Study On The Relationship Between Cerebral Edema And Impaired Glymphatic System Function After Status Epilepticus In Mice

BackgroundStatus epilepticus(SE)is a common neurological emergency,usually associated with acute cerebral edema and long-term cognitive dysfunction,and characterized pathologically by hyperphosphorylated Tau protein(pTau)deposition and neuronal degeneration.The glial-lymphatic system(GS)has a function similar to that of peripheral tissue lymphatics,directing the exchange of cerebrospinal fluid with interstitial fluid and removing metabolic waste from the brain mainly through the perivascular space(PVS),and its function is highly dependent on aquaporin-4(AQP4)on the astrocyte end-foot.We hypothesize that post-SE cerebral edema may lead to impaired GS function,and result in the deposition of metabolic wastes in the brain through the occupying effect of compressing the PVS,ultimately leading to long-term cognitive dysfunction.ObjectiveTo investigate the dynamic changes of GS function and cerebral edema after SE in mice,and confirm the correlation between brain edema formation and impaired GS function.Finally,verify whether intervention in cerebral edema formation can reduce impaired GS function and improve cognitive dysfunction in the chronic phase after SE.MethodsIn adult male C57BL/6J mice,SE was induced using lithium chloride-pilocarpine for 2.5 hours and then terminated by diazepam.Dynamic changes of GS function were assessed by in vivo two-photon microscopy and brain sections for 8 days after SE;dynamic changes in brain metabolic waste clearance were assessed by brain sections and lymph node;astrocyte proliferation and changes in AQP4 polarization status were assessed by immunofluorescence staining;dynamic changes in cerebral edema were assessed by magnetic resonance T2WI and DWI scanning;dynamic changes of GS function were assessed by magnetic resonance-enhanced T1WI scanning as well.The severity of IgG leakage was assessed by immunofluorescence staining.After reducing post-SE cerebral edema by glibenclamide administration treatment and Trpm4 knockout intervention,GS function was assessed by in vivo two-photon microscopy and brain sections;brain metabolic waste clearance was assessed by brain sections and lymph node;AQP4 polarization status was assessed by immunofluorescence staining;cognitive dysfunction in the chronic phase after SE was assessed by Morris water maze;pTau deposition and neuronal degeneration in the chronic phase after SE were assessed by immunofluorescence staining.ResultsWe found that GS function was temporarily impaired after SE modeling and termination in mice,declined and continued to diminish from 1 day after SE,reached a nadir level on 3 days after SE,remained unimproved on 5 days after SE,and was only partially restored on 8 days after SE.The brain’s ability to remove metabolic wastes declined from 2 days after SE and continued to diminish,again reaching a nadir level on 3 days after SE,but partially recovered on 5 days after SE and further recovered on 8 days after SE.Cerebral edema began to appear in the cortex of mice on 1 day after SE,peaked 3 days after SE,and subsided significantly 8 days after SE,with the main source probably being vasogenic edema,while the observed trend of impaired GS function was synchronized with the trend of changes in cerebral edema.After glibenclamide treatment and Trpm4 knockout intervention to reduce post-SE brain edema,GS function recovered earlier on 5 days after SE,cognitive dysfunction was reduced in the chronic phase after SE,and pTau deposition and neuronal degeneration were reduced.ConclusionTemporary impairment of GS function after SE in mice is closely related to changes in cerebral edema;cerebral edema may contribute to impaired GS function,causing pTau deposition and neuronal degeneration in the brain,and ultimately causing cognitive dysfunction after SE.