Journal of Life Science (생명과학회지)

Korean Society of Life Science (한국생명과학회)
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Cerebrolysin Attenuates Astrocyte Activation Following Repetitive Mild Traumatic Brain Injury: Implications for Chronic Traumatic Encephalopathy

만성외상성뇌병증과 관련된 반복적 경도 외상성뇌손상(rmTBI)모델에서 cerebrolysin의 별아교 세포활성 억제효과

  • Kang, Hyun Bae (Pathogen Resource TF, Center for Infectious Diseases, National Institute of Health, Korea Centers for Disease Control & Prevention) ;
  • Kim, GiHun (Department of Biology and Department of Microbiology and Biotechnology, DaeJeon University) ;
  • Kim, HyunJoong (Department of Biology and Department of Microbiology and Biotechnology, DaeJeon University) ;
  • Han, Sa Rang (Department of Anatomy, Chungnam National University School of Medicine) ;
  • Chae, Dong Jin (Department of Anatomy, Chungnam National University School of Medicine) ;
  • Song, Hee-Jung (Department of Neurology, Chungnam National University Hospital and School of Medicine) ;
  • Kim, Dong Woon (Department of Anatomy, Chungnam National University School of Medicine)
  • 강현배 (질병관리본부 국립보건연구원 감염병센터 병원체자원관리TF) ;
  • 김기훈 (대전대학교 생명과학과 면역질환생리생화학실) ;
  • 김현중 (대전대학교 생명과학과 면역질환생리생화학실) ;
  • 한사랑 (충남대학교 의학전문대학원 해부학교실) ;
  • 채동진 (충남대학교 의학전문대학원 해부학교실) ;
  • 송희정 (충남대학교병원 신경과) ;
  • 김동운 (충남대학교 의학전문대학원 해부학교실)
  • Received : 2013.08.24
  • Accepted : 2013.09.09
  • Published : 2013.09.30
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Abstract

Chronic traumatic encephalopathy (CTE), which is common in athletes, is a progressive neurodegenerative disease and a long-term consequence of repetitive closed head injuries. CTE is regarded as a chronic brain syndrome due to the effects of repetitive traumatic brain injury (TBI). Because neurotrophic factors are neuroprotective in models of brain and spinal cord injuries, we examined the effects of cerebrolysin, a mixture of various neurotrophic factors, on brain pathology in a mouse model of repetitive mild TBI (rmTBI), which is a good model of CTE. Five groups were created and treated as follows: groups 1 and 2: rmTBI for 4 weeks following cerebrolysin injection for 4 weeks; groups 3 and 4: rmTBI for 8 weeks with or without cerebrolysin injection for 4 weeks; group 5: control. We found that p-tau expression was increased in the pyramidal layer of the cortex and hippocampus, particularly the CA3 region, but not in the CA1 region and the dentate gyrus (DG). Intra-tail vein administration of cerebrolysin ($10{\mu}l$ of 1 mg/ml) after/during rmTBI treatment reduced p-tau expression in both the cortex and hippocampus. Histological analysis revealed mild astrocyte activation (increased expression of glial fibrillary acidic protein (GFAP)) but not microglia activation (ionized calcium binding adaptor molecule 1 (iba-1) expression) and peripheral macrophage infiltration (CD45). Additionally, administration of cerebrolysin after rmTBI resulted in reduced astrocyte activation. These observations in rmTBI demonstrated that cerebrolysin treatment reduces phosphorylation of tau and astrocyte activation, attenuates brain pathology, and mitigates function deficits in TBI. Taken together, our observations suggest that cerebrolysin has potential therapeutic value in CTE.

만성외상성뇌병증(Chronic traumatic encephalopathy, CTE)은 운동선수와 매우 밀접하게 관련되어 있으며 장기간에 걸쳐 반복적인 외상성뇌손상(traumatic brain injury, TBI)로 인한 퇴행성뇌질환이다. 신경영양인자(neurotrophic factor)는 여러 종류가 알려져 있으며 이들은 뇌와 척수의 물리적 손상시에 신경보호효과가 있다. 따라서, 신경영양인자의 혼합물인 cebrolysin을 이용하여 CTE질환에 가장 적합하다고 여겨지는 repetitive mild TBI (rmTBI) 모델에서 cerebrolysin의 신경보호효과를 알아보고자 하였다. 실험군은 5군(groups 1 and 2: rmTBI for 4 weeks following cerebrolysin injection for 4 weeks; groups 3 and 4: rmTBI for 8 weeks with or without cerebrolysin injection for 4 weeks; group 5: control)으로 나누어 진행하였다. CTE의 가장 대표적 표시인자인 tau 단백질의 인산화를 조직학적으로 조사한 결과, 대뇌겉질과 해마내 CA3 영역에서 phospho-tau단백질의 발현이 증가되었으며 cerebrolysin ($10{\mu}l$ of 1 mg/ml)를 미정맥으로 투여시 p-tau발현이 감소되었다. CTE의 병인으로 알려진 별아교세포와 미세아교세포의 활성을 각각의 표시인인 GFAP, iba-1을 이용하여 면역조직화학염색을 시행하였다. 별아교세포의 활성은 rmTBI에 의하여 증가하였으며 cerebrolysin에 의해 회복되었으나 미세아교세포의 활성은 관찰되지 않았다. 또한 rmTBI모델에서 체내 탐식세포(macrophage)의 뇌내유입유무를 관찰하고자 CD45 염색을 시행하였으나 유의한 차이를 관찰하지 못하였다. 이상의 결과를 종합하면, cerebrolysin이 rmTBI에 의한 tau단백질의 인산화 및 별아교세포의 활성을 조절하는 것으로 사료된다. 따라서 cerebrolysin이 CTE 환자에 대한 치료 약물의 후보가 될 수 있음을 시사한다.

Keywords

References

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