Antiepileptic and Neuroprotective Effects of Oleamide in Rat Striatum on Kainate-Induced Behavioral Seizure and Excitotoxic Damage via Calpain Inhibition.
Antiepileptic and Neuroprotective Effects of Oleamide in Rat Striatum on Kainate-Induced Behavioral Seizure and Excitotoxic Damage via Calpain Inhibition.
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DOI：
10.3389/fphar.2017.00817
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发表时间：
2017
影响因子：
5.6
通讯作者：
Kim HJ
中科院分区：
文献类型：
--
作者：
Nam HY;Na EJ;Lee E;Kwon Y;Kim HJ
油酰胺最初被认为是一种诱导睡眠的脂肪酸酰胺，后来被证明对不同的神经化学系统具有广泛的神经药理学作用。然而，油酰胺对脑损伤的影响几乎没有被研究，其作用的分子机制和部位仍然难以捉摸。红藻氨酸 (KA) 已被用来制作模拟人类颞叶癫痫的癫痫动物模型，并诱导钙蛋白酶激活的兴奋性毒性，这种毒性发生在许多神经退行性疾病中。在这项研究中，我们检查了油酰胺是否可以预防 KA 诱导的兴奋性毒性脑损伤，并伴有行为癫痫活动和神经元细胞死亡。此外，还研究了油酰胺的这些作用是否是由钙蛋白酶活性相关的细胞机制介导的。通过纹状体内注射 KA（5 nmole）产生 KA 诱导的癫痫大鼠。在 KA 注射前 30 分钟口服油酰胺（0.5、2 和 10 mg/kg）显示出对 KA 诱导的行为癫痫活动的剂量依赖性抑制，并在术后 60 至 180 分钟开始监测。注射 KA 后连续 4 天进一步重复口服油酰胺（每天一次）可产生显着的神经保护作用，防止因 KA 诱导的兴奋性毒性损伤而导致的神经元完整性受损，用甲酚紫、苏木精/伊红和氟玉 B 染色纹状体组织切片也证明了这一点。此外，油酰胺还可阻断 KA 诱导的细胞周期蛋白依赖性激酶 5 共激活剂的裂解(Cdk5-p35) 和塌陷素反应介导蛋白 2，据信它们是由 KA 诱导的癫痫大鼠纹状体组织中的钙蛋白酶激活介导的。油酰胺还逆转了 KA 诱导的内源性钙蛋白酶抑制蛋白、钙蛋白酶抑制蛋白和突触活性标记物突触蛋白-II 表达的减少。使用脑组织和无细胞且钙蛋白酶过度表达的神经元细胞系统中的体外钙蛋白酶测定，进一步研究了油酰胺可以诱导直接钙蛋白酶抑制的假设。这些发现共同表明，油酰胺对兴奋性毒性诱导的神经元死亡和行为性癫痫发作具有保护作用，部分是通过其直接的钙蛋白酶抑制活性。
Oleamide was first known as a sleep-inducing fatty acid amide, and later shown to have wide range of neuropharmacological effects upon different neurochemical systems. However, the effects of oleamide on brain damage have scarcely been studied, and the molecular mechanisms and sites of its action remain elusive. Kainic acid (KA) has been used to produce an epileptic animal model that mimics human temporal lobe epilepsy and to induce calpain-activated excitotoxicity, which occurs in numerous neurodegenerative disorders. In this study, we examined whether oleamide protects against the KA-induced excitotoxic brain damage accompanied by behavioral seizure activity and neuronal cell death. Moreover, whether these effects of oleamide were mediated by calpain activity-related cellular mechanisms was investigated. KA-induced epileptic rats were produced by an intrastriatal injection of KA (5 nmole). Oral administration of oleamide (0.5, 2, and 10 mg/kg) 30 min prior to the KA injection showed dose-dependent inhibition of the KA-induced behavioral seizure activities that were monitored starting from 60 to 180 min post-surgery. Further repetitive oral administration of oleamide (once per day) for the next 4 consecutive days post-KA injection produced significant neuroprotection against the disrupted neuronal integrity that resulted from KA-induced excitotoxic damage that was also demonstrated by staining of striatal tissue sections with cresyl violet, hematoxylin/eosin, and fluoro-Jade B. In addition, oleamide blocked the KA-induced cleavage of cyclin-dependent kinase-5 coactivator (Cdk5-p35) and collapsin response mediator protein-2, which are believed to be mediated by calpain activation in striatal tissues dissected from KA-induced epileptic rats. Oleamide also reversed the KA-induced reduction in expression of an endogenous calpain inhibitory protein, calpastatin, and a marker of synaptic activity, synapsin-II. The hypothesis that oleamide could induce direct calpain inhibition was further investigated using in vitro calpain assays in both brain tissue and a cell-free and calpain-overexpressed neuronal cell system. These findings together suggest that oleamide has protective effects against excitotoxicity-induced neuronal death and behavioral seizure, partly via its direct calpain inhibitory activity.
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影响因子：
3.3
作者：
Bortolatto, C. F.;Jesse, C. R.;Nogueira, C. W.
通讯作者：
Nogueira, C. W.
影响因子：
4.4
作者：
Araujo, Ines M.;Carreira, Bruno P.;Carvalho, Arselio P.
通讯作者：
Carvalho, Arselio P.
发酵乳制品对阿尔茨海默氏病的预防作用，并鉴定出具有增强的小胶质细胞增多症和抗炎活性的新型Oleamide。
影响因子：
3.7
作者：
Ano Y;Ozawa M;Kutsukake T;Sugiyama S;Uchida K;Yoshida A;Nakayama H
通讯作者：
Nakayama H
影响因子：
56.9
作者：
CRAVATT, BF;PROSPEROGARCIA, O;LERNER, RA
通讯作者：
LERNER, RA
影响因子：
25
作者：
Frerking, M;Malenka, RC;Nicoll, RA
通讯作者：
Nicoll, RA