2022
DOI: 10.1186/s40035-021-00278-7
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Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration

Abstract: Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Neverth… Show more

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Cited by 204 publications
(129 citation statements)
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References 178 publications
(207 reference statements)
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“…The common feature among all TBI is that part of the energy associated with the traumatic event (primary injury) is absorbed by the brain tissue, invariably triggering a plethora of biochemical, metabolic, and molecular alterations (secondary injury), profoundly affecting various biological processes and functions of neuronal cells [ 2 , 3 ]. Among them, glutamate (Glu) excitotoxicity [ 4 , 5 , 6 , 7 ] and alterations of the brain levels of numerous free amino acids (FAA) involved in relevant biochemical activities [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] have been reported to occur following TBI. For these reasons, TBI patients are still in search of valid pharmacological treatments that can ameliorate their outcome.…”
Section: Introductionmentioning
confidence: 99%
“…The common feature among all TBI is that part of the energy associated with the traumatic event (primary injury) is absorbed by the brain tissue, invariably triggering a plethora of biochemical, metabolic, and molecular alterations (secondary injury), profoundly affecting various biological processes and functions of neuronal cells [ 2 , 3 ]. Among them, glutamate (Glu) excitotoxicity [ 4 , 5 , 6 , 7 ] and alterations of the brain levels of numerous free amino acids (FAA) involved in relevant biochemical activities [ 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 ] have been reported to occur following TBI. For these reasons, TBI patients are still in search of valid pharmacological treatments that can ameliorate their outcome.…”
Section: Introductionmentioning
confidence: 99%
“…These ligand-gated ion channels have inspired a large number of studies because of their various structural subtypes and unique physiological functions [ 126 ]. NMDA receptor is an important target in clinical research of ischemic stroke, which is mainly located in dendritic spines, perisynaptic areas, and extra-synaptic areas [ 12 ]. It is generally believed that compared with AMPA and KA receptors, NMDA receptors are the most effective agonists for inducing neurotoxicity due to their higher voltage-dependent flux and permeability to calcium ions, and do not show concentration-dependent desensitization of glutamate [ 125 ].…”
Section: Postsynaptic Effect Of Glutamate As the Main Mechanism Of Ne...mentioning
confidence: 99%
“…After glutamate releasing from the presynapse, the activation of AMPAR removes magnesium ions blocking NMDAR channels, then NMDAR acts as an effective “coincidence detector” to transport Na 2+ and Ca 2+ into cells [ 127 , 128 ]. In addition, the coupling of various death-related signals related to the cytoplasmic tail of the NMDAR initiates a series of postsynaptic death events, which may also be the reason why synaptic NMDAR-mediated calcium currents can cause greater neurotoxicity than other calcium sources [ 12 , 38 ].…”
Section: Postsynaptic Effect Of Glutamate As the Main Mechanism Of Ne...mentioning
confidence: 99%
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“…There is now significant evidence that degeneration of presynaptic terminals precedes neuronal death in chronic neurodegenerative diseases of the CNS [25,26]. However, the contribution of axotomy to the neuronal loss in SCI remains controversial.…”
Section: Neuronal Lossmentioning
confidence: 99%