Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia

Activated microglia may exacerbate damage in neural disorders; however, it is unknown how they affect stem cells transplanted after stroke. Focal ischemia was induced by microinjections of 40 pmol of endothelin-1 into the motor cortex of adult rats. Ischemic animals were treated with sterile saline (n = 5), bone marrow mononuclear cells (BMMCs, n = 8), minocycline (n = 5) or concomitantly with minocycline and BMMCs (n = 5). BMMC-treated animals received 5 × 106 BMMCs through the caudal vein 24 h post-ischemia. Behavioral tests were performed to evaluate functional recovery. Morphometric and histological analyses were performed to assess infarct area, neuronal loss and microglia/macrophage activation up to 21 days post-ischemia. Treatments with minocycline, BMMCs or minocycline-BMMCs reduced infarct area, increased neuronal survival and decreased the number of caspase-3+ and ED-1+ cells, but these effects were more prominent in the minocycline-BMMC group. Behavioral analyses using the modified sticky-tape and open-field tests showed that ischemic rats concomitantly treated with BMMCs and minocycline showed better motor performance than rats treated with BMMCs or minocycline only. The results suggest that proper modulation of the inflammatory response through the blockage of microglia activation enhances neuroprotection and functional recovery induced by intravenous transplantation of BMMCs after motor cortex ischemia.