Messam C A, Greene J G, Greenamyre J T, Robinson M B
Children's Seashore House, Department of Pharmacology, University of Pennsylvania, Philadelphia 19104, USA.
Brain Res. 1995 Jul 3;684(2):221-4. doi: 10.1016/0006-8993(95)00435-s.
The effects of intrastriatal injections of a reversible inhibitor of succinate dehydrogenase, malonate, on the extracellular concentrations of amino acid neurotransmitters were examined using a microdialysis probe that was positioned a fixed distance from an injection cannula. Malonate (2 mumol) caused a 23 +/- 5-fold increase in extracellular glutamate (Glu), a 18 +/- 6-fold increase extracellular gamma-aminobutyric acid (GABA) and a modest increase in extracellular aspartate (Asp, 2.9 +/- 0.8-fold increase). Administration of the NMDA receptor antagonist MK-801 (5 mg/kg) prior to injection of malonate almost completely blocked these increases. This study provides direct evidence that inhibition of succinate dehydrogenase causes an increase in extracellular amino acid neurotransmitters and further evidence that bioenergetic defects may contribute to the pathogenesis of chronic neurodegenerative diseases through an excitotoxic mechanism.
使用一个与注射套管保持固定距离的微透析探针，研究了纹状体内注射琥珀酸脱氢酶可逆抑制剂丙二酸对氨基酸神经递质细胞外浓度的影响。丙二酸（2微摩尔）使细胞外谷氨酸（Glu）增加了23±5倍，使细胞外γ-氨基丁酸（GABA）增加了18±6倍，并使细胞外天冬氨酸（Asp）有适度增加（增加了2.9±0.8倍）。在注射丙二酸之前给予NMDA受体拮抗剂MK-801（5毫克/千克）几乎完全阻断了这些增加。这项研究提供了直接证据，表明琥珀酸脱氢酶的抑制会导致细胞外氨基酸神经递质增加，进一步证明生物能量缺陷可能通过兴奋性毒性机制促成慢性神经退行性疾病的发病机制。
