title: Minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats.
abstract: 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.
authors.affiliation: Department of Neurosurgery, Department of Neurology and Neurological Sciences, and Program in Neurosciences and Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sakata
authors.forename: Kuniyasu
authors.initials: K
authors.lastname: Niizuma
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Yoshioka
authors.forename: Gab Seok
authors.initials: GS
authors.lastname: Kim
authors.forename: Joo Eun
authors.initials: JE
authors.lastname: Jung
authors.forename: Masataka
authors.initials: M
authors.lastname: Katsu
authors.forename: Purnima
authors.initials: P
authors.lastname: Narasimhan
authors.forename: Carolina M
authors.initials: CM
authors.lastname: Maier
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Nishiyama
authors.forename: Pak H
authors.initials: PH
authors.lastname: Chan
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D019194:Ischemic Preconditioning / Q000379:methods*; D008297:Male; D008911:Minocycline / Q000494:pharmacology* / Q000627:therapeutic use; D058953:Neural Stem Cells / Q000187:drug effects / Q000637:transplantation*; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D055647:Rats, Transgenic; D033581:Stem Cell Transplantation / Q000379:methods*; D020521:Stroke / Q000473:pathology / Q000517:prevention & control* / Q000601:surgery
chemical_list: D018696:Neuroprotective Agents; D008911:Minocycline