Postconditioning promotes recovery in the neurovascular unit after stroke

Elga Esposito; Ester Licastro; Ornella Cuomo; Eng H Lo; Kazuhide Hayakawa; Giuseppe Pignataro

doi:10.3389/fncel.2023.1260389

Postconditioning promotes recovery in the neurovascular unit after stroke

Front Cell Neurosci. 2023 Sep 8:17:1260389. doi: 10.3389/fncel.2023.1260389. eCollection 2023.

Authors

Elga Esposito^{1

2}, Ester Licastro^{1

3}, Ornella Cuomo³, Eng H Lo^{1

2}, Kazuhide Hayakawa¹, Giuseppe Pignataro³

Affiliations

¹ Neuroprotection Research Laboratories, Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Charlestown, MA, United States.
² Consortium International pour la Recherche Circadienne sur l'AVC (CIRCA).
³ Division of Pharmacology, Department of Neuroscience, Reproductive and Dentistry Sciences, School of Medicine, University of Naples Federico II, Naples, Italy.

Abstract

Background and purpose: Experimental studies suggest that ischemic postconditioning interferes with cell death mechanisms and reduces infarction during the acute phase after focal cerebral ischemia. Postconditioning may be a practically feasible way to promote stroke recovery, but many drawbacks prevent its clinical translation. First, all existing studies are mostly on acute 24 h outcomes. Second, the mechanisms of protection and augmented long-term benefits remain unclear. Our study aims to define some of the mechanisms that explain long-term benefits of improved recovery.

Methods: Male Sprague-Dawley rats were subjected to 100-min transient middle cerebral artery occlusion (MCAO) or postconditioning (100-min middle cerebral artery occlusion plus 10-min reperfusion plus 10-min reocclusion). After 3 days or 2 weeks, infarct volumes, western blot, and immunohistochemical markers of neurogenesis and angiogenesis were quantified. Fluorocitrate (FC) or saline were administrated ICV (intraventricular injection) every other day starting on day 5 after focal cerebral ischemia, animals were recovered for 2 weeks.

Results: After postconditioning BDNF protein expression levels increased compared to animals subjected to MCAO. Immunostaining showed that BDNF increased specifically in astrocytes. Moreover, when astrocytes were metabolically inhibited by fluorocitrate the postconditioning neuroprotective effect together with the postconditioning-dependent new angiogenesis and neurogenesis, were no longer observed.

Conclusion: These results suggest for the first time that therapeutic effects of postconditioning may involve the promotion of neurogenesis and angiogenic remodeling, via BDNF released by astrocytes, during the recovery phase after focal cerebral ischemia.

Keywords: BDNF; angiogenesis; astrocytes; ischemic postcoditioning; neurogenesis; neuroprotecion; stroke.