Lau Yuen-Sum, Novikova Lesya, Roels Christina
Division of Pharmacology, University of Missouri-Kansas City School of Pharmacy, 2411 Holmes Street, Kansas City, MO 64108, USA.
Neurosci Res. 2005 Aug;52(4):371-8. doi: 10.1016/j.neures.2005.04.010.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) is currently a leading neurotoxic agent used for producing Parkinsonism in laboratory animals. The MPTP neurotoxicity in humans is irreversible and the consequential clinical and neurochemical features closely resemble those of the idiopathic Parkinson's disease. Therefore, handling of MPTP in laboratory may pose neurotoxic risk among researchers and animal caretakers. While it is well recognized that systemic administration of MPTP will cause Parkinsonian-like symptoms in humans and animals, it is not known whether similar neurological toxicity is transmittable and would develop in normal subjects housed closely with the MPTP-treated animals. In the present study, we treated mice daily with MPTP hydrochloride (30mg/kg, s.c.) for 5 consecutive days. In the same cage, a non-treated mouse (cagemate) was kept allowing for close physical interaction, free contact with the excreta, and sharing of food and water. Seventy-two hours after the treatment, the MPTP-treated mice and MPTP-exposed cagemates were analyzed for dopaminergic neurotoxicity comparing with the MPTP non-exposed control animals. We detected a significant number of TUNEL-positive cells, loss of tyrosine hydroxylase immunoreactivity in the substantia nigra, and depletion of dopamine in the striatum of MPTP-treated mice. However, these neurotoxic indices were not detected in the MPTP-exposed cagemates or MPTP non-exposed controls. Following each MPTP injection, approximately 42% of the chemical was excreted within 3h through the urine largely in the form of MPTP N-oxide, which is not expected to cross the blood-brain barrier and to cause dopaminergic toxicity in the brain when administered peripherally. These observations suggest that MPTP injections in mice do not transmit and cause Parkinsonian-like dopaminergic neurotoxicity in the neighboring normal cagemates through direct physical contact and exposure from the contaminated cage, food, water, and excreta.
1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP）是目前用于在实验动物中诱发帕金森症的主要神经毒性剂。MPTP对人类的神经毒性是不可逆的，其相应的临床和神经化学特征与特发性帕金森病极为相似。因此，在实验室中处理MPTP可能会给研究人员和动物饲养员带来神经毒性风险。虽然人们普遍认识到全身给予MPTP会在人类和动物中引起帕金森样症状，但尚不清楚类似的神经毒性是否具有传染性，以及与经MPTP处理的动物密切饲养的正常个体是否会出现这种毒性。在本研究中，我们连续5天每天给小鼠皮下注射盐酸MPTP（30mg/kg）。在同一个笼子里，饲养一只未接受处理的小鼠（同笼小鼠），使其与处理过的小鼠有密切的身体接触，自由接触排泄物，并共享食物和水。处理72小时后，对经MPTP处理的小鼠和接触过MPTP的同笼小鼠进行多巴胺能神经毒性分析，并与未接触MPTP的对照动物进行比较。我们在经MPTP处理的小鼠中检测到大量TUNEL阳性细胞、黑质中酪氨酸羟化酶免疫反应性丧失以及纹状体中多巴胺耗竭。然而，在接触过MPTP的同笼小鼠或未接触MPTP的对照小鼠中未检测到这些神经毒性指标。每次注射MPTP后，约42%的化学物质在3小时内通过尿液排出，主要以MPTP N-氧化物的形式存在，外周给药时预计该物质不会穿过血脑屏障并在脑中引起多巴胺能毒性。这些观察结果表明，给小鼠注射MPTP不会通过直接身体接触以及来自受污染的笼子、食物、水和排泄物的暴露，在相邻的正常同笼小鼠中传播并引起帕金森样多巴胺能神经毒性。
