CAJ | 학술논문

目的探讨孕酮预处理对局灶性脑缺血再灌注损伤(focal cerebral ischemic and reperfusion injury,fCIRI)的作用及机制.方法在建立大鼠fCIRI模型前96、48、1h分别给予孕酮(8mg/kg)1次性腹腔注射.建立大鼠fCIRI模型,在fCIRI后第3～8天,检查大鼠的空间记忆功能和缺血侧海马CA1区存活神经元数量.检测孕酮预处理后1～96 h的海马细胞外信号调节激酶1/2(ERK1/2)磷酸化水平和活化ERK1/2核转移.结果造模前48、1h经孕酮预处理的大鼠海马CA1区神经元存活数量(mm-1)较造模后明显增多(164.3±11.0、218.5±9.1与142.7±12.1,F=29.45,P＜0.01)；造模前48、1h经孕酮预处理的大鼠能明显缩短脑缺血导致的水迷宫逃避潜伏期(s)延长(32.4±14.3、10.3±11.1与19.2±9.6;F=35.84,P＜0.01).海马CA1区ERK1/2磷酸化水平在孕酮给药后的12 ～48 h明显增强,96 h恢复基线.核内ERK1/2磷酸化水平在孕酮给药后2h增加,并持续到48 h.孕酮增加胞质ERK1/2及胞核内ERK1/2磷酸化的水平能被RU486阻断.结论孕酮预处理对缺血引起的海马CA1区神经元死亡有保护作用,并能改善空间记忆功能；孕酮预处理的神经保护作用有48 h以上的有效时间窗；在孕酮的神经保护作用依赖于孕酮受体介导的ERK1/2信号通路.
목적 탐토잉동예처리대국조성뇌결혈재관주손상(focal cerebral ischemic and reperfusion injury,fCIRI)적작용급궤제.방법 재건립대서fCIRI모형전96、48、1h분별급여잉동(8mg/kg)1차성복강주사.건립대서fCIRI모형,재fCIRI후제3～8천,검사대서적공간기억공능화결혈측해마CA1구존활신경원수량.검측잉동예처리후1～96 h적해마세포외신호조절격매1/2(ERK1/2)린산화수평화활화ERK1/2핵전이.결과 조모전48、1h경잉동예처리적대서해마CA1구신경원존활수량(mm-1)교조모후명현증다(164.3±11.0、218.5±9.1여142.7±12.1,F=29.45,P＜0.01)；조모전48、1h경잉동예처리적대서능명현축단뇌결혈도치적수미궁도피잠복기(s)연장(32.4±14.3、10.3±11.1여19.2±9.6;F=35.84,P＜0.01).해마CA1구ERK1/2린산화수평재잉동급약후적12 ～48 h명현증강,96 h회복기선.핵내ERK1/2린산화수평재잉동급약후2h증가,병지속도48 h.잉동증가포질ERK1/2급포핵내ERK1/2린산화적수평능피RU486조단.결론 잉동예처리대결혈인기적해마CA1구신경원사망유보호작용,병능개선공간기억공능；잉동예처리적신경보호작용유48 h이상적유효시간창；재잉동적신경보호작용의뢰우잉동수체개도적ERK1/2신호통로.
Objective To investigate the effect of progesterone pretreatment of focal cerebral ischemic and reperfusion injury (fCIRI) and underlying molecular mechanisms.Methods A single intraperitoneal injection of progesterone (8 mg/kg) given 1 h,48 h and 96 h before fCIRI was established in male Sprague-Dawley rats.The number of survival of neurons in hippocampal CA1 region of the ischemiaside,as well as spatial memory function,was detected on days 3-8 after fCIRI.Extracellular-signalregulated kinase 1/2 phosphorylation (p-ERK1/2) and nuclear translocation of p-ERK1/2 in hippocampal CA1 region were examined using western blot.Results The number of survival of neuronal cells was significantly increased in ischemic groups treated with progesterone at 1 h and 48 h pre-fCIRI (164.3 ± 11.0,218.5 ± 9.1 and 142.7 ± 12.1,F =29.4,P ＜ 0.01) compared with fCIRI group treated with vehicle.Likewise,the escape-latency to reach the hidden-platform recorded in day 5 of Morris water maze test was reduced markedly in fCIRI-treatment groups compared with the vehicle group(10.3 ± 11.1,19.2 ±9.6 and 32.4 ± 14.3 ;F =35.8,P ＜0.01).The level of p-ERK1/2 was elevated notably during 24 h to 48 h postprogesterone by western blot,while restored to the baseline at 96 h post-progesterone.Improved nuclear translocation of p-ERK1/2 was observed from 2 h to 48 h post-progesterone.The progesterone receptor antagonist RU486 blocked the exaltation of either intracellular level or nuclear translocation of p-ERK1/2,which was induced by progesterone.Conclusions The pretreatment with progesterone exerts a neuroprotective effect against the ischemia-induced neuronal death and ameliorates the deficits in spatial memory through enhancing the activation of ERK1/2.The neuroprotection derived from pretreatment with progesterone achieves a time window of not less than 48 h,which is progesterone receptor-mediated ERK1/2 signaling pathway-dependent.