Excitotoxicity and stroke: identifying novel targets for neuroprotection.
By T. Lai, Shu Zhang, Y. Wang. Progress in neurobiology, 2014
1,054 citations recorded by the source corpus.
Excitotoxicity, the specific type of neurotoxicity mediated by glutamate, may be the missing link between ischemia and neuronal death, and intervening the mechanistic steps that lead to excitotoxicity can prevent stroke damage. Interest in excitotoxicity began fifty years ago when monosodium glutamate was found to be neurotoxic. Evidence soon demonstrated that glutamate is not only the primary excitatory neurotransmitter in the adult brain, but also a critical transmitter for signaling neurons to degenerate following stroke. The finding led to a number of clinical trials that tested inhibitors of excitotoxicity in stroke patients. Glutamate exerts its function in large by activating the calcium-permeable ionotropic NMDA receptor (NMDAR), and different subpopulations of the NMDAR may generate different functional outputs, depending on the signaling proteins directly bound or indirectly coupled to its large cytoplasmic tail. Synaptic activity activates the GluN2A subunit-containing NMDAR, leading to activation of the pro-survival signaling proteins Akt, ERK, and CREB. During a brief episode of ischemia, the extracellular glutamate concentration rises abruptly, and stimulation of the GluN2B-containing NMDAR in the extrasynaptic sites triggers excitotoxic neuronal death via PTEN, cdk5, and DAPK1, which are directly bound to the NMDAR, nNOS, which is indirectly coupled to the NMDAR via PSD95, and calpain, p25, STEP, p38, JNK, and SREBP1, which are further downstream. This review aims to provide a comprehensive summary of the literature on excitotoxicity and our perspectives on how the new generation of excitotoxicity inhibitors may succeed despite the failure of the previous generation of drugs.
Subfields: Cellular and Molecular Neuroscience, Developmental Neuroscience, Neurology
View Paper: https://www.semanticscholar.org/paper/9978715a6e1b5a2f23b9b79dec11a707606aaffc
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Citations in the corpus
- Neuronal Cell Death. (2018, positive): “Neurotoxic beta amyloid oligomers have been shown to sensitize mPTP in isolated brain mitochondria so that the pore can open at physiological levels of Ca2 (474).”
- Mechanisms of neuronal cell death in ischemic stroke and their therapeutic implications (2021, background): “357,358,364‐368 These compounds were designed to effectively avoid the potential neurological side effects observed with traditional NMDAR antagonists.(27) The injection of capsaicin, which causes the pungent taste of chili peppers and is known to reduce pain,(369) directly into the peri‐infarct are”
- Hallmarks of neurodegenerative diseases. (2023, neutral): “34,35,86,94,192,193 Similarly, the concomitant effects of axonal injury, excitotoxicity, and energy depletion promote neurodegeneration in SCI. 36,171 Assessment of energy homeostasis can be performed using FDG-PET, which enables to measure regional glucose metabolism in the brain.”
- Signaling pathways involved in ischemic stroke: molecular mechanisms and therapeutic interventions (2022, background): “Similarly, IC87201 has been found to disrupt pathogenic interactions between PSD95 and nNOS but without impairing normal nNOS activities.(27) Finally, a study has shed light on Neu2000, a sulfasalazine derivative and GluN2B antagonist that selectively blocks NMDARs and scavenges free radicals, which”