Pathobiochemical mechanisms of excitotoxicity: the role of astrocytic metabolic failure

Abstract

This work analyzes the pathobiochemical mechanisms of excitotoxicity arising from the impairment of the astrocytic glutamate-glutamine cycle (GGC). It has been established that dysfunction of key astrocytic proteins—the EAAT2 transporter and the enzyme glutamine synthetase (GS)—constitutes a central link in the pathogenesis of a wide spectrum of neurological disorders, ranging from acute ischemia to chronic neurodegeneration. Four primary biological initiators of this process have been recognized: energy depletion (ATP deficiency), oxidative stress, transcriptional interference, and direct toxic inhibition. It is demonstrated that the loss of astrocytic control over extracellular glutamate triggers a lethal cascade in neurons, which includes NMDA receptor hyperactivation, calcium overload, mitochondrial dysfunction, and the activation of lytic enzymes.