P38MAPK PROMOTES ASTROGLIOSIS AFTER FOCAL ISCHEMIC STROKE IN MICE

Purpose: Patients surviving ischemic stroke are often left with long term functional disabilities suggesting that the ischemia associated pathology continues to persist in long term and limits recovery. One such reason for limited functional recovery is formation of glial scar. Glial scar is formed in response to ischemic injury and may protect the cerebral tissue from further injury during early phase of injury. But in long term, this glial scar establishes a physical and chemical barrier to the axonal migration and growth and hinders recovery. The events of a post ischemic brain are prominently influenced by inflammation and p38MAPK is an important signal transducer of cell's response to inflammatory mediators. So in our current study we hypothesize that astrocyte activation and glial scar formation after stroke is regulated by astrocytic p38MAPK and its inhibition will attenuate the glial scar formation Methods: Primary astrocyte cultures isolated from GFAP/p38 knockout mice and wild type littermates were used for in vitro studies. In vitro hypoxic condition (0.5% O2 and 5%CO2) was simulated by depriving Oxygen and glucose (OGD) for 3 hours. Wound healing and Transwell assay were used to determine role of p38MPAK in astrocyte migration. For in vivo studies, permanent middle cerebral artery occlusion (pMCAO) was conducted to induce ischemic stroke. Astrogliosis morphometric analysis was performed using nucleator method to quantify glial scar in GFAP stained brain sections Results: Results from in vitro studies indicated that p38MAPK knockout significantly attenuated OGD induced increase in glial fibrillary acidic protein (GFAP) expression and reduced astrocyte migration. In vivo studies showed that conditional GFAP/p38 knockout mice after MCAO had a significantly smaller glial scar compared to their wild type litter mates Conclusions: Astrocyte reactivation and glial scar formation in brain after ischemic injury is mediated p38MAPK and its inhibition attenuates glial scar