Thiruchelvam Mona, McCormack Alison, Richfield Eric K, Baggs Raymond B, Tank A William, Di Monte Donato A, Cory-Slechta Deborah A
Department of Environmental Medicine, University of Rochester School of Medicine and Dentistry, Rochester, NY 14642, USA.
Eur J Neurosci. 2003 Aug;18(3):589-600. doi: 10.1046/j.1460-9568.2003.02781.x.
While advancing age is the only unequivocally accepted risk factor for idiopathic Parkinson's disease, it has been postulated that exposure to environmental neurotoxicants combined with ageing could increase the risk for developing Parkinson's disease. The current study tested this hypothesis by exposing C57BL/6 mice that were 6 weeks, 5 months or 18 months old to the herbicide paraquat, the fungicide maneb or paraquat + maneb, a combination that produces a Parkinson's disease phenotype in young adult mice. Paraquat + maneb-induced reductions in locomotor activity and motor coordination were age dependent, with 18-month-old mice most affected and exhibiting failure to recover 24 h post-treatment. Three months post-treatment, reductions in locomotor activity and deficits in motor coordination were sustained in 5-month-old and further reduced in 18-month-old paraquat + maneb groups. Progressive reductions in dopamine metabolites and dopamine turnover were greatest in 18-month-old paraquat + maneb and paraquat groups 3 months post-treatment. Increased tyrosine hydroxylase enzyme activity compensated for striatal tyrosine hydroxylase protein and/or dopamine loss following treatment in 6-week-old and 5-month-old, but not 18-month-old paraquat and paraquat + maneb mice. Numbers of nigrostriatal dopaminergic neurons were reduced in all age groups following paraquat alone and paraquat + maneb exposure, but these losses, along with decreases in striatal tyrosine hydroxylase protein levels, were progressive in 18-month-old paraquat and paraquat + maneb groups between 2 weeks and 3 months post-exposure. Collectively, these data demonstrate enhanced sensitivity of the ageing nigrostriatal dopamine pathway to these pesticides, particularly paraquat + maneb, resulting in irreversible and progressive neurotoxicity.
虽然高龄是特发性帕金森病唯一明确公认的风险因素，但据推测，接触环境神经毒物并伴随衰老可能会增加患帕金森病的风险。本研究通过将6周龄、5月龄或18月龄的C57BL/6小鼠暴露于除草剂百草枯、杀菌剂代森锰或百草枯+代森锰（一种能在年轻成年小鼠中产生帕金森病表型的组合）来验证这一假设。百草枯+代森锰诱导的运动活性和运动协调性降低具有年龄依赖性，18月龄小鼠受影响最大，在治疗后24小时未能恢复。治疗后三个月，5月龄小鼠的运动活性降低和运动协调性缺陷持续存在，而18月龄百草枯+代森锰组进一步降低。治疗后三个月，多巴胺代谢产物和多巴胺周转率的逐渐降低在18月龄百草枯+代森锰组和百草枯组中最为明显。酪氨酸羟化酶活性增加补偿了6周龄和5月龄，但不是18月龄百草枯和百草枯+代森锰小鼠治疗后纹状体酪氨酸羟化酶蛋白和/或多巴胺的损失。单独使用百草枯和百草枯+代森锰暴露后，所有年龄组的黑质纹状体多巴胺能神经元数量均减少，但这些损失以及纹状体酪氨酸羟化酶蛋白水平的降低在暴露后2周和3个月之间在18月龄百草枯和百草枯+代森锰组中呈进行性变化。总体而言，这些数据表明衰老的黑质纹状体多巴胺通路对这些农药，特别是百草枯+代森锰的敏感性增强，导致不可逆的进行性神经毒性。
