Previously we demonstrated that p53 mediates dopaminergic neurotoxicity via inducing mitochondrial burdens and proapoptotsis. However, little is known about the role of p53 in the excitotoxicity induced by psychostimulant, such as cocaine. Cocaine-induced kindling (convulsive) behaviors significantly increased p53 expression in the brain. Cocaine-induced p53 expression was more pronounced in hippocampus than in striatum or prefrontal cortex. Genetic depletion of p53 significantly attenuated cocaine-induced convulsive behaviors, followed by c-Fos immunoreactivity, and oxidative burdens in the hippocampus of mice. The antioxidant potentials mediated by genetic depletion of p53 were more pronounced in the mitochondrial-than cytosolic-fraction. Depletion of p53 significantly attenuated the changes in mitochondrial transmembrane potential, intramitochondrial Ca2+ level, and mitochondrial oxidative burdens induced by cocaine. Consistently, depletion of p53 significantly inhibited mitochondrial p53 translocation, and cleaved-PKCδ induced by cocaine. In addition, depletion of p53 protected from cytosolic cytochrome c release, and pro-apoptotic changes induced by cocaine. Importantly, the protective/anticonvulsant potentials by genetic depletion of p53 were comparable to those by pifithrin-μ (PFT), a p53 inhibitor. Our results suggest that depletion of p53 offers anticonvulsive and neuroprotective potentials mainly via attenuating mitochondrial oxidative burdens, mitochondrial dysfunction, and pro-apoptotic signalings against cocaine-induced convulsive neurotoxicity.

中文翻译：

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通过抑制线粒体的氧化负担，线粒体功能障碍和促凋亡变化，可以保护P53基因敲除小鼠免于可卡因诱导的点燃行为。

以前我们证明p53通过诱导线粒体负担和促凋亡介导多巴胺能神经毒性。然而，关于p53在由精神刺激剂如可卡因引起的兴奋性毒性中的作用了解甚少。可卡因引起的点燃（抽搐）行为显着增加了大脑中p53的表达。可卡因诱导的p53表达在海马中比在纹状体或前额叶皮层中更为明显。p53基因的耗竭显着减弱了可卡因诱导的惊厥行为，其次是小鼠海马的c-Fos免疫反应性和氧化负荷。由p53的遗传损耗介导的抗氧化电位在线粒体中比在细胞质中更明显。p53的耗竭显着减弱了线粒体跨膜电位的变化，内线粒体内的Ca2 +水平，以及可卡因引起的线粒体氧化负担。一致地，p53的耗竭显着抑制了可卡因诱导的线粒体p53易位和裂解的PKCδ。此外，p53的消耗可防止细胞溶质中的细胞色素c释放，以及可卡因诱导的促凋亡变化。重要的是，由于p53的遗传损耗而产生的保护/抗惊厥潜能与p53抑制剂pifithrin-μ（PFT）相当。我们的研究结果表明，p53的耗竭主要是通过减轻线粒体的氧化负担，线粒体功能障碍和针对可卡因引起的惊厥性神经毒性的促凋亡信号提供抗惊厥和神经保护的潜力。p53的耗竭显着抑制了可卡因诱导的线粒体p53易位和裂解的PKCδ。此外，p53的消耗可防止细胞溶质中的细胞色素c释放，以及可卡因诱导的促凋亡变化。重要的是，由于p53的遗传损耗而产生的保护/抗惊厥潜能与p53抑制剂pifithrin-μ（PFT）相当。我们的研究结果表明，p53的耗竭主要是通过减轻线粒体的氧化负担，线粒体功能障碍和针对可卡因引起的惊厥性神经毒性的促凋亡信号提供抗惊厥和神经保护的潜力。p53的耗竭显着抑制了可卡因诱导的线粒体p53易位和裂解的PKCδ。此外，p53的消耗可防止细胞溶质中的细胞色素c释放，以及可卡因诱导的促凋亡变化。重要的是，由于p53的遗传损耗而产生的保护/抗惊厥潜能与p53抑制剂pifithrin-μ（PFT）相当。我们的研究结果表明，p53的耗竭主要是通过减轻线粒体的氧化负担，线粒体功能障碍和针对可卡因引起的惊厥性神经毒性的促凋亡信号提供抗惊厥和神经保护的潜力。p53基因耗竭的保护/抗惊厥潜能与p53抑制剂pifithrin-μ（PFT）的潜能相当。我们的研究结果表明，p53的耗竭主要是通过减轻线粒体的氧化负担，线粒体功能障碍和针对可卡因引起的惊厥性神经毒性的促凋亡信号提供抗惊厥和神经保护的潜力。p53基因耗竭的保护/抗惊厥潜能与p53抑制剂pifithrin-μ（PFT）的潜能相当。我们的研究结果表明，p53的耗竭主要是通过减轻线粒体的氧化负担，线粒体功能障碍和针对可卡因引起的惊厥性神经毒性的促凋亡信号提供抗惊厥和神经保护的潜力。