Lack of cortistatin worsens neurological outcome and exacerbates aging-related glial and vascular dysfunction in stroke

Abstract

Ischemic stroke is the second leading cause of death globally. Neuroinflammation, blood-brain barrier (BBB) disruption, and immune dysregulation are key features of the pathogenesis and clinical outcomes of brain ischemia. A comprehensive understanding of the interconnected mechanisms and endogenous mediators that regulate these processes is essential for the development of effective therapeutic strategies. In this context, the present study investigates the role of cortistatin, a neuropeptide broadly distributed within the central nervous and immune systems. Given its anti-inflammatory, immunomodulatory, and neuroprotective properties, cortistatin positions as a promising endogenous factor in the pathogenesis of ischemic stroke. To evaluate its potential effects, we employed the widely recognized preclinical model of stroke, middle cerebral artery occlusion (MCAO), in young (3 months) and middle-aged (6 months) cortistatin-deficient mice and compared them with wild-type mice, assessing both short-term (48 hours) and long-term (7 days) outcomes. Our findings indicate that cortistatin deficiency in both young and middle-aged mice results in increased susceptibility to stroke and a significantly worsened prognosis, characterized by severe neurological deficits, altered microglial activity, impaired astrocytic scar formation, BBB disruption, dysregulated angiogenesis, and exacerbated immune infiltration and peripheral immune responses. Notably, the administration of cortistatin reversed these adverse outcomes, underscoring the critical role of cortistatin in regulating the complex interactions between the nervous and immune systems. Furthermore, cortistatin treatment for one week markedly improved key processes involved in stroke recovery, including neuronal repopulation, myelin repair, and the restoration of BBB integrity. The multifaceted therapeutic effects of cortistatin across various pathological stages and phenotypes suggest that multimodal therapies could represent a novel and more effective approach for treating ischemic stroke, offering advantages over current interventions that typically target only a single aspect of stroke pathology. In conclusion, our findings emphasize the significance of identifying the endogenous and therapeutic roles of neuro-immune mediators such as cortistatin in ischemic stroke