Effects of rehabilitative training and anti-inflammatory treatment on functional recovery and cellular reorganization following stroke.

Post-ischemic inflammation plays a critical role in cellular reorganization and functional recovery after stroke. We therefore address the hypothesis whether anti-inflammatory treatment with either indometacin or minocycline combined with rehabilitative training improve functional recovery and influence perilesional cellular response following focal cortical infarcts. Using the photothrombosis model in adult rats, focal cortical infarcts were induced in the fore- and hindlimb sensorimotor cortex. Inflammatory processes were blocked by intraperitoneal application of indometacin or minocycline twice daily during the first 2 weeks of the experiment. Immediately after the infarct, the animals received a daily session of skilled reaching training of the impaired forelimb. In addition, Bromodeoxyuridine (BrdU) was administrated for 5 sequential days post infarct. Proliferation and differentiation of astrocytes, microglia, immature and mature neurons in the perilesional zone were immunocytochemically quantified at days 14 and 42. Functional recovery was assessed in a sensorimotor walking task preoperatively and 4, 14 and 28 days post surgery. Combined rehabilitative training and indometacin or minocycline strongly improved sensorimotor performance and significantly reduced the number of proliferating microglia compared to reaching training alone. Furthermore, the combination increased the survival of proliferating astrocytes and, moreover, minocycline increased the doublecortin-positive cells in the perilesional zone. Anti-inflammatory drug application combined with rehabilitative training demonstrates improved functional recovery and significantly modifies proliferation and survival of distinct glial and neuronal subpopulations in the direct vicinity of cortical infarcts compared to reaching training alone.