PI3K/Akt pathway in ischemic stroke: A central regulator of neuronal survival and repair

Stroke is a leading cause of death and disability in the world, and the majority of ischemic strokes are caused by cerebral ischemia. Neurons are deprived of oxygen and nutrients when blood flow to the brain is disrupted, which initiates cascades of events that includes inflammation, oxidative stress, excitotoxicity, and ultimately cell death. However, cells also trigger defense signaling networks that impact neuronal survival. On activation of receptor tyrosine kinases (RTKs) by growth factors such as insulin-like growth factor-1 (IGF-1), brain-derived neurotrophic factor (BDNF), and vascular endothelial growth factor (VEGF), pro-survival reactions are initiated through the phosphoinositide 3-kinase/protein kinase B (PI3K/Akt) pathway, which modulates many downstream effectors, including mammalian target of rapamycin (mTOR), glycogen synthase kinase-3 beta (GSK-3β), nuclear factor erythroid 2-related factor 2 (Nrf2), nuclear factor kappa B (NF-κB), and forkhead box O (FOXO). These molecules collectively modulate apoptosis, stimulate neurogenesis, control autophagy, and lessen oxidative stress. Due to its various functions, the PI3K/Akt pathway is a feasible therapeutic target for treating ischemic brain injury. This review summarises an overview of our current knowledge of PI3K/Akt signaling in cerebral ischemia, including its upstream triggers and downstream mediators. We also discuss about how altering this system may lead to novel approaches to stroke recovery and neuroprotection. We emphasize focusing on PI3K/Akt pathway that might be essential for creating potent therapies for stroke and its long-term neurological effects.