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Protection of the brain by carnitine and its mechanism

肉碱对大脑的保护作用及其机制

基本信息

批准号：
07670417
负责人：
IGISU Hideki
金额：
$ 1.34万
依托单位：
University of Occupational and Environmental Health
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-07670417/
关键词：
Carnitine Seizures Pentylenetetrazol Cerebral protection Brain energy metabolism ATP

项目摘要

Carnitine (beta-hydroxy-gamma-N-trimethylaminobutyrate) is widely distributed among tissues and has been well established as an essential cofactor for the transport of long-chain acyl CoA through the inner mitochondrial membrane in extraneural tissues. In the brain, however, while carnitine is present, synthesized, and taken up after systemic administration, its physiological roles remain unknown. In our previous studies, we found that carnitine was effective clinically as well as biochemically in suppressing neurotoxicities of ammonia (see Igisu et al. J.Occup. Health 37 : 75-82,1995). In the present study, we examined effects of carnitine inseizures induced by pentylenetetrazol (PTZ), one of the most widely used epileptogenic agents. When ddY mice were pretreated with L-carnitine (5,10 and 20 mmol/kg), clonic as well as tonic seizures induced by PTZ were dose-dependently suppressed. Time-respones study (PTZ was injected 1,5,15 and 30 min after L-carnitine) showed that the anticonvulsive effects were apparent when the interval between L-carnitine and PTZ administration was 15-30 min. Saline containing 43% sucrose prolonged the latency to the first clonic seizure but less effective than 20 mmol/kg L-carnitine and did not suppress clonic or tonic seizures. Alterations in brain energy metabolites caused by PTZ including increase of lactate and decrease of ATP and phosphocreatine were also suppressed by L-carnitine. L-Carnitine was more potent than D-carnitine in prolonging the latency to the first clonic seizure and in decreasing the frequency of clonic as well as tonic seizures. The anticonvulsive effects of L-carnitine in PTZ-induced seizures may be unrelated to the transport of longchain acyl CoA since they were not interfered with by D-carnitine.

肉碱(β-羟基-γ-N-三甲基氨基丁酸酯)广泛分布于组织中，是长链乙酰辅酶A通过神经外组织线粒体膜转运的重要辅助因子。然而，在大脑中，虽然肉碱存在，合成，并在全身给药后被吸收，但其生理作用仍不清楚。在我们之前的研究中，我们发现肉碱在临床和生物化学上都有效地抑制了氨的神经毒性(见Igisu等人。J·奥卡普。健康37：75-82,1995)。在本研究中，我们研究了最广泛使用的致痫药物之一--戊四唑(PTZ)诱导的肉碱惊厥的效果。预先给予L肉碱(5，10和20 mmol/kg)可剂量依赖性地抑制戊四氮所致的阵挛发作和强直发作。时间-反应研究(在L肉碱给药后1、5、15、30min注射甲氨蝶呤)显示，L肉碱与甲硝唑给药间隔15~30min时抗惊厥作用明显。含43%蔗糖的生理盐水可延长小鼠首次阵挛发作的潜伏期，但作用不如20 mmol/kg L肉碱，也不能抑制阵挛发作或强直发作。L-卡尼汀也能抑制戊四氮所致的脑组织能量代谢产物的改变，包括乳酸升高、三磷酸腺苷和磷酸肌酸的降低。L-卡尼汀在延长至首次阵挛发作的潜伏期、减少阵挛发作和强直发作频率方面优于D-卡尼汀。L-卡尼汀在PTZ致痫中的抗惊厥作用可能与长链酰辅酶A转运无关，因为它们不受D-卡尼汀的干扰。