ABSTRACT
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.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Exercise Therapy/methods , Recovery of Function/physiology , Stroke/therapy , Animals , Anti-Inflammatory Agents, Non-Steroidal/pharmacology , Combined Modality Therapy , Doublecortin Protein , Male , Motor Cortex/cytology , Motor Cortex/drug effects , Physical Conditioning, Animal/methods , Physical Conditioning, Animal/physiology , Random Allocation , Rats , Rats, Wistar , Stroke/pathology , Treatment OutcomeABSTRACT
BACKGROUND: It is well known that focal ischemia increases neurogenesis in the adult dentate gyrus of the hippocampal formation but the cellular mechanisms underlying this proliferative response are only poorly understood. We here investigated whether precursor cells which constitutively proliferate before the ischemic infarct contribute to post-ischemic neurogenesis. To this purpose, transgenic mice expressing green fluorescent protein (GFP) under the control of the nestin promoter received repetitive injections of the proliferation marker bromodeoxyuridine (BrdU) prior to induction of cortical infarcts. We then immunocytochemically analyzed the fate of these BrdU-positive precursor cell subtypes from day 4 to day 28 after the lesion. RESULTS: Quantification of BrdU-expressing precursor cell populations revealed no alteration in number of radial glia-like type 1 cells but a sequential increase of later precursor cell subtypes in lesioned animals (type 2a cells at day 7, type 3 cells/immature neurons at day 14). These alterations result in an enhanced survival of mature neurons 4 weeks postinfarct. CONCLUSIONS: Focal cortical infarcts recruit dentate precursor cells generated already before the infarct and significantly contribute to an enhanced neurogenesis. Our findings thereby increase our understanding of the complex cellular mechanisms of postlesional neurogenesis.
