Valproic acid enhances the effect of bone marrow-derived mononuclear cells in a rat ischemic stroke model

• A combination of treatment MNCs and VPA ameliorated ischemic brain injury.
• Administration of VPA enhanced the anti-inflammatory effect of MNCs.
• Administration of VPA enhanced the protective effects on endothelial damage of MNCs.
• Administration of VPA protected MNCs from the hostile environment after brain ischemia.

Bone marrow derived mononuclear cell (MNC) transplantation is a potential therapy for ischemic stroke. Here, we hypothesized that valproic acid (VPA) would modulate transplantation effects of MNCs in a rat ischemic stroke model. Male Sprague–Dawley rats were subjected to transient 90 min middle cerebral artery occlusion. Infarct volume, neurological outcome, and immunohistological assessments were performed 7 days after ischemia. MNCs injected 6 or 24 h but not 48 or 72 h after ischemia significantly reduced infarct volume and improved neurological deficits. We then tested whether the therapeutic window of MNC transplantation could be expanded through combination therapy with VPA. MNC transplantation at 48 h combined with VPA injection three times at 47, 53, and 72 h after ischemia significantly ameliorated infarct volume and neurological deficits compared to a vehicle group. Combination therapy reduced the number of myeloperoxidase-positive cells, ionized calcium binding adapter molecule 1-positive cells, tumor necrosis factor-α-positive cells, and von Willebrand factor-positive cells in the ischemic boundary zone. The number of engrafted MNCs that were fluorescently labeled with PKH 26, on day 7, was significantly higher after combination therapy than after that MNC transplantation alone. Our results demonstrated that combination therapy with VPA enhanced the anti-inflammatory and vasculo-protective effects against endothelial damage following ischemia, and increased the survival of transplanted cells, leading to expansion of the therapeutic time window for MNC transplantation. Together, these findings suggest that VPA may be an appropriate partner for cell-based treatment of ischemic stroke.