丙戊酸的新作用??对脑损伤的保护作用

neuroprotective effects of valproic acid against hemin toxicity: possible involvement of the down-regulation of

heme oxygenase-1 by regulating ubiquitin-proteasomal pathway.

丙戊酸通过调节泛素蛋白酶通道从而下调了亚铁血红素氧合酶-1对抗了脑出血后高铁血红素而产生了神经保护作用上海东方医院神经外科魏社鹏

ja kwon k, nam kim j, kyeong kim m, young kim s, suk cho k, jin jeon s, young kim h, hoon ryu j, han sy, hoon cheong j, j ignarro l, han sh, young shin c.

脑出血后导致的脑损伤当中，血红蛋白副产品产生了了有害的作用；亚铁血红素氧合酶-1 (ho-1)的诱导同样在脑出血中的神经毒性作用中起到了关键的作用。丙戊酸是个抗癫痫药物，已有报道称，其在缺血性脑卒中能对抗各种神经元损伤而产生神经保护作用。本组作者在脑出血的动物模型中，研究了丙戊酸对亚铁血红素氧合酶-1（ho-1）介导的神经毒性的作用。作者研究了丙戊酸对皮层神经元中亚铁血红素氧合酶-1蛋白的作用：通过rt-pcr和wb来检测亚铁血红素氧合酶-1 (ho-1)mrna和 蛋白表达水平；通过mtt比色法和活性氧（ros）检测来判断细胞活力和ros（活性氧）增值；采用ip-wb来检测丙戊酸（vpa）对信号通道的调节；通过高铁血红素显微注射和活体内免疫组化来检测丙戊酸（vpa）在高铁血红素（hemin）诱导的细胞死亡的作用。脑出血时，鼠脑皮层神经元和鼠脑组织当中，血红蛋白崩解释放出高铁血红素（hemin），丙戊酸的治疗作用在于部分的阻止了高铁血红素导致的细胞死亡。丙戊酸的作用被发现，无论是在体内还是体外，均显著的降低了亚铁血红素氧合酶-1 (ho-1)蛋白的表达。通过皮层神经元中细胞外信号调节激酶（erk1/2）和c-jun氨基端激酶（jnk）激活，增加的遍在蛋白化（ubiquitination）和亚铁血红素氧合酶-1（ho-1）降解，从而使得经过丙戊酸的预处理后，高铁血红素诱导了铁血红素氧合酶-1 (ho-1)蛋白的表达的过程被部分的阻止了了。作者的研究结果表明，丙戊酸通过下调ho-1蛋白表达，抑制了高铁血红素的毒性，从而提供了一条治疗途径，来减缓脑出血后的神经损伤。

source

department of neurology, center for neuroscience research, smart institute of advanced biomedical science, school of medicine, konkuk university, 1 hwayang-dong, gwangjin-gu, seoul 143-701, republic of korea.

abstract

during hemorrhagic stroke induced by intracerebral hemorrhage (ich), brain injury occurs from the deleterious actions of hemoglobin byproducts; induction of heme oxygenase-1 (ho-1) also plays a critical role in the neurotoxicity in ich. valproic acid (vpa), which is a commonly used drug in the treatment of epilepsy, has been reported to have neuroprotective effects against various neuronal insults including ischemic stroke. we investigated the effect of vpa on ho-1-mediated neurotoxicity in an experimental model of ich. we investigated the effects of vpa on ho-1 protein in primary cortical neurons: (1) the expression levels of ho-1 mrna and protein measured by rt-pcr and western blotting; (2) the cell viability and ros generation by mtt reduction assay and ros measurement; (3) the signal pathway regulated by vpa using ip-western blotting; (4) the effects of vpa on hemin-induced cell death by hemin microinjection and immunohistochemistry in vivo. vpa treatment partially blocked cell death induced by hemin, which is released from hemoglobin during ich, both in rat primary cortical neurons and rat brain. treatment of vpa significantly decreased the expression of ho-1 protein both in vitro and in vivo. hemin treatment induced ho-1 protein expression and this was partially blocked by pretreatment with vpa, which might be mediated by increased ubiquitination and degradation of ho-1 via erk1/2 and jnk activation in primary cortical neurons. our results indicate that vpa inhibits hemin toxicity by downregulating ho-1 protein expression, and provide a therapeutic strategy to attenuate intracerebral hemorrhagic injury.