Previously, Kranz et al. showed that double infusion of placenta derived MSCs at 8 hours and 24 hours improved functional outcome in experimental stroke, however, a single injection at 24 hours did not improve outcome. Additionally, a recently published study by Yu et al. showed that transplantation of 16106 stem cell-like placenta cells improved functional recovery when administered at 3 hours after stroke in dogs. In our previous study, we demonstrated that PDA-001 LY2835219 treatment improves functional outcome in young adult rats when administered 4 hours after middle cerebral artery occlusion. However, treatment administration within four hours after stroke may not always be feasible in clinical practice. Furthermore, to maximize successful translation of an effective therapy from the lab to the clinic, efficacy of treatment should also be demonstrated in older animals. Therefore, in the present study, we investigated the efficacy of PDA-001 treatment when administered 24 hours after MCAo in both young adult and older rats. Our data demonstrate that treatment of stroke with PDA-001, when administered 24 hours after MCAo, improves functional outcome as measured by adhesive-removal test, mNSS and foot-fault test. This beneficial effect is observed in both young adult and older rats. In young adult rats, the optimal number of transplanted PDA001 cells is 46106. A similar optimal number of transplanted cells was observed in a previous study when PDA-001 were administered 4 hours after MCAo. Treatment with a lower or a higher number of cells is not effective. In addition, our data shows that in older rats, treatment with both 46106 and 86106 PDA-001 cells improve functional outcome. The data show that when young rats are treated with PDA-001 cells, significant improvement in functional recovery is observed as early as 7 days post MCAo. However, in treated older rats, significant improvement in functional recovery is delayed and starts at 21 days after MCAo. This is consistent with other published studies, e.g., two previous studies testing sildenafil in young and aged rats showed that the therapeutic response was weaker and delayed in older rats compared to young rats. Thus, brain repair/remodeling processes seem to be age dependent. In a previous study, we demonstrated that PDA-001 therapy is neuroprotective when administered 4 hours after MCAo as measured by reduction in the ischemic lesion volume and improvement in functional outcome. In the current study, we found that treatment of stroke with PDA-001, when administered 24 hours after stroke in young adult and older rats, has no effect on the volume of cerebral infarction. Thus, functional outcome after PDA-001 treatment when administered 24 hours after stroke, likely results from neurorestorative effect rather than a neuroprotective effect. Additionally, functional improvement after PDA-001 cell treatment is accompanied by a significant increase in endothelial proliferation, vascular density and perimeter and an increased expression of synaptophysin. The cerebral vascular system mainly develops through angiogenesis. The adult brain vascular system is stable under normal conditions but is activated in response to pathological conditions including stroke.
Capillary sprouting in the brain is initiated at the border of the infarct and new vessels develop in the ischemic boundary zone
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