Protection of the brain by carnitine and its mechanism

肉毒碱（β-羟基-γ-N-三甲基氨基丁酸盐）广泛分布于组织中，并已被确定为神经组织中长链酰基CoA通过线粒体内膜转运的重要辅因子。然而，在大脑中，虽然肉毒碱是存在的，合成的，并采取了全身给药后，其生理作用仍然未知。在我们以前的研究中，我们发现肉毒碱在临床上以及在生物化学上有效地抑制氨的神经毒性（参见Igisu等人，J.Occup. Health 37：75- 82，1995）。在本研究中，我们研究了肉毒碱对戊四氮（PTZ）诱导的癫痫发作的影响，PTZ是最广泛使用的致痫剂之一。左旋卡尼汀（5、10和20 mmol/kg）预处理ddY小鼠，可剂量依赖性地抑制PTZ诱发的强直性和阵挛性癫痫发作。时间效应研究（L-卡尼汀后1、5、15和30 min注射PTZ）显示，L-卡尼汀与PTZ间隔15-30 min时，PTZ的抗惊厥作用明显。含43%蔗糖的生理盐水延长首次阵挛发作的潜伏期，但效果不及20 mmol/kg L-卡尼汀，且不抑制阵挛发作或强直发作。左旋卡尼汀还能抑制PTZ引起的脑能量代谢的改变，包括乳酸的增加和ATP和磷酸肌酸的减少。左旋卡尼汀在延长首次阵挛发作潜伏期、降低阵挛发作和强直发作频率方面比右旋卡尼汀更有效。左旋卡尼汀对戊四氮诱发癫痫的抗惊厥作用可能与长链酰基辅酶A的转运无关，因为它们不受左旋卡尼汀的干扰。

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.