외상성 뇌 손상 후 운동에 의해 활성화된 BDNF-ERK 신호전달 경로가 소뇌에서 발생된 퍼킨제 세포 사멸과 astrogliosis에 미치는 역할 규명
Studies on exercise-activated BDNF-ERK pathway in Purkinje cell loss and astrogliosis in the cerebellum after forebrain traumatic contusion injury
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본 연구는 외상성 대뇌 타박 손상 후 트레드밀 운동에의해 활성화된 BDNF-ERK1/2 신호전달 경로가 소뇌 퍼킨제 세포의 생존율을 증가시키고, 과립세포층 (granule layer)과 분자층(molecular layer)에서 반응성 성상교세포의 군집율을 감소시켜 astrogliosis에 변화를 가져올 수 있는지를 확인하는데 그 목적이있다. 7주령 Sprague-Dawley 계열의 수컷 흰쥐 36마리를 실험 전 일주일 동안 실험실 환경에 적응시킨 후, 무작위 표본추출법에의해 실험집단을 가성 수술군 (sham operation group, n=12), 외상성 뇌 손상군 (traumatic brain injury group, n=12) 그리고 외상성뇌 손상＋운동군 (traumatic brain injury＋exercise group, n=12)으로 나누었다. 운동은 하루 30분씩 10일간 트레드밀 운동을 시킨결과, 외상성 뇌 손상 후 퍼킨제 세포 수는 급격히 감소하였지만, 손상 후 운동 수행에 의해 퍼킨제 세포의 사멸이 억제되었다. 또한 별아교세포는 외상성 뇌손상 후 분자층 (ml)과 과립층 (gl) 모두에서 증가하였다. 그러나 운동은 별아교 세포의 활성도를감소시켰다. 외상성 뇌 손상 후 소뇌 8-9번 소엽에서 calbindin 발현량은 감소하였으나, 운동에 의해 통계적으로 유의하게 증가하였다. 또한 별아교 세포의 활성화를 확인하는 GFAP도 외상성 뇌 손상 후 소뇌 8-9번 소엽에서 증가하였고, 운동에 의해 통계적으로유의하게 감소하였다. 외상성 뇌 손상 후 인산화된 ERK1/2와 BDNF는 퍼킨제 뉴런의 사멸로 인해 발현량이 감소하였지만, 운동은퍼킨제 뉴런에서 인산화된 ERK1/2와 BDNF의 발현량을 증가시켰다. 외상성 뇌 손상 후 소뇌에서 인산화된 ERK1/2와 BDNF는 발현량이 감소하였지만, 운동은 인산화된 ERK1/2와 BDNF의 발현을 촉진시켰다. 결론적으로 운동은 외상성 뇌 손상으로 인해 발생되는소뇌의 기능장애를 개선시킬 수 있는 중요한 매개체라는 것을 알 수 있다.
Abstract
The cerebellum is selectively vulnerable to forebrain traumatic brain injuries (TBI). Physical exercise in animals has been implicated in promoting cell survival and functional recovery after brain injuries. The purpose of this study is to investigate the effects of exercise-increased BDNF (Brain-derived neurotrophic factor) and p-ERK1/2(phospho-extracular signal-regulated kinase1/ell2) on Purkinje neuron survival and astrogiosis in the gyrus of lobules VIII and IX of the cerebellum after TBI. The rats were divided into three groups：the sham-operation group, the TBI-induction group, and the TBI-induction with exercise group. All tissues were used for immunofluorescence staining and Western blot. Calbindin-positive Purkinje neurons were decreased and GFAP (Glial fibrillary acidic protein)-positive astrocytes were increased in the posterior region of the cerebellum after TBI. Treadmill exercise after TBI significantly upregulated induction levels of calbindin, BDNF and p-ERK1/2 as well as decreased GFAP expression levels in lobules of VIII and IX of the cerebellum after TBI. The present study provides the possibility that treadmill exercise may be an important mediator to prevent Purkinje neuron loss and formation of astrogliosis via activation of BDNF and p-ERK1/2.
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