Lee Eun-Sook Y, Chen Hongtao, Soliman Karam F A, Charlton Clivel G
College of Pharmacy and Pharmaceutical Sciences, Florida A&M University, Tallahassee, FL 32307, USA.
Neurotoxicology. 2005 Jun;26(3):361-71. doi: 10.1016/j.neuro.2005.01.008.
Long-term treatment of levodopa for Parkinson's disease (PD) patients is known to elevate homocysteine level in their plasma. The present study was designed to examine the possible neurotoxic effects of the increased homocysteine level on the dopaminergic system. Homocysteine was administered into Sprague-Dawley male rats intracerebroventricularly or C57BL/6 mice intraperitoneally. Following homocysteine injection the locomotor activities, the levels of dopamine (DA) and its metabolites, 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), and immunohistochemistry of dopaminergic neurons were examined. The results obtained indicate that homocysteine administration (1 or 2 micromol, i.c.v.) into the rat brains for 5 days significantly decreased the locomotor activities and dopamine as well as its metabolites, DOPAC and HVA, in the rat striatal regions. Two different doses of homocysteine (50 and 100mg/100g, i.p. daily) were administered into mice for 36 days to evaluate the effect of systemic treatment of homocysteine on the dopaminergic neurons of the brain. The intraperitoneal injections of two doses of homocysteine significantly increased homocysteine levels in the striatal regions of mouse brains by 21.5 and 39.2%, while reducing dopamine turnover rates in the striatal regions by decreasing (DOPAC+HVA)/DA, 23.7 and 51.6%, respectively. Accordingly, homocysteine decreased locomotor activities significantly by decreasing movement time by 29 and 38%, total distance by 32 and 42%, and numbers of movement by 28 and 41%, respectively. Moreover, homocysteine decreased tyrosine hydroxylase immunoreactivity in substantia nigra of mouse brain. The data obtained indicate that the potential of homocysteine to be toxic to the dopaminergic system. Consequently, long-term levodopa therapy for PD may accelerate the progression of PD, at least in part by elevated homocysteine.
已知帕金森病（PD）患者长期使用左旋多巴治疗会使其血浆中的同型半胱氨酸水平升高。本研究旨在检测同型半胱氨酸水平升高对多巴胺能系统可能产生的神经毒性作用。将同型半胱氨酸经脑室内注射到雄性Sprague-Dawley大鼠体内，或经腹腔注射到C57BL/6小鼠体内。在注射同型半胱氨酸后，检测其运动活性、多巴胺（DA）及其代谢产物3,4-二羟基苯乙酸（DOPAC）和高香草酸（HVA）的水平，以及多巴胺能神经元的免疫组化情况。所得结果表明，向大鼠脑内注射同型半胱氨酸（1或2微摩尔，脑室内注射）5天，可显著降低大鼠纹状体区域的运动活性、多巴胺及其代谢产物DOPAC和HVA。向小鼠腹腔内注射两种不同剂量的同型半胱氨酸（50和100毫克/100克，每日腹腔注射），持续36天，以评估同型半胱氨酸全身治疗对脑内多巴胺能神经元的影响。腹腔注射这两种剂量的同型半胱氨酸可使小鼠脑纹状体区域的同型半胱氨酸水平分别显著升高21.5%和39.2%，同时通过降低（DOPAC+HVA）/DA分别使纹状体区域的多巴胺周转率降低23.7%和51.6%。相应地，同型半胱氨酸分别使运动时间减少29%和38%、总距离减少32%和42%、运动次数减少28%和41%，从而显著降低运动活性。此外，同型半胱氨酸还降低了小鼠脑黑质中酪氨酸羟化酶的免疫反应性。所得数据表明同型半胱氨酸对多巴胺能系统具有潜在毒性。因此，PD患者长期使用左旋多巴治疗可能会加速PD的进展，至少部分原因是同型半胱氨酸水平升高。
