Harnessing a pro-survival signal: forskolin mitigates stroke damage through CREB activation

Cerebral stroke is a predominant cause of disability and mortality, with restricted therapeutic alternatives beyond the initial period. The transcription factor Creb1 is a pivotal regulator of genes that govern neuronal survival, plasticity, and memory; nevertheless, its endogenous activation frequently proves inadequate after ischemia injury. Forskolin, a direct stimulant of adenylate cyclase, increases intracellular cAMP, which may result in Creb1 activation through Protein Kinase A (PKA). The exact mechanism and therapeutic effectiveness of this route in cerebral stroke are still insufficiently investigated.This work seeks to clarify the mechanism by which forskolin activates Creb1 and to assess its neuroprotective efficacy in an in vivo model of cerebral stroke.We employed a transient middle cerebral artery occlusion (tMCAO) paradigm in adult C57BL/6 mice. Animals were randomly allocated to receive either forskolin or a vehicle control following reperfusion. The infarct volume was evaluated using TTC staining and LSC imaging. Neurological deficiency scores were assessed at 3 and 7 days. The activation of the cAMP/PKA/Creb1 pathway was assessed via Western blotting for Creb1 and p-Creb1 (Ser133). The expression levels of apoptosis and autophagy-related protein genes (Bax, Bcl-2, Beclin1, and LC3B) were assessed via western blotting. Our research indicates that forskolin provides substantial neuroprotection against ischemic stroke through the activation of the Creb1 signaling pathway. These findings establish forskolin as a potential therapeutic agent for enhancing endogenous healing processes and improving outcomes following cerebral stroke.