Abstract:

Excitotoxicity and neuronal cell death: Glutamate is the main excitatory neurotransmitter of the central nervous system and functionally involved in most brain activities, including brain development, synaptic plasticity, learning and memory. Excitatory synaptic transmission is primarily mediated by ligand-gated ion channels, including α‐amino‐3‐hydroxy‐5‐methylisoxazole‐4‐propionic acid (AMPA), N-methyl-D-aspartate (NMDA) and kainate receptors. Activation of glutamate receptors, particularly NMDA receptors, usually leads to calcium influx, which can act as a second messenger for several processes to mediate synaptic activity and brain function. Nevertheless, excessive release of glutamate neurotransmitter may produce intracellular calcium overload, leading to a cascade of events mediating cytoskeleton damage accompanied with reactive oxygen species (ROS) generation, mitochondrial dysfunction and ultimately neuronal cell death. These toxic effects of glutamate are known as excitotoxicity. Neuronal excitotoxicity has been linked to several acute and chronic brain diseases, such as stroke/ischemia, epilepsy and a range of neurodegenerative disorders, including Alzheimer’s disease (AD), Huntington’s disease, amyotrophic lateral sclerosis (ALS) and Parkinson’s disease (PD), contributing to the neuronal lost in different brain regions. Unfortunately, treating nervous system disorders with general glutamate receptor blockers has been associated with undesirable side effects, becoming increasingly necessary to unravel downstream effectors in the excitotoxicity-dependent cell death pathway in order to develop novel therapeutic strategies.