Dysregulation of the CNS supporting vascular and glial cells induces the late posttraumatic epilepsy in mice with mild traumatic brain injury

[Speaker] Kenta Sakai:1
[Co-author] Fuyuko Takata:1, Shinya Dohgu:1, Mitsuhisa Koga:1, Ikuya Kimura:1, Atsushi Yamauchi:1, Yasufumi Kataoka:1
1:Department of Pharmaceutical Care and Health Sciences, Faculty of Pharmaceutical Sciences Fukuoka University, Japan

Traumatic brain injury (TBI) develops posttraumatic epilepsy (PTE) which is characterized by delayed onset (more than several months to several years after TBI). Epidemiological evidences suggested that prophylactic therapy with typical antiepileptic drugs for this late onset PTE have not succeed. Thus, an understanding of the mechanism by which TBI causes late PTE is urgently needed for its prevention, early diagnosis and treatment. In this study, we hypothesized that TBI gradually occurs the vulnerability to epileptogenesis due to dysfunction of the central nervous system (CNS) supporting cells such as vascular and glial cells, leading to late PTE. To address this question, we induced TBI by controlled cortical impact (CCI) in C57BL/6J mice. Sham-operated mice were served as controls. We evaluated the neurological functions with neurological severity score (NSS) and the epileptogenesis with the threshold value for pilocarpine (PILO)-induced seizure on 7 and 28 days after CCI. Histological analysis was performed on 2, 7 and 28 days after CCI. Brain water content was measured to determine the brain edema formation (7 and 28 days after CCI). Latency to the occurrence of PILO-induced tonic seizure was increased in CCI group on 7 and 28 days after injury when compared to sham group. CCI induced edema in the ipsilateral brain; this was markedly aggravated on 28 days after when compared to that in 7 days after CCI. In the immunohistochemical analysis, increased signals for PDGFRβ, a marker of pericyte, were observed in the ipsilateral hippocampus on 2 and 7 days but not 28 days after CCI. Astrocytes and microglia were activated in the hippocampus on 2, 7 and 28 days after CCI. In this study, we established CCI mice showing the high susceptibility to epileptogenesis as an index of PILO-induced seizure. The development of epileptogenesis after CCI could be generated by brain edema and altered function of the CNS supporting cells (vascular and glial cells).
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