Fonck C, Baudry M
Neuroscience Program, HNB124, USC, Los Angeles, CA 90089-2520, USA.
Brain Res. 2001 Jun 29;905(1-2):199-206. doi: 10.1016/s0006-8993(01)02551-3.
MPTP is a toxin presumed to damage dopamine-secreting neurons by an oxygen free radical-mediated mechanism. Two steps in MPTP metabolism are the primary candidates for oxygen free radical generation: (a) MPTP oxidation to MPP(+) by a monoamine oxidase and (b) NADH dehydrogenase inhibition by MPP(+). In order to test the idea that MPTP toxicity is mediated by oxygen free radicals, we assessed lipid peroxidation and the effects of antioxidants in dopaminergic PC12 cells treated with MPTP or MPP(+). For comparison purposes, we also examined the effects of the pro-oxidant tert-butyl-hydroperoxide (TBHP) and of the dopaminergic toxin 6-hydroxydopamine (6-OHDA) in PC12 cells. MPTP and MPP(+), unlike TBHP, failed to induce lipid peroxidation in PC12 cells after a 4-h exposure. All toxins tested (MPTP, MPP(+), TBHP and 6-OHDA) caused a dose-dependent decrease in [(3)H]dopamine ((3)H-DA) uptake in PC12 cultures. The hydroperoxide scavengers glutathione and N-acetyl-cysteine and the superoxide and peroxide scavenger EUK-134 protected PC12 cells from TBHP- and 6-OHDA-induced decrease in (3)H-DA uptake. However, no protection by these antioxidants at various concentrations and time regimens was observed against MPTP- or MPP(+)-induced decreases in (3)H-DA uptake in PC12 cells. In addition, incubation of PC12 cells with the energy-rich substrate, NADH, attenuated MPP(+)-induced decrease in (3)H-DA uptake. These results suggest that MPTP-induced toxicity in dopaminergic PC12 cell cultures, does not involve oxygen free radical production, but rather may be caused by impairment in energy metabolism.
MPTP是一种毒素，推测其通过氧自由基介导的机制损害分泌多巴胺的神经元。MPTP代谢的两个步骤是氧自由基产生的主要候选步骤：(a) 单胺氧化酶将MPTP氧化为MPP(+)，以及(b) MPP(+)抑制NADH脱氢酶。为了检验MPTP毒性由氧自由基介导这一观点，我们评估了经MPTP或MPP(+)处理的多巴胺能PC12细胞中的脂质过氧化作用以及抗氧化剂的影响。为作比较，我们还研究了促氧化剂叔丁基过氧化氢(TBHP)和多巴胺能毒素6-羟基多巴胺(6-OHDA)对PC12细胞的影响。与TBHP不同，MPTP和MPP(+)在4小时暴露后未能在PC12细胞中诱导脂质过氧化。所有测试的毒素(MPTP、MPP(+)、TBHP和6-OHDA)均导致PC12培养物中[(3)H]多巴胺((3)H-DA)摄取呈剂量依赖性下降。过氧化氢清除剂谷胱甘肽和N-乙酰半胱氨酸以及超氧化物和过氧化物清除剂EUK-134保护PC12细胞免受TBHP和6-OHDA诱导的(3)H-DA摄取下降。然而，在不同浓度和时间方案下，未观察到这些抗氧化剂对MPTP或MPP(+)诱导的PC12细胞中(3)H-DA摄取下降有保护作用。此外，用富含能量的底物NADH孵育PC12细胞可减弱MPP(+)诱导的(3)H-DA摄取下降。这些结果表明，MPTP在多巴胺能PC12细胞培养物中诱导的毒性不涉及氧自由基的产生，而可能是由能量代谢受损引起的。
