Protection of the brain by carnitine and its mechanism

肉碱（β -羟基- γ - n -三甲氨基丁酸盐）广泛分布于组织中，已被确定为长链酰基辅酶a通过神经外组织线粒体内膜运输的必要辅助因子。然而，在大脑中，虽然肉碱存在、合成并在全身给药后被吸收，但其生理作用仍然未知。在我们之前的研究中，我们发现肉碱在临床上和生物化学上都有效地抑制氨的神经毒性（见Igisu等人）。J.Occup。保健37:75-82,1995年)。在本研究中，我们检测了肉碱在戊四唑（PTZ）引起的癫痫发作中的作用，PTZ是最广泛使用的致痫药物之一。以5、10、20 mmol/kg的左旋肉碱（L-carnitine）预处理ddY小鼠，PTZ诱导的阵挛性和强直性癫痫发作均受到剂量依赖性抑制。时间反应研究（分别在左旋肉碱后1、5、15和30 min注射PTZ）表明，当左旋肉碱与PTZ的注射间隔为15-30 min时，抗惊厥作用明显。含43%蔗糖的生理盐水可延长首次阵挛性发作的潜伏期，但效果不及20 mmol/kg左旋肉碱，且对阵挛性或强直性发作无抑制作用。左旋肉碱还能抑制PTZ引起的脑能代谢产物的改变，包括乳酸的增加和ATP和磷酸肌酸的减少。左旋肉碱比d -左旋肉碱在延长第一次阵挛性发作的潜伏期和降低阵挛性和强直性发作的频率方面更有效。左旋肉碱在ptz诱导的癫痫发作中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d -左旋肉碱的干扰。

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.