Deciphering the role of cortistatin in neuro-immune dysregulation and blood-brain barrier breakdown underlying ischemic strokes

Resumen

Ischemic stroke is the result of a permanent or transient occlusion of a major brain artery that provokes irreversible tissue injury and long-term sequelae. Beyond neurodegeneration, the subsequent energy/oxygen deprivation triggers a cascade of cellular and molecular events encompassing the nervous, immune, and vascular systems. Despite ongoing improvements, therapeutic failure remains notorious, and stroke carries an enormous global burden, being the second leading cause of death worldwide. Neuroinflammation, blood-brain barrier (BBB) breakdown, and immune deregulation are the major hallmarks of the pathogenesis and outcomes of brain ischemia. Importantly, these processes unfold over different spatio-temporal scales, including both responses to damage and the ensuing attempts at recovery. Understanding the interconnected and complex mechanisms that globally modulate these responses is essential for developing successful therapeutic strategies, and also emphasizes the need to comprehensively explore endogenous mediators. In this context, our study focuses on cortistatin, a neuropeptide widely distributed in the central nervous and immune systems. The anti-inflammatory, immunomodulatory, and neuroprotective properties of cortistatin make it an attractive endogenous target and a potentially novel therapeutic agent for neuroinflammatory-vascular disorders including stroke. Therefore, our investigation explores the involvement of this neuropeptide in neuroinflammation, immune dysregulation, and BBB dysfunction associated with stroke, as well as its potential therapeutic application. For this purpose, we used the widely-known preclinical model of stroke MCAO (middle cerebral artery occlusion) in young (3 months old) and middle-aged (6 months old) wild-type and cortistatin-deficient mice. Our findings reveal that the absence of cortistatin increases susceptibility to stroke and worsens prognosis in cortistatin-deficient mice (i.e., worsened neurological score, severe microglial response, impaired astrocyte scar, disrupted BBB, dysregulated angiogenesis, and exacerbated immune infiltration and peripheral response). Furthermore, we found that the endogenous lack of cortistatin predisposes brain endothelium to weakening, leading to increased permeability, tight-junctions breakdown, dysregulated immune activity, and disrupted and/or deactivated genetic programming. These pathways, crucial for both basic physiology and repair after damage (e.g., extracellular matrix remodelling, angiogenesis, response to oxygen, signaling, and metabolites transport), become dysfunctional, rendering cortistatin-deficient brain endothelium unresponsive to further injury. Our results also demonstrate that treatment with cortistatin at later stages in wild-type and cortistatin-deficient mice of both age groups reverses stroke outcomes. This is evidenced by improved neurological score, smaller lesions, reduced/modulated glial response, regulation of the glial scar formation, BBB recovery, and decreased peripheral immune response. Importantly, we reported that cortistatin targets hyperpermeability, tight-junctions disruption, and the inflammatory response observed after ischemic conditions in the human and mouse brain endothelium. In conclusion, our results highlight the key role of cortistatin in regulating the intricate interplay between the nervous and the immune systems, modulating dysregulated cellular and molecular responses from both systems that could impact brain homeostasis. This also underscores the importance of shifting the focus of stroke therapies towards regulating and balancing neurotoxic processes, to prevent chronic detrimental responses rather than entirely halting them. Moreover, our findings suggest that cortistatin-based therapies may represent a novel multifunctional treatment for ischemic stroke, holding great promise compared to interventions targeting only a single aspect of stroke pathophysiology. Finally, the efficient application of these multimodal therapies at later times and across different ages and phenotypes opens the door for extending the therapeutic window for many patients who unfortunately do not meet the current clinical criteria.