Brannan T, Prikhojan A, Yahr M D
Department of Neurology, Mount Sinai School of Medicine, New York, NY, USA.
J Neural Transm (Vienna). 1997;104(1):77-87. doi: 10.1007/BF01271296.
Inhibitors of the enzyme catechol-O-methyl transferase (COMT) may be useful adjuncts to L-DOPA in the treatment of Parkinson's disease as they offer the possibility of increasing the availability of the amino acid. It is unknown whether a COMT inhibitor which penetrates the blood-brain barrier is preferable to one restricted to extra-cerebral inhibition. We measured liver and brain COMT activity two hours following administration of two COMT inhibitors: entacapone (ENT), mainly peripherally acting, and dinitrocatechol (DNC), peripheral and central acting. As expected, the full spectrum inhibitor DNC (30 mg/kg) induced a near total inhibition of liver and brain COMT activity. Unexpectedly, however, ENT, at 30 mg/kg, produced the same degree of liver and brain COMT inhibition as DNC; using 10mg/kg, ENT still inhibited both liver and brain COMT activity by 80%. Only at 2.5 and 5 mg/kg did ENT achieve a differential inhibition of liver (80% inhibition) versus brain (10-30% inhibition) COMT activity. In a second series of experiments, we administered ENT (2.5, 10, and 30 mg/kg) and DNC (30 mg/kg) to rats and monitored extracellular striatal dopamine and dopamine metabolite levels with cerebral microdialysis both under basal conditions and following L-DOPA/carbidopa administration. No compound modified basal striatal levels of dopamine. ENT at 30 mg/kg (but not 2.5 or 10 mg), as well as DNC, decreased striatal levels of the methylated dopamine metabolite homovanillic acid (HVA). When L-DOPA/carbidopa was administered, dopamine formation was greatest and HVA formation least in animals pretreated with DNC and 30 mg/kg ENT (but not 2.5 or 10 mg/kg ENT). The finding that ENT at doses relatively specific for peripheral enzyme inhibition did not promote dopamine or inhibit HVA formation is most likely due to the 20% residual liver COMT activity present when the inhibitor was used at less than full doses. Our data indicate that DNC and ENT both inhibit striatal HVA formation and increase dopamine formation from exogenously administered L-DOPA. The dopamine promoting effect of ENT is only present, however, at doses which inhibit central as well as peripheral COMT activity.
儿茶酚-O-甲基转移酶（COMT）抑制剂可能是左旋多巴治疗帕金森病的有用辅助药物，因为它们有可能增加这种氨基酸的可用性。一种能够穿透血脑屏障的COMT抑制剂是否比仅限于脑外抑制的抑制剂更具优势尚不清楚。我们在给予两种COMT抑制剂后两小时测量了肝脏和大脑的COMT活性：恩他卡朋（ENT），主要作用于外周；二硝基儿茶酚（DNC），外周和中枢均有作用。正如预期的那样，全谱抑制剂DNC（30毫克/千克）几乎完全抑制了肝脏和大脑的COMT活性。然而，出乎意料的是，30毫克/千克的ENT对肝脏和大脑COMT的抑制程度与DNC相同；使用10毫克/千克时，ENT仍然能抑制肝脏和大脑COMT活性达80%。只有在2.5毫克/千克和5毫克/千克时，ENT才实现了对肝脏（80%抑制）与大脑（10 - 30%抑制）COMT活性的差异抑制。在第二系列实验中，我们给大鼠注射ENT（2.5、10和30毫克/千克）和DNC（30毫克/千克），并在基础条件下以及注射左旋多巴/卡比多巴后，用脑微透析监测细胞外纹状体多巴胺和多巴胺代谢物水平。没有一种化合物改变基础状态下纹状体的多巴胺水平。30毫克/千克的ENT（但不是2.5毫克或10毫克）以及DNC降低了甲基化多巴胺代谢物高香草酸（HVA）的纹状体水平。当给予左旋多巴/卡比多巴时，在用DNC和30毫克/千克ENT预处理的动物中（但不是2.5毫克/千克或10毫克/千克的ENT），多巴胺生成最多，HVA生成最少。相对特异性抑制外周酶的剂量下，ENT未能促进多巴胺生成或抑制HVA生成，这一发现很可能是由于在使用低于全剂量抑制剂时肝脏中仍存在20% 的残余COMT活性。我们的数据表明，DNC和ENT都能抑制纹状体HVA生成，并增加外源性给予左旋多巴后的多巴胺生成。然而，ENT的多巴胺促进作用仅在抑制中枢和外周COMT活性的剂量下才存在。
