Excitatory Synaptic Transmission in Ischemic Stroke: A New Outlet for Classical Neuroprotective Strategies

Abstract

Stroke is one of the leading causes of death and disability in the world, of which ischemia accounts for the majority. There is growing evidence of changes in synaptic connections and neural network functions in the brain of stroke patients. Currently, the studies on these neurobiological alterations mainly focus on the principle of glutamate excitotoxicity, and the corresponding neuroprotective strategies are limited to blocking the overactivation of ionic glutamate receptors. Nevertheless, it is disappointing that these treatments often fail because of the unspecificity and serious side effects of the tested drugs in clinical trials. Thus, in the prevention and treatment of stroke, finding and developing new targets of neuroprotective intervention is still the focus and goal of research in this field. In this review, we focus on the whole processes of glutamatergic synaptic transmission and highlight the pathological changes underlying each link to help develop potential therapeutic strategies for ischemic brain damage. These strategies include: (1) controlling the synaptic or extra-synaptic release of glutamate, (2) selectively blocking the action of the glutamate receptor NMDAR subunit, (3) increasing glutamate metabolism, and reuptake in the brain and blood, and (4) regulating the glutamate system by GABA receptors and the microbiota–gut–brain axis. Based on these latest findings, it is expected to promote a substantial understanding of the complex glutamate signal transduction mechanism, thereby providing excellent neuroprotection research direction for human ischemic stroke (IS).

Common Signaling Pathways Involved in Alzheimer’s Disease and Stroke: Two Faces of the Same Coin

“…Glutamate has an important role in ischemia-induced excitotoxicity. Astrocytes dynamically control synaptic transmission and trigger excitotoxicity by the secretion of glutamate in stroke [ 22 ]. The mechanism of astrocytic glutamate secretion has been mysterious.…”

Research progress and perspectives of N-methyl-D-aspartate receptor in myocardial and cerebral ischemia-reperfusion injury: A review

“…For example, MK-801, ketamine, and memantine are a class of noncompetitive NMDAR antagonists that bind to the ion channels of the NMDAR and block cation passage; memantine and dextromethorphan are a class of low-affinity noncompetitive NMDAR antagonists that bind to the ion channels of the NMDAR but are effective only in the presence of high levels of glutamate; ifenprodil, Ro25-6981, etc are a class of selective NR2B subunit antagonists, which can bind to the NR2B subunit and inhibit NMDAR in the presence of high levels of NR2B, [92] and AP5, AP7, etc are a class of competitive NMDAR antagonists, which can compete for the glutamate-binding site and prevent glutamate from activating NMDAR. [45] NMDAR modulators: These drugs can improve cerebral IRI by affecting the expression, transport, assembly, and degradation of NMDAR to regulate the amount or function of NMDAR. For example, thioredoxin can ameliorate cerebral IRI by decreasing the expression of NR1 and NR2A subunits, [93] thiol-based redox-active proteins can be cardioprotective therapeutic agents for cardiovascular diseases, [94] and hydrogen sulfide can protect neurons by inhibiting phosphorylation of NR2B subunits and activation of CaMKII.…”

GABAergic system and chloride cotransporters as potential therapeutic targets to mitigate cell death in ischemia

“…This lack of blood and consequent oxygen supply can trigger complex biological processes that lead to cell death. Mechanisms such as excitotoxicity—primarily mediated by the neurotransmitter glutamate—oxidative stress, and inflammation are involved in the outcome (Qin et al., 2022; F. Wang et al., 2022). Therefore, the heightened neuronal excitability significantly impacts the protection or recovery of nerve tissue after an ischemic event, emphasizing the importance of neutralizing this response to mitigate the damage.…”

“…This lack of blood and consequent oxygen supply can trigger complex biological processes that lead to cell death. Mechanisms such as excitotoxicity-primarily mediated by the neurotransmitter glutamate-oxidative stress, and inflammation are involved in the outcome (Qin et al, 2022;F. Wang et al, 2022).…”