Transplantation of neural stem cells (NSCs) offers a novel therapeutic strategy for
stroke; however, massive grafted cell death following
transplantation, possibly due to a hostile host brain environment, lessens the effectiveness of this approach. Here, we have investigated whether reprogramming NSCs with
minocycline, a broadly used
antibiotic also known to possess cytoprotective properties, enhances survival of grafted cells and promotes neuroprotection in
ischemic stroke. NSCs harvested from the subventricular zone of fetal rats were preconditioned with
minocycline in vitro and transplanted into rat brains 6 h after transient
middle cerebral artery occlusion. Histological and behavioral tests were examined from days 0-28 after
stroke. For in vitro experiments, NSCs were subjected to
oxygen-
glucose deprivation and reoxygenation. Cell viability and
antioxidant gene expression were analyzed.
Minocycline preconditioning protected the grafted NSCs from ischemic
reperfusion injury via upregulation of Nrf2 and Nrf2-regulated
antioxidant genes. Additionally, preconditioning with
minocycline induced the NSCs to release paracrine factors, including
brain-derived neurotrophic factor,
nerve growth factor,
glial cell-derived neurotrophic factor, and
vascular endothelial growth factor. Moreover,
transplantation of the
minocycline-preconditioned NSCs significantly attenuated
infarct size and improved neurological performance, compared with non-preconditioned NSCs.
Minocycline-induced neuroprotection was abolished by transfecting the NSCs with Nrf2-small interfering
RNA before
transplantation. Thus, preconditioning with
minocycline, which reprograms NSCs to tolerate oxidative stress after ischemic
reperfusion injury and express higher levels of paracrine factors through Nrf2 up-regulation, is a simple and safe approach to enhance the effectiveness of
transplantation therapy in
ischemic stroke.