Spreading depolarization: A wave that precedes and drives cerebral ischemic cell death—Target for neuroprotection

Spreading depolarization (SD) is an all-or-none response of gray matter, evolutionarily conserved from insects to mammals and characterized by near-complete breakdown of transmembrane ion gradients and cytotoxic edema. In humans, SD has been recorded in diverse neurological conditions, including cerebral ischemia and hemorrhage, traumatic brain injury (TBI), and even during whole-brain death following cardiac arrest or during continued systemic circulation. During migraine aura, initial hyperemia accompanies short-lived and benign SD. SD under energy deficiency is also initially reversible. However, if intraneuronal Ca²⁺ increases persist for too long, cell death develops, characterized by a negative ultraslow potential. The same SD wave can be long-lasting and deadly in one place, but short and harmless in another. Energy depletion after arterial obstruction triggers SD within minutes, but SD can also arise in non-ischemic tissue and trigger vasoconstriction and ischemia as a result of an inverse hemodynamic response. Overall, SD may be both adaptive and maladaptive, depending on the tissue conditions. As final reversible stage before ischemic neuronal death, it is not only an orderly retreat from life, but can also allow a reboot. SD is a biomarker of neuronal injury during neurocritical care and a compelling yet complex therapeutic target for neuroprotection.