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

Ischemic stroke remains a leading cause of mortality and disability worldwide, with few therapies addressing its complex pathophysiology. Neuroinflammation, blood-brain barrier disruption, and immune dysregulation contribute to acute damage and long-term decline. Cortistatin, an immunomodulatory neuropeptide, has shown therapeutic benefit in acute stroke, though its endogenous role during onset and recovery remains unknown. Using an integrative approach combining transcriptomics from human and murine datasets, a preclinical stroke model, and tissue-level analysis in young and middle-aged mice, we demonstrated the causal and protective role of cortistatin during acute and subacute stroke phases. Our findings reveal that cortistatin deficiency increases stroke susceptibility and worsens outcomes. The lack of cortistatin triggers an amplified transcriptional response to ischemia, driving heightened neuroinflammation, glial dysfunction, compromising neurovascular integrity, and suppressing repair-associated pathways. Indeed, cortistatin levels were inversely associated with stroke severity. Notably, cortistatin deficiency accelerated aging-associated pathological features following stroke, underscoring its relevance in neuroimmune and cerebrovascular health. Administration of exogenous cortistatin reversed many detrimental effects, improving neuronal survival, mitigating immune dysregulation, preserving myelin, and promoting vascular recovery. Overall, cortistatin emerges as a key endogenous regulator of stroke pathophysiology and a promising multimodal therapy, supporting neuroimmune integrative approaches to tackle the multifaceted nature of stroke.