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Background <p>Ischemic stroke remains a leading cause of death and disability, with limited therapies addressing its pathophysiology. Neuroinflammation, blood–brain barrier disruption, and immune dysregulation critically contribute to both acute neuronal injury and chronic functional decline. Elucidating the endogenous factors that govern these processes and understanding the intricate interplay among them is essential for developing effective therapeutic strategies. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory actions, but its role in neuroinflammatory diseases remains unclear.</p> Methods <p>In this study, we combined human and murine transcriptomic analyses with a preclinical stroke model in cortistatin-deficient mice to investigate the endogenous and therapeutic roles of cortistatin during the acute (48&#xa0;h) and subacute (7&#xa0;days) phases of ischemic stroke.</p> Results <p>We demonstrate for the first time that cortistatin deficiency amplified ischemia-induced transcriptional programs, heightening neuroinflammation and glial/neurovascular dysfunction, and worsening neurological outcomes. Interestingly, cortistatin deficiency accelerated aging-associated pathological features, underscoring its essential role in neuroimmune and cerebrovascular homeostasis. Conversely, cortistatin administration improved neuronal survival, mitigated immune dysfunction, and preserved myelin and vascular integrity during both the acute and subacute stages.</p> Conclusions <p>These findings provide the first evidence identifying cortistatin as an endogenous neuroimmune regulator in ischemic stroke and a promising multimodal therapeutic agent for improving acute and long-term outcomes.</p>

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Lack of cortistatin drives neuroimmune and vascular dysfunction in brain ischemia

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月20日

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  • Julia Castillo-González,
  • Pablo Vargas-Rodríguez,
  • Ignacio Serrano-Martínez,
  • Alejandro Cuenca-Martagón,
  • Irene Forte-Lago,
  • Melanie Price,
  • Lara Buscemi,
  • Lorenz Hirt,
  • José Luis Ruiz,
  • Elena González-Rey

摘要

Background

Ischemic stroke remains a leading cause of death and disability, with limited therapies addressing its pathophysiology. Neuroinflammation, blood–brain barrier disruption, and immune dysregulation critically contribute to both acute neuronal injury and chronic functional decline. Elucidating the endogenous factors that govern these processes and understanding the intricate interplay among them is essential for developing effective therapeutic strategies. Cortistatin, a neuropeptide expressed in the nervous and immune systems, exhibits potent immunomodulatory actions, but its role in neuroinflammatory diseases remains unclear.

Methods

In this study, we combined human and murine transcriptomic analyses with a preclinical stroke model in cortistatin-deficient mice to investigate the endogenous and therapeutic roles of cortistatin during the acute (48 h) and subacute (7 days) phases of ischemic stroke.

Results

We demonstrate for the first time that cortistatin deficiency amplified ischemia-induced transcriptional programs, heightening neuroinflammation and glial/neurovascular dysfunction, and worsening neurological outcomes. Interestingly, cortistatin deficiency accelerated aging-associated pathological features, underscoring its essential role in neuroimmune and cerebrovascular homeostasis. Conversely, cortistatin administration improved neuronal survival, mitigated immune dysfunction, and preserved myelin and vascular integrity during both the acute and subacute stages.

Conclusions

These findings provide the first evidence identifying cortistatin as an endogenous neuroimmune regulator in ischemic stroke and a promising multimodal therapeutic agent for improving acute and long-term outcomes.