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AD and OGD-induced cell death are reduced in Slc7a11sut mice, which lack a functional cystine/glutamate antiporter. ( A ) Voltage-clamp recording of OGD-activated currents in mouse acute slices. The anoxic current amplitude was reduced in the xCT-deficient ( sut/sut ; n = 13) mice when compared with that in wild-type mice ( +/+ ; n = 14). However, the latency to AD was unchanged. ( B ) Histograms show the average amplitude (pA ± SEM) and latency (minutes ± SEM) of the OGD-induced current for each genotype. * P < 0.05. ( C ) Simultaneous extracellular DC field potential recording in acute slices from wild-type and sut/sut mice subjected to OGD. Histogram shows the average DC field potential (mV ± SEM) for each genotype. * P < 0.05. ( D ) Cell death measured by LDH release in organotypic cultures from wild-type and sut/sut mice exposed to 45 minutes of OGD and 24 hours of reoxygenation. Data are expressed as the mean ± SEM ( n = 3). ( E ) Representative fields demonstrate propidium iodide labeling of organotypic slices treated as in D . Scale bar: 1 mm.
Source publication
During brain ischemia, an excessive release of glutamate triggers neuronal death through the overactivation of NMDA receptors (NMDARs); however, the underlying pathways that alter glutamate homeostasis and whether synaptic or extrasynaptic sites are responsible for excess glutamate remain controversial. Here, we monitored ischemia-gated currents in...
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Citations
... Considering its biochemical functions and its widespread distribution in the CNS, system x c − has been studied in several neurological disorders in which dysregulated excitatory transmission contributes to nervous insults and neurodegeneration. In particular, increased xCT expression has been documented in models of Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis as well as in stroke or glioblastoma [19][20][21][22][23][24]. A role for system x c − was also documented in the modulation of inflammatory responses, raising further interest for its implication in pathologies combining neuroinflammation and increased neuronal excitation [19]. ...
Background
Despite the high prevalence of neuropathic pain, treating this neurological disease remains challenging, given the limited efficacy and numerous side effects associated with current therapies. The complexity in patient management is largely attributed to an incomplete understanding of the underlying pathological mechanisms. Central sensitization, that refers to the adaptation of the central nervous system to persistent inflammation and heightened excitatory transmission within pain pathways, stands as a significant contributor to persistent pain. Considering the role of the cystine/glutamate exchanger (also designated as system xc⁻) in modulating glutamate transmission and in supporting neuroinflammatory responses, we investigated the contribution of this exchanger in the development of neuropathic pain.
Methods
We examined the implication of system xc⁻ by evaluating changes in the expression/activity of this exchanger in the dorsal spinal cord of mice after unilateral partial sciatic nerve ligation. In this surgical model of neuropathic pain, we also examined the consequence of the genetic suppression of system xc⁻ (using mice lacking the system xc⁻ specific subunit xCT) or its pharmacological manipulation (using the pharmacological inhibitor sulfasalazine) on the pain-associated behavioral responses. Finally, we assessed the glial activation and the inflammatory response in the spinal cord by measuring mRNA and protein levels of GFAP and selected M1 and M2 microglial markers.
Results
The sciatic nerve lesion was found to upregulate system xc⁻ at the spinal level. The genetic deletion of xCT attenuated both the amplitude and the duration of the pain sensitization after nerve surgery, as evidenced by reduced responses to mechanical and thermal stimuli, and this was accompanied by reduced glial activation. Consistently, pharmacological inhibition of system xc⁻ had an analgesic effect in lesioned mice.
Conclusion
Together, these observations provide evidence for a role of system xc⁻ in the biochemical processes underlying central sensitization. We propose that the reduced hypersensitivity observed in the transgenic mice lacking xCT or in sulfasalazine-treated mice is mediated by a reduced gliosis in the lumbar spinal cord and/or a shift in microglial M1/M2 polarization towards an anti-inflammatory phenotype in the absence of system xc⁻. These findings suggest that drugs targeting system xc⁻ could contribute to prevent or reduce neuropathic pain.
... PostC ischemic postconditioning, Ru265 ruthenium red 265; sham, control + Ru265 10 µM Page 10 of 14 that MCU plays a key role in the PostC pathway. During I/R injury, an excessive release of glutamate occurs, leading to over-activation of NMDAR (Bonova et al. 2013;Dávalos et al. 1997;Soria et al. 2014). This cascade leads to cell necrosis or apoptosis by excess Ca 2+ influx into the neuron, triggering a range of downstream pro-death signaling events such as calpain activation, generation of reactive oxygen species and damage to mitochondria (Curcio et al. 2016;Kristián and Siesjö 1998;Lau and Tymianski 2010). ...
The phenomenon of ischemic postconditioning (PostC) is known to be neuroprotective against ischemic reperfusion (I/R) injury. One of the key processes in PostC is the opening of the mitochondrial ATP-dependent potassium (mito-KATP) channel and depolarization of the mitochondrial membrane, triggering the release of calcium ions from mitochondria through low-conductance opening of the mitochondrial permeability transition pore. Mitochondrial calcium uniporter (MCU) is known as a highly sensitive transporter for the uptake of Ca²⁺ present on the inner mitochondrial membrane. The MCU has attracted attention as a new target for treatment in diseases, such as neurodegenerative diseases, cancer, and ischemic stroke. We considered that the MCU may be involved in PostC and trigger its mechanisms. This research used the whole-cell patch-clamp technique on hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca²⁺ concentration, mitochondrial membrane potential, and N-methyl-d-aspartate receptor (NMDAR) currents under inhibition of MCU by ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased the occurrence of sEPSCs (p = 0.014), NMDAR currents (p < 0.001), intracellular Ca²⁺ concentration (p < 0.001), and dead cells (p < 0.001) significantly after reperfusion, reflecting removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was weakened, compared to PostC (p = 0.004). These results suggest that MCU affects mitochondrial depolarization in PostC to suppress NMDAR over-activation and prevent elevation of intracellular Ca²⁺ concentrations against I/R injury.
Graphical Abstract
... Many acute and chronic neurodegenerative disorders are characterized by deficits in glutamate uptake systems, which causes extracellular glutamate concentrations to increase to neurotoxic levels. Hypoxic ischemic conditions can further exacerbate deregulation of glutamate homeostasis through enhanced extrasynaptic glutamate release via the cystine/glutamate antiporter, System XC [11] (Figure 1). Thus, while in healthy condition, the action of glutamate is restricted to the synapse, in neurodegenerative diseases, glutamate receptors located outside synaptic contacts are being activated. ...
... Indeed, the cell pathology common to virtually all neurodegenerative conditions is highly reminiscent of the typical pathological triad triggered by the activation of eNMDARs: loss of structural integrity (i.e., the loss of synapses and dendrites), mitochondrial dysfunction (i.e., the breakdown of the mitochondrial membrane potential, metabolic/energy insufficiency, and increased production of reactive oxygen species), and transcriptional deregulation (i.e., CREB shut-off and reduced expression of activity-regulated neurotrophic/neuroprotective genes) [4,5,38]. One reason for the convergence of different pathomechanisms on toxic eNMDAR signaling is that virtually all neurodegenerative conditions are burdened with faulty or deregulated glutamate uptake systems, resulting in the leakage of synaptically released glutamate and a subsequent rise in glutamate levels at extrasynaptic locations [7,11,[117][118][119]. Deregulated glutamate homeostasis is further enhanced via neuroinflammatory responses and a leaky bloodbrain barrier, both of which are often associated with degenerative processes in the brain. ...
... Indeed, the cell pathology common to virtually all neurodegenerative conditions is highly reminiscent of the typical pathological triad triggered by the activation of eNMDARs: loss of structural integrity (i.e., the loss of synapses and dendrites), mitochondrial dysfunction (i.e., the breakdown of the mitochondrial membrane potential, metabolic/energy insufficiency, and increased production of reactive oxygen species), and transcriptional deregulation (i.e., CREB shut-off and reduced expression of activity-regulated neurotrophic/neuroprotective genes) [4,5,38]. One reason for the convergence of different pathomechanisms on toxic eNMDAR signaling is that virtually all neurodegenerative conditions are burdened with faulty or deregulated glutamate uptake systems, resulting in the leakage of synaptically released glutamate and a subsequent rise in glutamate levels at extrasynaptic locations [7,11,[117][118][119]. Deregulated glutamate homeostasis is further enhanced via neuroinflammatory responses and a leaky blood-brain barrier, both of which are often associated with degenerative processes in the brain. ...
With the discovery that the acquisition of toxic features by extrasynaptic NMDA receptors (NMDARs) involves their physical interaction with the non-selective cation channel, TRPM4, it has become possible to develop a new pharmacological principle for neuroprotection, namely the disruption of the NMDAR/TRPM4 death signaling complex. This can be accomplished through the expression of the TwinF domain, a 57-amino-acid-long stretch of TRPM4 that mediates its interaction with NMDARs, but also using small molecule TwinF interface (TI) inhibitors, also known as NMDAR/TRPM4 interaction interface inhibitors. Both TwinF and small molecule TI inhibitors detoxify extrasynaptic NMDARs without interfering with synaptic NMDARs, which serve important physiological functions in the brain. As the toxic signaling of extrasynaptic NMDARs contributes to a wide range of neurodegenerative conditions, TI inhibitors may offer therapeutic options for currently untreatable human neurodegenerative diseases including Amyotrophic Lateral Sclerosis, Alzheimer’s disease, and Huntington’s disease.
... In addition, the dysfunction of the xc-system that leads to glutathione depletion also occurs in ferroptosis [78][79][80]. Oxidative glutamate intoxication, also known as oxidative glutamate intoxication, is a glutamate-induced cell death mediated by blocking of the xc-system [81]. ...
Diabetic cardiomyopathy (DC) is a serious heart disease caused by diabetes. It is unrelated to hypertension and coronary artery disease and can lead to heart insufficiency, heart failure and even death. Currently, the pathogenesis of DC is unclear, and clinical intervention is mainly symptomatic therapy and lacks effective intervention objectives. Iron overdose mediated cell death, also known as ferroptosis, is widely present in the physiological and pathological processes of diabetes and DC. Iron is a key trace element in the human body, regulating the metabolism of glucose and lipids, oxidative stress and inflammation, and other biological processes. Excessive iron accumulation can lead to the imbalance of the antioxidant system in DC and activate and aggravate pathological processes such as excessive autophagy and mitochondrial dysfunction, resulting in a chain reaction and accelerating myocardial and microvascular damage. In-depth understanding of the regulating mechanisms of iron metabolism and ferroptosis in cardiovascular vessels can help improve DC management. Therefore, in this review, we summarize the relationship between ferroptosis and the pathogenesis of DC, as well as potential intervention targets, and discuss and analyze the limitations and future development prospects of these targets.
... The extrasynaptic glutamate level is sensitive to abnormal and pathological conditions. For example, in rodents, stressful stimuli such as body restraint, forced swimming, and hypoxic insults can selectively increase the extrasynaptic glutamate concentration to over 30 µM or higher [143][144][145]. In stroke and brain injuries, the reduced extracellular volume associated with brain edema elevates the extrasynaptic glutamate concentration as a contributing factor in excitatory neuronal damage [146]. ...
... Compatible with the lower concentrations, extrasynaptic glutamate preferably activates the main population of eNMDARs of higher affinity, e.g., GluN2B-containing NMDARs. GluN2B-containing eNMDARs were proposed to be responsible for ischemia-induced excitotoxicity [179,180], and extrasynaptic glutamate is a primary contributor to ischemic and traumatic damage in the brain [143,146,181]. The activation of eNMDARs, perhaps together with the impaired protective function of sNMDARs, contributes to downstream cascades of necrotic and programmed cell death pathways [179,182]. ...
Stroke and late-onset Alzheimer’s disease (AD) are risk factors for each other; the comorbidity of these brain disorders in aging individuals represents a significant challenge in basic research and clinical practice. The similarities and differences between stroke and AD in terms of pathogenesis and pathophysiology, however, have rarely been comparably reviewed. Here, we discuss the research background and recent progresses that are important and informative for the comorbidity of stroke and late-onset AD and related dementia (ADRD). Glutamatergic NMDA receptor (NMDAR) activity and NMDAR-mediated Ca ²⁺ influx are essential for neuronal function and cell survival. An ischemic insult, however, can cause rapid increases in glutamate concentration and excessive activation of NMDARs, leading to swift Ca ²⁺ overload in neuronal cells and acute excitotoxicity within hours and days. On the other hand, mild upregulation of NMDAR activity, commonly seen in AD animal models and patients, is not immediately cytotoxic. Sustained NMDAR hyperactivity and Ca ²⁺ dysregulation lasting from months to years, nevertheless, can be pathogenic for slowly evolving events, i.e. degenerative excitotoxicity, in the development of AD/ADRD. Specifically, Ca ²⁺ influx mediated by extrasynaptic NMDARs (eNMDARs) and a downstream pathway mediated by transient receptor potential cation channel subfamily M member (TRPM) are primarily responsible for excitotoxicity. On the other hand, the NMDAR subunit GluN3A plays a “gatekeeper” role in NMDAR activity and a neuroprotective role against both acute and chronic excitotoxicity. Thus, ischemic stroke and AD share an NMDAR- and Ca ²⁺ -mediated pathogenic mechanism that provides a common receptor target for preventive and possibly disease-modifying therapies. Memantine (MEM) preferentially blocks eNMDARs and was approved by the Federal Drug Administration (FDA) for symptomatic treatment of moderate-to-severe AD with variable efficacy. According to the pathogenic role of eNMDARs, it is conceivable that MEM and other eNMDAR antagonists should be administered much earlier, preferably during the presymptomatic phases of AD/ADRD. This anti-AD treatment could simultaneously serve as a preconditioning strategy against stroke that attacks ≥ 50% of AD patients. Future research on the regulation of NMDARs, enduring control of eNMDARs, Ca ²⁺ homeostasis, and downstream events will provide a promising opportunity to understand and treat the comorbidity of AD/ADRD and stroke.
... Cytosolic Ca 2+ in ux into the mitochondrial matrix via MCU leads to the elevation of mitochondrial Ca 2+ concentration and induces the regulation of various mitochondrial metabolism: mitochondrial respiration, adenosine triphosphate (ATP) production, mitophagy/autophagy and even the death pathway of apoptosis or necrosis [34][35][36]. Meanwhile, it is known that during I/R injury, an excessive release of glutamate occurs and induces over-activation of NMDAR [37][38][39]. This cascade leads to cell necrosis or apoptosis by excessing Ca 2+ in ux into the neurons and triggering subsequently a range of downstream pro-death signaling events such as calpain activation, reactive oxygen species (ROS) generation and mitochondrial damage [40][41][42]. ...
Ischemic postconditioning (PostC) phenomenon is known as the neuroprotection against ischemic reperfusion (I/R) injury. One of the key processes in PostC is opening of mitochondrial ATP dependent potassium (mito-K ATP ) channel and depolarization of mitochondrial membrane potential, which triggers the release of calcium ion from mitochondria through the low conductance opening of mitochondrial permeability transition pore (mPTP). Mitochondrial calcium uniporter (MCU) is known as the highly sensitive transporter for uptake of Ca ²⁺ inwardly existed on the inner mitochondrial membrane. Furthermore, it has attracted attention as a new target of treatments in disease such as neurodegenerative disease, cancer, and ischemic stroke. Thus, we considered that MCU may involve in PostC and trigger its mechanism. In this research, we used the whole-cell patch clamp technique to hippocampal CA1 pyramidal cells from C57BL mice and measured changes in spontaneous excitatory post-synaptic currents (sEPSCs), intracellular Ca ²⁺ concentration, mitochondrial membrane potential and N-methyl-D-aspartate receptor (NMDAR) currents under the inhibition of MCU by Ruthenium red 265 (Ru265) in PostC. Inhibition of MCU increased sEPSCs occurrence (p = 0.008), NMDAR currents (p < 0.001), intracellular Ca ²⁺ concentration (p < 0.001) and dead cells (p < 0.001) significantly after reperfusion, indicating the removal of the neuroprotective effects in PostC. Moreover, mitochondrial depolarization in PostC with Ru265 was gradually decreased after reperfusion (p < 0.001). These results suggest that MCU plays an important role in PostC by maintaining mitochondrial depolarization, which suppresses hyperactivation of NMDARs and prevents the elevation of intracellular Ca ²⁺ concentration against I/R injury.
... Besides, the researches on other mechanisms mediating ischemic glutamate release have made progress. Recently, extrasynaptic glutamate release through cystine/glutamate antiporter 25 and volume-regulated anion channel SWELL1 26 is reported to promote ischemic damage. These glutamatereleasing approaches are almost stimulated within several minutes to hours, leading to narrow time window for neuroprotective treatment, though they are critical to the irreversible injury ultimately resulting in the infarction. ...
... Anoxic depolarization (AD) currents in brain slices were induced by oxygen and glucose deprivation (OGD) and recorded as reported 25 . Voltage-clamp recording pipettes (4e6 MU) were filled with a solution containing 135 mmol/L CsCl, 4 mmol/L NaCl, 0.7 mmol/L CaCl 2 , 10 mmol/L BAPTA, 10 mmol/L HEPES, 4 mmol/L Mg-ATP, and 0.5 mmol/L Na 2 -GTP (pH 7.3). ...
... The effective infection of cortex neurons and the overexpression of BEST1 were verified 21 days after the virus microinjection ( Fig. 6C and D). Consistent with previous report 25 , OGD induced an obvious inward current in control slices (infected with AAV-CMV-3Flag-T2A-GFP), corresponding to AD (Fig. 6E). The OGD-induced current in BEST1 WT -overexpressed slices was larger ( Fig. 6E and F, F (2,32) Z 9.308, P Z 0.009), but almost abolished by concomitant application of AP-5 and CNQX with OGD ( Fig. 6E and F, F (2,32) Z 9.308, P Z 0.001), indicating glutamate release through overexpressed BEST1. ...
Many efforts have been made to understand excitotoxicity and develop neuroprotectants for the therapy of ischemic stroke. The narrow treatment time window is still to be solved. Given that the ischemic core expanded over days, treatment with an extended time window is anticipated. Bestrophin 1 (BEST1) belongs to a bestrophin family of calcium-activated chloride channels. We revealed an increase in neuronal BEST1 expression and function within the peri-infarct from 8 to 48 h after ischemic stroke in mice. Interfering the protein expression or inhibiting the channel function of BEST1 by genetic manipulation displayed neuroprotective effects and improved motor functional deficits. Using electrophysiological recordings, we demonstrated that extrasynaptic glutamate release through BEST1 channel resulted in delayed excitotoxicity. Finally, we confirmed the therapeutic efficacy of pharmacological inhibition of BEST1 during 6–72 h post-ischemia in rodents. This delayed treatment prevented the expansion of infarct volume and the exacerbation of neurological functions. Our study identifies the glutamate-releasing BEST1 channel as a potential therapeutic target against ischemic stroke with a wide time window.
... In response to ischemic stimuli, the release of glutamate-based excitatory amino acids from the intracellular compartment into the extracellular compartment leads to an increase in glutamate levels in the extracellular compartment. The underlying mechanism mainly involves the release of glutamate from the cystine/glutamate retrotransporter, as well as the dysfunction or even retro-transportation of the glutamate uptake system, which mainly comprises excitatory amino acid transporters (EAAT) [e.g., glutamate transporter-1 (GLT-1) and glutamate aspartate transporter (GLAST)] (Soria et al., 2014). In a mouse model of transient MCAO, glutamate concentrations increased rapidly at the onset of cerebral ischemia, reduced during reperfusion, and increased again 1 h after reperfusion; however, anti-HMGB1 antibody could prevent the increase in glutamate concentration after reperfusion , suggesting that HMGB1 promotes extracellular glutamate aggregation after cerebral ischemia. ...
Introduction:
High-mobility group box 1 protein (HMGB1) is extensively involved in causing ischemic stroke, pathological damage of ischemic brain injury, and neural tissue repair after ischemic brain injury. However, the precise role of HMGB1 in ischemic stroke remains to be elucidated.
Methods:
Comprehensive literature search and narrative review to summarize the current field of HMGB1 in cerebral ischemic based on the basic structure, structural modification, and functional roles of HMGB1 described in the literature.
Results:
Studies have exhibited the crucial roles of HMGB1 in cell death, immunity and inflammation, thrombosis, and remodeling and repair. HMGB1 released after cerebral infarction is extensively involved in the pathological injury process in the early stage of cerebral infarction, whereas it is involved in the promotion of brain tissue repair and remodeling in the late stage of cerebral infarction. HMGB1 plays a neurotrophic role in acute white matter stroke, whereas it causes sustained activation of inflammation and plays a damaging role in chronic white matter ischemia.
Conclusions:
HMGB1 plays a complex role in cerebral infarction, which is related to not only the modification of HMGB1 and bound receptors but also different stages and subtypes of cerebral infarction. future studies on HMGB1 should investigate the spatial and temporal dynamics of HMGB1 after cerebral infarction. Moreover, future studies on HMGB1 should attempt to integrate different stages and infarct subtypes of cerebral infarction.
... Gene enrichment analysis using gene ontology showed differential enrichment of biological functions involved in cell adhesion (n = 10) (p = 7.09 × 10 -6 ), negative regulation of response to wounding (n = 5) (p = 1.02 × 10 -6 ), and sprouting angiogenesis (n = 4) (p = 1.22 × 10 -5 ) (blue bars in Fig. 1F). A select number of genes with known roles in synapse formation and neuronal migration (SEMA3E, SLIT2 [69], TCF4 [70]), apoptosis (FEM1B), cell adhesion (FAT4), neuroinflammation (HDAC9) [71,72], stress responses (glucocorticoid receptor or NR3C1), serine/glutamine transport (SLC38A2) [73], and glutamate transport and excitotoxicity (SLC7A11) [74,75] were significantly downregulated in BG of THC/SIV RMs. Additional file 2: Table S4 lists the full names, read counts and fold change of 35 differentially downregulated genes in BG of THC/SIV RMs. ...
... Following SLC38A2-mediated uptake into the presynaptic terminals, glutamine is metabolized by the phosphateactivated mitochondrial enzyme glutaminase to glutamate, which is then released into the synaptic cleft during neuronal activation, thereby increasing extracellular glutamate levels. Expression of SLC7A11, a cystine/glutamate transporter is significantly increased in malignant glioma [74] and during brain ischemia [75] contributing to increased extracellular glutamate levels resulting in overstimulation of NMDA receptors, seizures and neuronal death. As seizures are common in glioma patients, sulfasalazine, an FDA-approved potent but short-term inhibitor of SLC7A11 commonly prescribed to inflammatory bowel disease patients to alleviate colonic inflammation reduced glutamate excitotoxicity and seizures in a pilot study involving nine glioma patients [74]. ...
Background
Although the advent of combination anti-retroviral therapy (cART) has transformed HIV into a manageable chronic disease, an estimated 30–50% of people living with HIV (PLWH) exhibit cognitive and motor deficits collectively known as HIV-associated neurocognitive disorders (HAND). A key driver of HAND neuropathology is chronic neuroinflammation, where proinflammatory mediators produced by activated microglia and macrophages are thought to inflict neuronal injury and loss. Moreover, the dysregulation of the microbiota–gut–brain axis (MGBA) in PLWH, consequent to gastrointestinal dysfunction and dysbiosis, can lead to neuroinflammation and persistent cognitive impairment, which underscores the need for new interventions.
Methods
We performed RNA-seq and microRNA profiling in basal ganglia (BG), metabolomics (plasma) and shotgun metagenomic sequencing (colon contents) in uninfected and SIV-infected rhesus macaques (RMs) administered vehicle (VEH/SIV) or delta-9-tetrahydrocannabinol (THC) (THC/SIV).
Results
Long-term, low-dose THC reduced neuroinflammation and dysbiosis and significantly increased plasma endocannabinoid, endocannabinoid-like, glycerophospholipid and indole-3-propionate levels in chronically SIV-infected RMs. Chronic THC potently blocked the upregulation of genes associated with type-I interferon responses (NLRC5, CCL2, CXCL10, IRF1, IRF7, STAT2, BST2), excitotoxicity (SLC7A11), and enhanced protein expression of WFS1 (endoplasmic reticulum stress) and CRYM (oxidative stress) in BG. Additionally, THC successfully countered miR-142-3p-mediated suppression of WFS1 protein expression via a cannabinoid receptor-1-mediated mechanism in HCN2 neuronal cells. Most importantly, THC significantly increased the relative abundance of Firmicutes and Clostridia including indole-3-propionate (C. botulinum, C. paraputrificum, and C. cadaveris) and butyrate (C. butyricum, Faecalibacterium prausnitzii and Butyricicoccus pullicaecorum) producers in colonic contents.
Conclusion
This study demonstrates the potential of long-term, low-dose THC to positively modulate the MGBA by reducing neuroinflammation, enhancing endocannabinoid levels and promoting the growth of gut bacterial species that produce neuroprotective metabolites, like indole-3-propionate. The findings from this study may benefit not only PLWH on cART, but also those with no access to cART and more importantly, those who fail to suppress the virus under cART.
... Finally, blockade of glutamate receptors eliminated the differences in AD latency between xCT −/− and WT mice, suggesting that the lower levels of tonic glutamate in xCT −/− mice delay AD by slowing the activation of postsynaptic glutamate receptors during anoxia. These results reinforce, extend, and interpret findings of reduced neuronal death after ischaemic challenge in cell culture systems (Hsieh et al., 2017;Jackman et al., 2012;Soria et al., 2014;Thorn et al., 2015) as well as protection from epileptogenesis Leclercq et al., 2019;Sears et al., 2019), cerebral ischaemia (Hsieh et al., 2017) and spinal cord injury (Sprimont et al., 2021) in vivo when system x c − is absent or inhibited. ...
... A previous study (Soria et al., 2014) reported a somewhat different pattern of responses after CPG treatment during combined oxygen and glucose deprivation; the drug decreased AD wave amplitudes, but did not affect AD latency. This investigation, however, recorded voltage-clamp currents from cultured slices in cortical layer V of P18-P30 Sprague-Dawley rats for these measurements, and only provided 1 h of CPG pretreatment -a potentially insufficient epoch for system x c − antagonism to thoroughly decrease ambient glutamate levels in the extracellular space. ...
... As noted above, synapses in xCT −/− mice have a higher abundance of AMPARs that produce larger postsynaptic currents in response to synaptic glutamate release (Williams & Featherstone, 2014); more AMPARs would tend to accelerate AD rather than delay it. That being said, a specific change in extrasynaptic NMDARs as a consequence of system x c − activity remains plausible (Soria et al., 2014). In fact, the tonic activation of NMDARs by ambient glutamate (Dalby & Mody, 2003;Sah et al., 1989) can enhance cell excitability by increasing the proclivity toward regenerative depolarization (Cavelier et al., 2005). ...
In stroke, the sudden deprivation of oxygen to neurons triggers a profuse release of glutamate that induces anoxic depolarization (AD) and leads to rapid cell death. Importantly, the latency of the glutamate‐driven AD event largely dictates subsequent tissue damage. Although the contribution of synaptic glutamate during ischaemia is well‐studied, the role of tonic (ambient) glutamate has received far less scrutiny. The majority of tonic, non‐synaptic glutamate in the brain is governed by the cystine/glutamate antiporter, system xc⁻. Employing hippocampal slice electrophysiology, we showed that transgenic mice lacking a functional system xc⁻ display longer latencies to AD and altered depolarizing waves compared to wild‐type mice after total oxygen deprivation. Experiments which pharmacologically inhibited system xc⁻, as well as those manipulating tonic glutamate levels and those antagonizing glutamate receptors, revealed that the antiporter's putative effect on ambient glutamate precipitates the ischaemic cascade. As such, the current study yields novel insight into the pathogenesis of acute stroke and may direct future therapeutic interventions. image
Key points
Ischaemic stroke remains the leading cause of adult disability in the world, but efforts to reduce stroke severity have been plagued by failed translational attempts to mitigate glutamate excitotoxicity.
Elucidating the ischaemic cascade, which within minutes leads to irreversible tissue damage induced by anoxic depolarization, must be a principal focus.
Data presented here show that tonic, extrasynaptic glutamate supplied by system xc⁻ synergizes with ischaemia‐induced synaptic glutamate release to propagate AD and exacerbate depolarizing waves.
Exploiting the role of system xc⁻ and its obligate release of ambient glutamate could, therefore, be a novel therapeutic direction to attenuate the deleterious effects of acute stroke.
