Tetrahydrofolate attenuates cognitive impairment after hemorrhagic stroke by promoting hippocampal neurogenesis via PTEN signaling

Intracerebral hemorrhage (ICH), the most common subtype of hemorrhagic stroke, leads to cognitive impairment and imposes significant psychological burdens on patients. Hippocampal neurogenesis has been shown to play an essential role in cognitive function. Our previous study has shown that tetrahydrofolate (THF) promotes the proliferation of neural stem cells (NSCs). However, the effect of THF on cognition after ICH and the underlying mechanisms remain unclear. Here, we demonstrated that administration of THF could restore cognition after ICH. Using Nestin-GFP mice, we further revealed that THF enhanced the proliferation of hippocampal NSCs and neurogenesis after ICH. Mechanistically, we found that THF could prevent ICH-induced elevated level of PTEN and decreased expressions of phosphorylated Akt and mTOR. Furthermore, conditional deletion of PTEN in NSCs of hippocampus attenuated the inhibitory effect of ICH on the proliferation of NSCs and abnormal neurogenesis. Taken together, these results provide molecular insights into ICH-induced cognitive impairment and suggest translational clinical therapeutic strategy for hemorrhagic stroke.Significance Statement Intracerebral hemorrhage (ICH) has been associated with cognitive dysfunction, yet its underlying mechanism remains elusive. Tetrahydrofolate (THF) has shown potential in promoting the proliferation of neural stem cells (NSCs), but its specific impact on cognitive recovery following ICH is still to be confirmed. Through the utilization of the Nestin-GFP genetic marker to track endogenous NSCs in mice, our study revealed that THF could regulate PTEN pathway to ameliorate cognitive impairment post-ICH by enhancing the proliferation of NSCs and sustaining neurogenesis. These findings contribute to valuable insights into the molecular mechanisms involved and suggest potential clinical applications for enhancing cognitive function recovery after ICH.