Cerebral Lymphatic Drainage In A Mouse Model Of Subarachnoid Hemorrhage

Subarachnoid hemorrhage(SAH)is a serious cerebrovascular disease.It not only causes high mortality,but also can cause permanent brain impairment.It is important to clarify the pathogenesis of secondary pathological damages and find effective intervention to improve the prognosis of SAH.Recently,it has been found that glymphatic system is implicated in removal of large molecular metabolites in the brain,and the lymphatics in the dura have the function of transporting large molecular substances and lymphocytes within the cerebrospinal fluid to the deep cervical lymph nodes.However,the role of cerebral lymphatic clearance system in the pathological process of SAH needs to be further clarified.In this study,autologous blood was injected into the cisterna magna of mice to establish SAH model.Neuropathological and behavioral analyses were performed 1 weeks later.The results showed that compared with controls,SAH model mice had a series of pathological changes,such as activation of glial cells in the cerebral cortex and hippocampus,increased levels of brain interleukin-1β and tumor necrosis factor-α,activation of NF-κB signaling pathway and hippocampal neuronal apoptosis,as well as decreases in neurological function score and spontaneous inquiry ability.Although there was no obvious abnormality in the brain water content in the SAH mice,there were still decreased transport of intracisternally injected fluorescent tracers into the parenchyma and deep cervical lateral lymph nodes,increased total Tau protein and phosphorylated Tau protein,and disrupted polarization of aquaporin-4 a functional marker of the glial lymphatic system.This study also found that prior blocking dural lymphatic pathway via ligation of lateral cervical lymph nodes did not aggravate the neuropathological damage,suppression of glial lymphatic transport and behavioral dysfunction in SAH mice.Although the lymph ligation in control mice could lead to the increase of total Tau and phosphorylated Tau in the brain and new object recognition deficits.The present results suggest that persistent glial lymphatic system dysfunction and neuropathological damage exist after SAH,and targeting at lymphatic clearance system potentially serves as a new strategy for the treatment of SAH.