, and hypertension. Buyang Huanwu decoction is traditionally used to treat stroke in China for more than 200 years and has a significant effect on cerebral ischemia, and RAP is monarch medicine of Buyang Huanwu decoction. Therefore, this study was designed to observe the regulatory effect of RAP on transmembrane iron transporters and ferroptosis-related factors in cerebral ischemia-reperfusion injury (CIRI) in rats...

BACKGROUND: Secondary brain injury (SBI) has been confirmed as a leading cause for the poor prognosis of patients suffering from intracerebral hemorrhage (ICH). SBI co-exists in ischemia and hemorrhagic stroke. Neuro-excitotoxicity is considered the initiating factor of ICH-induced SBI. Our previous research has revealed alpha-asarone (ASA)'s efficacy against cerebral ischemia-reperfusion stroke by mitigating neuro-excitotoxicity. It is not yet known if ASA exhibit neuroprotection against ICH...

BACKGROUND: Traumatic brain injury (TBI) is one of the major contributors to disability and death worldwide. Glutamate-mediated excitotoxicity, one of the secondary injuries occurring after TBI, leads to extreme neuronal apoptosis, and can be a potential target for intervention. Bone marrow mesenchymal stem cells-derived exosomes (BMSCs-Exos) have demonstrated neuroprotective effects on TBI. However, their precise role and the underlying mechanism by which they regulate glutamate-mediated excitotoxicity have not yet been determined...

BACKGROUND: Traumatic brain injury (TBI) leads to cell and tissue impairment, as well as functional deficits. Stem cells promote structural and functional recovery and thus are considered as a promising therapy for various nerve injuries. Here, we aimed to investigate the role of ectoderm-derived frontal bone mesenchymal stem cells (FbMSCs) in promoting cerebral repair and functional recovery in a murine TBI model. METHODS: A murine TBI model was established by injuring C57BL/6 N mice with moderate-controlled cortical impact to evaluate the extent of brain damage and behavioral deficits...

Maintaining glutamate homeostasis through astrocyte-enriched glutamate transporter 1 (GLT-1) is critical for neuronal survival, but it is often disrupted after brain injury. Hericium erinaceus (HE), an edible mushroom, was reported to be anti-inflammatory and neuroprotective against brain ischemia, but its effect on glutamate homeostasis was unknown. Here we investigated the neuroprotective effect of erinacine A (EA), an active component of HE, with special focus on the GLT-1 function in the in vitro and in vivo cerebral ischemia mouse models...

Traumatic brain injury (TBI) is currently a substantial public health problem and one of the leading causes of morbidity and mortality worldwide. However, the cellular and transcriptional changes in TBI at single-cell level have not been well characterized. In this study, we reanalyzed a single-cell RNA sequencing (scRNA-seq) dataset of mouse hippocampus to identify the key cellular and transcriptional changes associated with TBI. Specifically, we found that oligodendrocytes were the most abundant cell type in mouse hippocampus, and detected an expanded astrocyte population, which was significantly activated in TBI...

As one of the key injury incidents, tissue acidosis in the brain occurs very quickly within several minutes upon the onset of ischemic stroke. Glutamate, an excitatory amino acid inducing neuronal excitotoxicity, has been reported to trigger the decrease in neuronal intracellular pH (pHi) via modulating proton-related membrane transporters. However, there remains a lack of clarity on the possible role of glutamate in neuronal acidosis via regulating metabolism. Here, we show that 200 μM glutamate treatment quickly promotes glycolysis and inhibits mitochondrial oxidative phosphorylation of primary cultured neurons within 15 min, leading to significant cytosolic lactate accumulation, which contributes to the rapid intracellular acidification and neuronal injury...

Cell transplantation is an attractive treatment strategy for a variety of brain disorders, as it promises to replenish lost functions and rejuvenate the brain. In particular, transplantation of astrocytes has come into light recently as a therapy for amyotrophic lateral sclerosis (ALS); moreover, grafting of astrocytes also showed positive results in models of other conditions ranging from neurodegenerative diseases of older age to traumatic injury and stroke. Despite clear differences in etiology, disorders such as ALS, Parkinson's, Alzheimer's, and Huntington's diseases, as well as traumatic injury and stroke, converge on a number of underlying astrocytic abnormalities, which include inflammatory changes, mitochondrial damage, calcium signaling disturbance, hemichannel opening, and loss of glutamate transporters...

Traumatic brain injury has a complex pathophysiology that produces both rapid and delayed brain damage. Rapid damage initiates immediately after injury. Treatment of traumatic brain injury is typically delayed many hours, thus only delayed damage can be targeted with drugs. Delayed traumatic brain injury includes neuroinflammation, oxidative damage, apoptosis, and glutamate toxicity. Both the speed and complexity of traumatic brain injury pathophysiology present large obstacles to drug development. Repurposing of Food and Drug Administration-approved drugs may be a highly efficient approach to get therapeutics to the clinic...

In the newborn brain, moderate-severe hypoxia-ischaemia induces glutamate excitotoxicity and inflammation, possibly via dysregulation of candidate astrocytic glutamate transporter ( Glt1 ) and pro-inflammatory cytokines (e.g. Tnfα , Il1β , Il6 ). Epigenetic mechanisms may mediate dysregulation. Hypotheses: (1) hypoxia-ischaemia dysregulates mRNA expression of these candidate genes; (2) expression changes in Glt1 are mediated by DNA methylation changes; and (3) methylation values in brain and blood are correlated...