The overlooked aspect of excitotoxicity: Glutamate‐independent excitotoxicity in traumatic brain injuries

Abstract

Traumatic brain injury (TBI) is a leading major cause of morbidity and mortality in youth and individuals under 45 year age. A wide variety of cellular and molecular mechanisms have been identified contributing to the pathogenesis of TBI. A better understanding of the pathophysiology behind TBI is essential for providing more effective treatment. Excitotoxicity as one of the secondary molecular events is a major contributing factor in apoptosis and neuronal death following the initial injury in TBI. Excitotoxicity is the rapid overload and influx of calcium into the cell cytoplasm, activating a series of deleterious signaling cascades causing the cell to undergo apoptosis. Conventional understanding is that the rapid influx of calcium is initiated through glutamate release. However, there are overlooked glutamate‐independent mechanisms that cause the rapid calcium influx into the neuronal cytoplasm, evoking or contributing to excitotoxicity. Therefore, the focus of this review will be on the role of the glutamate‐independent excitotoxic mechanisms of the mechanosensitive response of NMDA receptors, mechanoporation of the cell membrane, ischemia, and the release of calcium from intracellular stores. In conclusion, the shear and stretch forces during a TBI event may result in the mechanosensitive activation of NMDA receptors which contribute to glutamate‐independent excitotoxicity.

The Role of NLRP3 Inflammasome in the Pathogenesis of Traumatic Brain Injury

“…Excitotoxicity may also be independent from glutamate and is mainly due to the glutamate-independent opening of NMDA receptors since the unexpected movements of the head activate neuronal membranes mechanoporation, eventually activating ischemic events, intracellular calcium accumulation and cell death mechanisms following TBI [ 19 , 20 ]. As a matter of fact, NMDA receptors respond to mechanical stress following TBI and GluN2B subunit is considered as a mediator of the mechanosensitive responses, thus activating pro-death signals.…”

“…TBI causes severe alterations in cell membranes, promoting calcium influx, and calcium may also directly induce excitotoxicity as a consequence of TBI. Moreover, calcium influx may be promoted following ischemic processes related to TBI [ 19 ]. In particular, the anaerobic environment after ischemia activates sodium–calcium exchangers (NCX), acid-sensing ion channels (ASIC) and transient receptor potential channels (TRPM), thus increasing intracellular calcium levels and consequently activating excitotoxic pathways and cell death processes independently of glutamate [ 25 , 26 , 27 , 28 ].…”

Chinese Herbal Medicine Interventions in Neurological Disorder Therapeutics by Regulating Glutamate Signaling

“…Glutamate induces neuronal Ca 2+ overload via overactivating the NMDA receptors, with the production of reactive oxygen species and reactive nitrogen radicals. Glutamate also induces Na + influx by overactivating AMPA and KA receptors, with acute osmotic swelling of nerve cells [ 35 , 36 ]. Both these harmful cascades then lead to neuronal death mainly through the dysfunction of calcium homeostasis, which plays a critical role in the process [ 34 ].…”

Targeting Intracellular Calcium Stores Alleviates Neurological Morbidities in a DFP-Based Rat Model of Gulf War Illness

“…Ca 2+ -induced Ca 2+ -release (CICR) is one such process that is mediated by ryanodine receptors (RyRs) and inositol tris-phosphate receptors (IP 3 R) that amplify Ca 2+ signal by releasing additional Ca 2+ from the endoplasmic reticulum (ER) in response to Ca 2+ influx via plasmalemmal channels. Disruptions in neuronal Ca 2+ homeostasis are implicated in many neurodegenerative disorders including Alzheimer’s disease (Popugaeva et al , 2017), Parkinson’s disease (Surmeier et al , 2017), acquired epilepsy (Nagarkatti et al , 2009), and traumatic brain injury (TBI) (Tehse and Taghibiglou, 2018). These disorders manifest psychiatric comorbidities like those seen in GWI Veterans.…”