Camp D M, Loeffler D A, LeWitt P A
Clinical Neuroscience Program, Sinai Hospital, Detroit, Michigan, USA.
J Neurochem. 2000 Mar;74(3):1229-40. doi: 10.1046/j.1471-4159.2000.741229.x.
The debate about the toxicity of L-DOPA to dopaminergic neurons has not been resolved. Even though enzymatic and nonenzymatic metabolism of L-DOPA can produce hydrogen peroxide and oxygen free radicals, there has been controversy as to whether L-DOPA generates an oxidant stress in vivo. This study determined whether acute or repeated administration of L-DOPA caused in vivo production of hydroxyl radicals in striatum and other brain regions in rats with a unilateral 6-hydroxydopamine lesion of the dopaminergic nigrostriatal projections. Salicylate trapping combined with in vivo microdialysis provided measurements of extracellular 2,3-dihydroxybenzoic acid (2,3-DHBA) in striatum following L-DOPA administration systemically (100 mg/kg, i.p.) or by intrastriatal perfusion (1 mM, via the microdialysis probe). Tissue concentrations of 2,3-DHBA and salicylate were also measured in striatum, ventral midbrain, and cerebellum following repeated administration of L-DOPA (50 mg/kg, i.p., once daily for 16 days). In each instance, treatment with L-DOPA did not increase 2,3-DHBA concentrations, regardless of the nigrostriatal dopamine system's integrity. When added to the microdialysis perfusion medium, L-DOPA resulted in a significant decrease in the striatal extracellular concentration of 2,3-DHBA. These results suggest that administration of L-DOPA, even at high doses, does not induce hydroxyl radical formation in vivo and under some conditions may actually diminish hydroxyl radical activity. Furthermore, prior damage to the nigrostriatal dopamine system does not appear to predispose surviving dopaminergic neurons to increased hydroxyl radical formation following L-DOPA administration. Unlike L-DOPA, systemic administration of methamphetamine (10 mg/kg, s.c.) produced a significant increase in the concentration of 2,3-DHBA in striatal dialysate, suggesting that increased formation of hydroxyl radicals may contribute to methamphetamine neurotoxicity.
关于左旋多巴（L-DOPA）对多巴胺能神经元毒性的争论尚未解决。尽管L-DOPA的酶促和非酶促代谢可产生过氧化氢和氧自由基，但对于L-DOPA在体内是否会产生氧化应激一直存在争议。本研究确定了在患有多巴胺能黑质纹状体投射单侧6-羟基多巴胺损伤的大鼠中，急性或重复给予L-DOPA是否会导致纹状体和其他脑区在体内产生羟基自由基。水杨酸盐捕获结合体内微透析提供了在全身给予L-DOPA（100mg/kg，腹腔注射）或通过纹状体内灌注（1mM，通过微透析探针）后纹状体中细胞外2,3-二羟基苯甲酸（2,3-DHBA）的测量值。在重复给予L-DOPA（50mg/kg，腹腔注射，每天一次，共16天）后，还测量了纹状体、腹侧中脑和小脑中2,3-DHBA和水杨酸盐的组织浓度。在每种情况下，无论黑质纹状体多巴胺系统的完整性如何，用L-DOPA治疗均未增加2,3-DHBA浓度。当添加到微透析灌注介质中时，L-DOPA导致纹状体细胞外2,3-DHBA浓度显著降低。这些结果表明，即使高剂量给予L-DOPA，在体内也不会诱导羟基自由基的形成，并且在某些情况下实际上可能会降低羟基自由基的活性。此外，黑质纹状体多巴胺系统先前的损伤似乎不会使存活的多巴胺能神经元在给予L-DOPA后更容易形成更多的羟基自由基。与L-DOPA不同，全身给予甲基苯丙胺（10mg/kg，皮下注射）会使纹状体透析液中2,3-DHBA的浓度显著增加，这表明羟基自由基形成的增加可能导致甲基苯丙胺的神经毒性。
