Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke.
Bryostatin improves survival and reduces ischemic brain injury in aged rats after acute ischemic stroke.
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DOI：
10.1161/strokeaha.113.002411
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发表时间：
2013-12
期刊：
影响因子：
8.3
通讯作者：
Huber JD
中科院分区：
文献类型：
--
作者：
Tan Z;Turner RC;Leon RL;Li X;Hongpaisan J;Zheng W;Logsdon AF;Naser ZJ;Alkon DL;Rosen CL;Huber JD
苔藓虫素是一种有效的蛋白激酶C （PKC）激活剂，在联想记忆、阿尔茨海默病、全脑缺血和创伤性脑损伤的临床前模型中显示出治疗效果。在这项研究中，我们通过老龄大鼠组织纤溶酶原激活剂（tPA）再灌注脑缺血的临床相关模型，验证了苔藓抑素在减少脑损伤和改善脑卒中预后方面具有治疗作用的假设。研究了18-20月龄雌性Sprague-Dawley大鼠右脑中动脉可逆性闭塞（MCAO），采用自体血凝块介导tpa再灌注。在MCAO后6 h，以及MCAO后3、6、9、12、15和18 d给予苔藓虫素。术后2、7、14、21 d进行功能评估。分别在mcao后2、7、21 d检测病变体积和半球肿胀/萎缩。在mcao后24小时进行PKC同工酶的组织学评估。苔藓虫素治疗的大鼠在mcao后的存活率有所提高，尤其是在前4天。mcao后反复给药苔藓虫素可减少梗死面积，半球肿胀/萎缩，并在mcao后21天改善神经功能。苔藓抑素处理大鼠mcao后24小时神经元中PKC α和PKC epsilon表达发生变化。mcao后反复给药苔藓抑素可保护脑免受mcao后的严重神经损伤。苔藓虫素治疗提高了生存率，减少了病变体积，通过减少坏死和梗死周围星形胶质细胞形成挽救了梗死半球的组织，并改善了MCAO后的功能预后。
Bryostatin, a potent protein kinase C (PKC) activator, has demonstrated therapeutic efficacy in preclinical models of associative memory, Alzheimer's disease, global ischemia, and traumatic brain injury. In this study, we tested the hypothesis that administration of bryostatin provides a therapeutic benefit in reducing brain injury and improving stroke outcome using a clinically relevant model of cerebral ischemia with tissue plasminogen activator (tPA) reperfusion in aged rats. Acute cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery (MCAO) in 18-20 month old female Sprague-Dawley rats using an autologous blood clot with tPA-mediated reperfusion. Bryostatin was administered at 6 h post-MCAO then at 3, 6, 9, 12, 15, and 18 d after MCAO. Functional assessment was conducted at 2, 7, 14, and 21 d after MCAO. Lesion volume and hemispheric swelling/atrophy were performed at 2, 7, and 21 d post-MCAO. Histological assessment of PKC isozymes was performed at 24 h post-MCAO. Bryostatin-treated rats showed improved survival post-MCAO, especially during the first 4 d. Repeated administration of bryostatin post-MCAO resulted in reduced infarct volume, hemispheric swelling/atrophy, and improved neurological function at 21 d post-MCAO. Changes in PKC alpha expression and PKC epsilon expression in neurons were noted in bryostatin-treated rats at 24 h post-MCAO. Repeated bryostatin administration post-MCAO protected the brain from severe neurological injury post-MCAO. Bryostatin treatment improved survival rate, reduced lesion volume, salvaged tissue in infarcted hemisphere by reducing necrosis and peri-infarct astrogliosis, and improved functional outcome following MCAO.