Post-acute phase Rac1/Pak1/p38/β-catenin signalling activation promotes ischemic recovery and facilitates migration of neural stem cells

Ischemic stroke is one of the world's leading causes of death and disability. During ischemic stroke, neuronal death is caused by inflammation, oxidative stress, apoptosis, and excitatory toxicity. For a long time, there has been a lot of interest in various studies to promote the repair of nerve damage after stroke. However, the mechanisms underlying the complex pathophysiological processes remain to be fully elucidated. Cerebral Ras-related C3 botulinum toxin substrate (Rac) 1 was initially associated with poor prognosis after stroke. However, some recent studies suggest that Rac1 may contribute to the repair process of nerve injury after stroke and promote the recovery of nerve function. However, the current conflicting findings may be related to the timing of Rac1 interventions. Our study found that post-acute Rac1 activation contributes to ischemic recovery. Here, we first investigated the specific role of neuron Rac1 in neuroprotection and recovery of neurological function in the post-acute phase of stroke. We found that intraventricular injection of Rac1 activator beginning one week after MACO significantly improved brain atrophy and neurological function after MACO. Considering the important role of Rac1 in cell migration. In vitro experiments, we found that Rac1 induced NSCs migration after exogenous and endogenous activator stimulation. In vivo, the addition of Rac1 activator in the post-acute phase helped promote the migration of NSCs in SVC to the lesion area and differentiation into mature nerve cells. It is worth noting that Pak1 is an essential downstream protein of Rac1. Our results suggest that while Rac1 activates Pak1, Pak1 can promote the migration and differentiation of neural stem cells through the downstream p38/β-catenin signalling pathway. While promoting neurogenesis, we found that Rac1 promoted angiogenesis and axon remodelling, and enhanced the synaptic plasticity to support the process of nerve repair during the post-acute phase via downstream Pak1/p38/β-catenin signalling. It suggests that Rac1/Pak1/p38/β-catenin signalling may be a potential therapeutic target in the recovery stage of ischemic stroke.