PATHOLOGICAL NEURONAL DEPOLARIZATION AND NEUROINFLAMMATION A BIDIRECTIONAL CYCLE OF NEURONAL INJURY

Abstract

Neuronal depolarization is essential for normal neuronal communication but becomes harmful when excessive or sustained. During cerebral ischemia, traumatic brain injury, and epilepsy, metabolic failure and disruption of ion gradients cause pathological depolarization, excessive glutamate release, calcium influx, mitochondrial dysfunction, oxidative stress, and excitotoxic neuronal death. Damaged neurons release danger-associated molecular patterns that activate microglia and astrocytes. These glial cells produce inflammatory cytokines, reactive oxygen species, and other mediators that further impair ion homeostasis and glutamate clearance. Neuroinflammation can therefore increase neuronal excitability and promote additional depolarization, creating a self-amplifying cycle of neuronal injury. This review summarizes the mechanisms linking neuronal depolarization, calcium overload, excitotoxicity, glial activation, and neuroinflammation and discusses their relevance to ischemic stroke, epilepsy, traumatic brain injury, and neurodegenerative diseases.