Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke
Neuroprotection by Chlorpromazine and Promethazine in Severe Transient and Permanent Ischemic Stroke
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氯丙嗪和异丙嗪对严重短暂性和永久性缺血性中风的神经保护作用。
DOI：
10.1007/s12035-016-0280-x
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发表时间：
2017-12-01
影响因子：
5.1
通讯作者：
Ding, Yuchuan
中科院分区：
文献类型：
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作者：
Geng, Xiaokun;Li, Fengwu;Ding, Yuchuan
先前的研究已经证明了吩噻嗪类神经抑制剂[氯丙嗪和异丙嗪（C + P）组合]在大脑活动中的抑郁或冬眠样作用。这项缺血性卒中研究旨在通过缺血后C + P给药降低氧化应激和改善脑代谢来建立神经保护作用。Sprague-Dawley大鼠进行短暂的（2或4小时）大脑中动脉闭塞（MCAO），然后再灌注6或24小时，或永久性（28小时）MCAO无再灌注。在缺血发作后2小时，大鼠接受腹膜内（IP）注射生理盐水或两个剂量的C + P。体温，脑梗死体积和神经功能缺损进行了检查。氧化代谢和应激通过ATP、NADH和活性氧（ROS）水平来确定。蛋白激酶C-δ（PKC-δ）和Akt表达通过蛋白质印迹法测定。C + P给药在短暂性和永久性缺血模型中都诱导了神经保护作用，证据是卒中后梗死体积和神经功能缺损显著减少。C + P在缺血后5 min就诱导体温呈剂量依赖性降低，并持续至12 h。然而，降低体温只是轻微或没有增强C + P诱导的神经保护。C + P治疗改善了脑代谢，如通过增加ATP水平和NADH活性以及减少ROS产生所确定的。这些治疗效果与PKC-δ和Akt蛋白表达的改变有关。C + P治疗通过抑制代谢事件的破坏性级联反应，在严重卒中模型中赋予神经保护作用，最有可能独立于药物诱导的低温。这些发现进一步证明了C + P治疗的临床潜力，并可能指导我们更接近开发一种有效的神经保护疗法。
Previous studies have demonstrated depressive or hibernation-like roles of phenothiazine neuroleptics [combined chlorpromazine and promethazine (C + P)] in brain activity. This ischemic stroke study aimed to establish neuroprotection by reducing oxidative stress and improving brain metabolism with post-ischemic C + P administration. Sprague-Dawley rats were subjected to transient (2 or 4 h) middle cerebral artery occlusion (MCAO) followed by 6 or 24 h reperfusion, or permanent (28 h) MCAO without reperfusion. At 2 h after ischemia onset, rats received either an intraperitoneal (IP) injection of saline or two doses of C + P. Body temperatures, brain infarct volumes, and neurological deficits were examined. Oxidative metabolism and stress were determined by levels of ATP, NADH, and reactive oxygen species (ROS). Protein kinase C-delta (PKC-delta) and Akt expression were determined by Western blotting. C + P administration induced a neuroprotection in both transient and permanent ischemia models evidenced by significant reduction in infarct volumes and neurological deficits post-stroke. C + P induced a dose-dependent reduction in body temperature as early as 5 min post-ischemia and lasted up to 12 h. However, reduction in body temperature either only slightly or did not enhance C + P-induced neuroprotection. C + P therapy improved brain metabolism as determined by increased ATP levels and NADH activity, as well as decreased ROS production. These therapeutic effects were associated with alterations in PKC-delta and Akt protein expression. C + P treatments conferred neuroprotection in severe stroke models by suppressing the damaging cascade of metabolic events, most likely independent of drug-induced hypothermia. These findings further prove the clinical potential for C + P treatment and may direct us closer towards the development of an efficacious neuroprotective therapy.