Low-dose candesartan enhances molecular mediators of neuroplasticity and subsequent functional recovery after ischemic stroke in rats.
Low-dose candesartan enhances molecular mediators of neuroplasticity and subsequent functional recovery after ischemic stroke in rats.
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DOI：
10.1007/s12035-014-8830-6
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发表时间：
2015
影响因子：
5.1
通讯作者：
Fagan SC
中科院分区：
文献类型：
--
作者：
Ishrat T;Pillai B;Soliman S;Fouda AY;Kozak A;Johnson MH;Ergul A;Fagan SC
我们之前报道过坎地沙坦阻断血管紧张素1型受体（AT1R）在实验性脑缺血后发挥神经血管保护作用。在这里，我们验证了低剂量坎地沙坦通过增强缺血再灌注损伤大鼠的神经营养因子表达来增强神经可塑性和随后的功能恢复的假设。雄性Wistar大鼠（290 ~ 300 g）脑中动脉闭塞90 min，再灌注时给予坎地沙坦（0.3 mg/kg）或生理盐水，然后每24 h 1次，连用7 d。在MCAO后1、3、7和14天采用盲法评估功能缺陷。动物中风后14天处死，用甲酚紫灌注脑梗死面积。Western blot和免疫组化检测生长因子和突触蛋白的表达。坎地沙坦治疗的动物显示梗死面积显著减少[t (13)= - 5.5， P= 0.0001]， Bederson功能恢复[F (1,13)=7.9， P=0.015]，梁行走[F (1,13)=6.7， P=0.023]，握力[F (1,13)=15.2， P=0.0031]，旋转性能[F (1,14)=29.8， P<0.0001]。此外，坎地沙坦处理的动物活性金属蛋白酶-3 （MMP-3）、层粘连蛋白和血管生成素-1 （Ang-1）的表达显著增加。坎地沙坦处理后，血管内皮生长因子（VEGF）和脑源性神经营养因子（BDNF）及其受体的表达显著升高。此外，我们还观察到神经可塑性标志物、突触素和PSD-95显著增加。这些结果表明，低剂量坎地沙坦对可塑性测量具有巨大而持久的影响，并伴随缺血性卒中后的功能恢复。
We have previously reported that angiotensin type 1 receptor (AT1R) blockade with candesartan exerts neurovascular protection after experimental cerebral ischemia. Here, we tested the hypothesis that a low, subhypotensive dose of candesartan enhances neuroplasticity and subsequent functional recovery through enhanced neurotrophic factor expression in rats subjected to ischemia reperfusion injury. Male Wistar rats (290–300 g) underwent 90 min of middle cerebral artery occlusion (MCAO) and received candesartan (0.3 mg/kg) or saline at reperfusion and then once every 24 h for 7 days. Functional deficits were assessed in a blinded manner at 1, 3, 7, and 14 days after MCAO. Animals were sacrificed 14-day post-stroke and the brains perfused for infarct size by cresyl violet. Western blot and immunohisto-chemistry were used to assess the expression of growth factors and synaptic proteins. Candesartan-treated animals showed a significant reduction in the infarct size [t (13)=−5.5, P= 0.0001] accompanied by functional recovery in Bederson [F (1, 13)=7.9, P=0.015], beam walk [F (1, 13)=6.7, P=0.023], grip strength [F (1, 13)=15.2, P=0.0031], and rotarod performance [F (1, 14)=29.8, P<0.0001]. In addition, candesartan-treated animals showed significantly higher expression of active metalloproteinase-3 (MMP-3), laminin, and angiopoietin-1 (Ang-1). The expression of vascular endothelial growth factor (VEGF) and brain-derived neurotrophic factor (BDNF) and its receptor was significantly increased in the animals treated with candesartan. Also, we observed significant increases in neuroplasticity markers, synaptophysin, and PSD-95. These results indicate that low-dose candesartan had a large and enduring effect on measures of plasticity, and this accompanied the functional recovery after ischemic stroke.