Inhibition Of Microglial Activation And Monocytes Infiltration Ameliorates Cerebellar Hemorrhage Induced Brain Injury And Ataxia

Cerebellar hemorrhage(CH) is one of the most destructive forms of stroke with high rate of disability.A majority of CH patients have been reported to experience lifelong disabilities on account of cerebellar ataxia symptoms,including gait abnormality,postural instability and motor incoordination.Unfortunately,therapies with effective outcome for CH are still lacking.Accumulating clinical evidence shows that CH treatments targeting the primary injury due to hematoma formation by surgical hematoma evacuation provide little impact on functional improvement.Therefore,targeting the mechanisms of secondary brain injury,such as neuroinflammation,may provide alternative therapeutic strategies for CH.It is generally known that microglia play a vital role in the process of brain injury as the principal resident immune cells in the central nervous system.However,the role of cerebellar microglia and subsequent neuroinflammation in CH-induced secondary injury remains unknown.In the present study,we reveal the activation of microglia and expression of inflammatory mediator following CH.Specific inhibition of microglial activation or microglial depletion lessens not only the pro-inflammatory cytokines release,but also cerebellar monocyte and macrophage infiltration,and consequently ameliorates brain damage and ataxialike motor dysfunctions in CH.In addition,microglia-derived CCL-2 is essential for recruitment of peripheral immune cells to lesion sites in the cerebellum,and aggravates neuroinflammation.Inhibition of chemokine CCL-2 production ameliorate CHinduced brain injury and ataxia.These results indicate that microglial activation and subsequent neuroinflammation is one of the most important mechanisms underlying CH-induced secondary brain injury.Therefore,our findings define the mechanisms underlying development of CH-induced brain injury,and contribute to screen and develop novel therapeutic targets and strategies for treatment of CH by targeting secondary brain injury.