The great promise of using stem cells to treat stroke has been inhibited by challenges to stem cell survival in the toxic environment of post-stroke tissue. Reperfusion (removal of clot) can be achieved mechanically (thrombectomy, <6-8hrs or by tissue plasminogen activator (tPA, <4.5 hrs), but ischemia/reperfusion injury limits the treatment time window. Furthermore, deleterious non-thrombolytic off-target effects of delayed tPA infusion (e.g., >4.5hrs) have been shown within brain parenchyma, increasing vascular injury and death of neurons. Previously, we reported that human neural stem cell (hNSC) transplantation 24hrs after stroke shows multiple beneficial short-term effects within 48hrs post-stroke, reducing inflammation, blood-brain barrier (BBB) damage, and infarct size. Since delayed tPA administration exacerbates BBB damage and increases hemorrhage, we reasoned that ameliorating inflammation and BBB damage by pretreating with neuroprotectants (i.e., minocycline) prior to tPA might synergize to expand the time window for tPA and provide a better environment for NSC survival, thus increasing NSC efficacy. We utilized the middle cerebral artery occlusion stroke mouse model to induce focal cerebral ischemia followed by reperfusion (MCAO/R). 6hrs post-MCAO, we administered tPA intravenously. Minocycline was administered intraperitoneally at various time points prior to tPA injection. One day post-stroke, we injected hNSCs intracranially. Previously, we reported that minocycline pretreatment prior to tPA and hNSC transplantation reduced the mortality of delayed tPA-treated aged mice within 48hrs post-stroke. In this study, we investigated the effect of hNSCs treated with minocycline-plus-delayed tPA treatment on long-term benefits on neurological function. We performed a behavioral test of motor function beginning 24hrs after hNSC transplantation. Rotarod test was carried out 3 days(d) consecutively pre-stroke (as training) and from 2d to 28d post-stroke. Here, we report that by combining minocycline prior to tPA significantly ameliorates neurological deficit in aged mice. Furthermore, transplanting hNSCs ameliorated the pathophysiology caused by delayed tPA.
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