The Role Of Acid-sensing Ion Channel1a In The Complex Febrile Seizure

Febrile seizures (FS), generally defined as seizures taking place during fever, are themost common type of convulsive events in infants and young children, which is oftendefined as simple and complex. Complex febrile seizure not only brings harm to patient’sbody, but also leads to increased circuit excitability in the hippocampus, as well as thecognitive dysfunction. Retrospective studies have linked a history of FS and subsequenttemporal lobe epilepsy (TLE), particularly the complex febrile seizures, which mayaccompany with lots of pathologic changes in the brain, such as intracranial lactic acidaccumulation and acidification. As one kind of proton-gated cation channel, acid-sensingion channel1a (ASIC1a) is strongly expressed in nervous system, which can be onlyactivated by acidosis. Accumulating evidences suggested that ASIC1a may be involved inthe pathological process of many brain disorders, including epilepsy, and blocking ofASIC1a might have neuroprotective effects. Given that the complex febrile seizure oftenresults in the tissue acidification due to prolonged convulsions, it is not clear whetherASIC1a is abnormally activated and mediates cell damage in the complex febrile seizure.Here, we first examined the expression of ASIC1a in the hippocampus of rat model ofcomplex febrile seizure. Then we explored the effects of the ASIC1a blocker, amiloride,on the complex febrile seizures. Objectives1. To observe the expression of ASIC1a in the hippocampus of rat model of complexfebrile seizure.2. To examine the effects of pretreatment of amiloride on the febrile seizure.3. To examine the effects of posttreatment of amiloride on the cognitive function ofrat pups.MethodsWe established the animal model of complex febrile seizure by giving hyperthermiagas bath to P10male SD rat pups and having tonic-closure seizures (30minutes).1. Weobserved the changes of ASIC1a expression in hippocampus after the modeling.2. Afterpretreatment of amiloride, we observed its effect on convulsion in the process of modeling.3. After posttreatment with amiloride, we tested cognitive function and observed thepathological changes in hippocampus.Results1. By using immunohistochemistry and Western Blot, we found that the membraneexpression and total protein of ASIC1a in hippocampus significantly increased in FSgroup (p<0.05).2. Animals injected amiloride (AMI)1hour before the modeling obviously laggedbehind FS group in the arrival of39.5℃and seizure onset (p<0.01), meanwhile, thethreshold of tonic-closure seizures was obviously higher than that of FS group (p<0.01).3. After modeling, we administrated amiloride intraperitoneally for14days. By usingDAB staining and Western blot, we found that astrocytes were strongly activated, andblocking ASIC1a by amiloride could inhibit astrocytic activation. Results of Morris watermaze revealed that post-treatment with amiloride can significantly improve the cognitivefunction of rat pups. ConclusionThe expression of ASIC1a protein was strongly increased in the animal model ofcomplex febrile seizure. Amiloride may play a role in preventing the progress of complexfebrile seizure, including anticonvulsant function, ameliorated cognitive dysfunction,suppressed astrocytic activation, and reduced inflammatory response. ASIC1a may play arole in the pathophysiological process of complex febrile seizure.