Smad1 Inhibition Attenuates Cerebral Ischemia-Reperfusion Damage and Promotes Brain Repair from Neural Stem Cells

Stroke is a devastating disease of the central nervous system (CNS). Scientists and physicians have put numerous efforts and resources developing new pharmacological and cell therapeutic approaches. Neural stem cell (NSC) therapy has implicated tremendous promise for neural repair after stroke, but has been hurdled by the poor survival of endogenous or implanted exogenous NSCs due to oxidative stress in post-stroke environment. Our recent study using a mutant mouse strain with conditional knockout (cKO) of Smad1 (a transcriptional factor of BMP/Smad family) in the CNS revealed that Smad1 deletion confers cell protection against oxidative stress in vitro and transient ischemia-reperfusion stroke in vivo. We also found that Smad1 signaling plays a crucial role in the regulation of NSCs¿ self-renewal, proliferation and differentiation, as well as their activation and function after stroke. Based on these exciting results, we hypothesize that Smad1 inhibition from chemical compound DMH1, a small molecule BMP receptor inhibitor, confers neural protection against stroke damage in vivo, promotes NSCs survival and enhances their reparative function in post-stroke brain, leading to better protection and repair of CNS from stroke damage. In aim 1, we will test the hypothesis that Smad1 inhibition from DMH1 attenuates neuronal loss, oxidative stress and brain damage from ischemic stroke, as we have observed in Smad1 cKO mice. Effects on astroglia and inflammatory responses in post-stroke brain from Smad1 inhibition will be examined, too. In aim 2, we will test the hypothesis that Smad1 inhibition with DMH1 favors survival of endogenous and exogenous NSCs, as well as their post-stroke reparative functions and integration into host brains. We hypothesize that the outcome of ischemic stroke can be improved with DMH1 treatment through synergic effects of attenuation of brain damage and promotion of neurogenesis from NSCs. Results from the current proposal are likely to increase our knowledge of the protective mechanisms against stroke, as well as the signaling pathway that regulates NSCs and their repair function in stroke setting. The gene manipulation from chemical compound and neural stem cells therapy are highly translational for clinical applications.