Rao K V, Qureshi I A
Division of Medical Genetics, Sainte-Justine Hospital, Montreal, Que, Canada.
Neuropharmacology. 1999 Mar;38(3):383-94. doi: 10.1016/s0028-3908(98)00160-9.
Our earlier studies on the pharmacotherapeutic effects of acetyl-L-carnitine (ALCAR), in sparse-fur (spf) mutant mice with X linked ornithine transcarbamylase deficiency, have shown a restoration of cerebral ATP, depleted by congenital hyperammonemia and hyperglutaminemia. The reduced cortical glutamate and increased quinolinate may cause a down-regulation of the N-methyl-D-aspartate (NMDA) receptors, observed by us in adult spf mice. We have now studied the kinetics of [3H]-MK-801 binding to NMDA receptors in spf mice of different ages to see the effect of chronic hyperammonemia on the glutamate neurotransmission. We have also studied the Ca2+-dependent and independent (4-aminopyridine (AP) and veratridine-mediated) release of glutamate and the uptake of [3H]-glutamate in synaptosomes isolated from mutant spf mice and normal CD-1 controls. All these studies were done with and without ALCAR treatment (4 mmol/kg wt i.p. daily for 2 weeks), to see if its effect on ATP repletion could correct the glutamate neurotransmitter abnormalities. Our results indicate a normal MK-801 binding in 12-day-old spf mice but a significant reduction immediately after weaning (21 day), continuing into the adult stage. The Ca2+-independent release of endogenous glutamate from synaptosomes was significantly elevated at 35 days, while the uptake of glutamate into synaptosomes was significantly reduced in spf mice. ALCAR treatment significantly enhanced the MK-801 binding, neutralized the increased glutamate release and restored the glutamate uptake into synaptosomes of spf mice. These studies point out that: (a) the developmental abnormalities of the NMDA sub-type of glutamate receptor in spf mice could be due to the effect of sustained hyperammonemia, causing a persistent release of excess glutamate and inhibition of the ATP-dependent glutamate transport, (b) the modulatory effects of ALCAR on the NMDA binding sites could be through a repletion of ATP, required by the transporters to efficiently remove extracellular glutamate.
我们早期对乙酰-L-肉碱（ALCAR）在患有X连锁鸟氨酸转氨甲酰酶缺乏症的稀毛（spf）突变小鼠中的药物治疗作用进行的研究表明，先天性高氨血症和高谷氨酰胺血症导致的脑ATP耗竭得到了恢复。我们在成年spf小鼠中观察到，皮质谷氨酸减少和喹啉酸增加可能会导致N-甲基-D-天冬氨酸（NMDA）受体下调。我们现在研究了不同年龄的spf小鼠中[3H]-MK-801与NMDA受体结合的动力学，以观察慢性高氨血症对谷氨酸神经传递的影响。我们还研究了从突变的spf小鼠和正常CD-1对照中分离出的突触体中谷氨酸的钙依赖性和非依赖性（4-氨基吡啶（AP）和藜芦碱介导）释放以及[3H]-谷氨酸的摄取。所有这些研究均在有或没有ALCAR治疗（每天腹腔注射4 mmol/kg体重，持续2周）的情况下进行，以观察其对ATP补充的作用是否可以纠正谷氨酸神经递质异常。我们的结果表明，12日龄的spf小鼠中MK-801结合正常，但断奶后（21日龄）立即显著降低，并持续到成年期。在35天时，突触体中内源性谷氨酸的非钙依赖性释放显著升高，而spf小鼠中谷氨酸摄取到突触体中的量显著减少。ALCAR治疗显著增强了MK-801结合，中和了增加的谷氨酸释放，并恢复了spf小鼠突触体中谷氨酸的摄取。这些研究指出：（a）spf小鼠中谷氨酸受体NMDA亚型的发育异常可能是由于持续高氨血症的影响，导致过量谷氨酸持续释放并抑制了ATP依赖性谷氨酸转运；（b）ALCAR对NMDA结合位点的调节作用可能是通过补充转运蛋白有效清除细胞外谷氨酸所需的ATP来实现的。
