Abstract
Excitotoxicity is a form of neuronal death induced by increased Glutamate (Glu) signaling which has been implicated in the pathophysiology of a myriad of neuropsychiatric conditions, such as dementia, motor disorders and epilepsy, among many others. The molecular mechanisms underlying excitotoxicity involve alterations of Glu and ionic calcium metabolism, Glu receptor –particularly N-Methyl-D-Aspartate receptors (NMDARs)– and Glu transporter functioning, activation of downstream enzymes including phospholipases and proteases, and activation of pro-apoptotic mechanisms such as the conformation of mitochondrial permeability pores and release of pro-apoptotic factors. Different mechanisms appear to be more relevant in distinct acute or chronic contexts. Knowledge of these aspects has propelled use of NMDAR antagonists such as memantine in the therapeutic management of disorders where excitotoxicity is prominent. In this review, we explore the current views on the neurobiological and clinical aspects of excitotoxicity, presenting this process as a complex organized crime at the cellular level.
Highlights
Excitotoxicity is a form of neuronal death caused by hyperactivity of excitatory amino acids –mainly Glutamate (Glu)-in the mammal Central Nervous System (CNS) [1]
The activation of the GluN2B subunit of N-Methyl-D-Aspartate receptors (NMDARs) has been identified as a promoter of excitotoxicity induced by mutant huntingtin protein [116] which has been confirmed with the use of ifenprodil, a GluN2B antagonist in HD mouse cultured neurons in which it has been observed the absence of toxicity after administrating the drug [117]
Analysis of neuronal death by excitotoxicity as a crime scene allows for the proposal of novel therapeutic approaches to diseases where this phenomenon is prominent
Summary
Excitotoxicity is a form of neuronal death caused by hyperactivity of excitatory amino acids –mainly Glutamate (Glu)-in the mammal Central Nervous System (CNS) [1]. Once formed, influx of ions and water into the mitochondrial matrix leads to loss of the membrane potential, swelling of the mitochondrial matrix, respiratory chain damage and a consequent decrease of oxidative phosphorylation, This results in diminished ATP production, free radical generation, and EMM rupture, followed by release of calcium and apoptotic factors [59,60] These include molecules from the BCL-2 family (Bax, Bad, amongst others) [61], cytochrome C, pro-caspases 2, 3 and 9, apoptosis inducing factor and the second caspase activator derived from Smac/Diablo proteins [62]; which activate caspase-dependent apoptosis or autophagy in the cytosol [63].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
