Novel concepts in excitotoxic neurodegeneration after stroke

Abstract

Brain injury following cerebral ischaemia (stroke) involves a complex combination of pathological processes, including excitotoxicity and inflammation leading to necrotic and apoptotic forms of cell death. At the cellular level, excitotoxicity is mediated by glutamate and its cognate receptors, resulting in increased intracellular calcium and free radical production, and eventual cell death. Recent evidence suggests that scaffolding molecules that associate with glutamate receptors at the postsynaptic density allow coupling of receptor activity to specific second messengers capable of mediating excitotoxicity. These findings have important implications in the search for effective neuroprotective therapies in treating stroke.

Sigma-1 Receptors and Neurodegenerative Diseases: Towards a Hypothesis of Sigma-1 Receptors as Amplifiers of Neurodegeneration and Neuroprotection

“…As the primary insult (e.g., direct mechanical damage) cannot be therapeutically influenced, the goal of treatment is to limit secondary injury processes. Following cerebral ischemia, both necrotic and apoptotic cell death can be induced through complex interactions of pathological processes, including excitotoxicity and inflammation [8, 9]. Neuroprotective and neurorestorative effects of sigma-1 agonists (e.g., decreasing cell death, protecting against tissue damage, and increasing synaptic protein expression) have been shown in multiple animal models of stroke, including mouse [10], rat [11–16], gerbil [17] and cat [18].…”

Molecular and cellular mechanisms of excitotoxic neuronal death

“…These intracellular signaling molecules make significant contributions to the excitotoxic death of neurons [121,122].…”

Homer-1a immediate early gene expression correlates with better cognitive performance in aging

“…Scaffolding proteins play a critical role in maintaining synaptic integrity by organizing synaptic proteins (Aarts et al 2003;Hayashi et al 2009;Haucke et al 2011). Vesl/Homer proteins are a group of scaffolding proteins that facilitate the effective conversion of extracellular into intracellular signals at excitatory synapses by clustering and organizing signaling proteins at synaptic sites.…”