Delta-opioid receptor-mediated neural protection and regeneration.

Ischemic stroke (IS) ranks as the second leading cause of death and a primary cause of long-term disability worldwide, characterized by its high incidence, recurrence, and morbidity rates (). IS is precipitated by the stenosis or occlusion of cerebral arteries, which results in a critical reduction of cerebral blood flow. This hemodynamic failure induces focal ischemia and hypoxia, ultimately culminating in neuronal necrosis and the rapid loss of neurological functions governed by the affected regions. While modern medical management has successfully lowered mortality rates, many survivors are left with varying degrees of neurological deficits. These impairments often manifest as motor, sensory, cognitive, or linguistic dysfunction. Collectively, they represent a major challenge and impose a profound burden on global public health (). While reperfusion therapies are widely applied, the risk of recurrence remains high, and survivors frequently endure persistent functional sequelae. Beyond the local metabolic imbalance caused by the acute interruption of cerebral blood supply, ischemia triggers complex pathological cascades involving excitotoxicity, neuroinflammation, oxidative stress, and blood–brain barrier (BBB) disruption, which collectively drive secondary brain injury (). Notably, growing evidence suggests that these pathological processes are not merely isolated events confined to the brain, but act as systemic triggers interacting with neuroendocrine stress responses (). Specifically, the hypothalamic–pituitary–adrenal (HPA) axis, acting as a bridge between the central nervous system (CNS) and peripheral physiology, plays a central role in regulating the adaptive response to ischemic injury. Upon the onset of an IS event, the HPA axis is rapidly activated as an integral component of the systemic stress response, precipitating a cascading release of corticotropin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH), and glucocorticoids (GCs)—specifically cortisol in humans and corticosterone in rodents. The resulting sustained release of GCs facilitates their binding to GRs located on vascular endothelial cells, glial cells, and neurons. This interaction exerts a dual regulatory effect dictated by strict dose and temporal boundaries. During the hyperacute window, transient physiological GC elevations confer neuroprotection by maintaining cerebral hemodynamics and restraining early excessive inflammation. Conversely, prolonged exposure to supraphysiological GC levels during the subacute and chronic phases transitions into a neurotoxic driver of post-ischemic injury (; ).