莫达非尼对1-甲基-4苯基-1,2,3,6-四氢吡啶所致的帕金森病的神经保护作用

目的　观察莫达非尼对 1 甲基 4苯基 1,2 ,3,6 四氢吡啶 (MPTP)诱导的帕金森病 (PD)模型的神经保护作用。方法给C5 7BL 6小鼠腹腔注射MPTP4d制备PD模型 ,与MPTP同时给予莫达非尼 (ip ,5 0or10 0mg·kg- 1 ·d- 1 ) 4天后 ,再连续给莫达非尼 10天。观测莫达非尼对小鼠的自发活动 ,震颤潜伏期、维持期和震颤评分及爬杆时间的影响 ,及对纹状体和黑质的酪氨酸羟化酶 (TH)阳性细胞和尼氏体的影响。测定纹状体中多巴胺 (DA) ,去甲肾上腺素 (NA)和 5 羟色胺 ( 5 HT)含量。结果　莫达非尼 ( 5 0和 10 0mg·kg- 1 )呈剂量依赖性显著减少了自发活动、震颤和爬杆的行为缺陷 (P <0 .0 5和P <0 .0 1,n =10 ) ,阻止了MPTP造成的TH和尼氏体数量的减少 (P <0 .0 5 ,n =10 ) ,及纹状体中DA ,NA和 5 HT含量的降低 (P <0 .0 5 ,n =10 )。结论在MPTP诱导的PD小鼠模型中 ,莫达非尼可改善MPTP引起的帕金森病行为缺陷 ,且对单胺能神经细胞的损伤有保护作用。     

黄芪甲苷对帕金森病体外、体内模型的神经保护作用研究

目的:研究黄芪甲苷对帕金森病(PD)体外、体内模型的神经保护作用。方法:MPP+诱导PC12细胞损伤复制体外PD模型,1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)复制PD小鼠模型。采用MTT法测定黄芪甲苷对MPP+诱导的PC12细胞的存活率及培养液中乳酸脱氢酶(LDH)和丙二醛(MDA)的影响,以及对模型小鼠自发活动及纹状体多巴胺(DA)及其高香草酸(HVA)含量的影响。结果:25、50、100μmol·L-1黄芪甲苷可呈浓度依赖性抑制MPP+诱导的PC12细胞存活率降低,并显著降低培养上清液中LDH和MDA的含量;10、20、40mg·kg-1黄芪甲苷可显著增加模型小鼠自发活动计数值,并显著降低纹状体DA及HVA的含量。结论:黄芪甲苷对PD体外、体内模型均有显著的神经保护作用。     

人参皂苷Rg1对小鼠1—甲基—4—苯基—1，2，3，6—四氢吡啶诱导的黑质神经元凋亡的保护作用

目的:探讨人参皂苷Rg1对抗1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的C57BL小鼠黑质神经元凋亡的可能机制.方法:MPTP(30 mg·kg~(-1)·d~(-1)×5 d)腹腔注射制备C57BL小鼠帕金森病模型,同时预防组分别以不同剂量人参皂苷Rg1(2.5、5.0、10.0 mg·kg~(-1)·d~(-1)×8 d)于MPTP注射前预先腹腔注射小鼠.用Nissl染色和TH组化染色观察黑质损害情况,TUNEL染色检测细胞凋亡,同时运用免疫组织化学方法检测caspase-3的活性片段以及Bcl-2、Bcl-xl、Bax、iNOS和 nNOS的表达情况.结果:人参皂苷Rg1(5.0和10.0 mg/kg)预处理能使黑质致密带Nissl阳性神经元和TH阳性神经元的脱失减少,同时降低了TUNEL阳性率,并伴有Bcl-2和Bcl-xl表达增加,Bax和iNOS表达减少以及抑制caspase-3的激活.结论:人参皂苷Rg1预处理对MPTP诱导的小鼠黑质神经元凋亡有明显的保护作用,其作用可能是通过降低iNOS和Bax蛋白表达,增加Bcl-2和Bcl-xl蛋白表达以及抑制caspase-3的激活来实现的.     

瓜子金皂苷己对MPP~+诱导PC12细胞凋亡的保护作用

目的观察瓜子金皂苷己(polygalasaponin F,PS-F)对1-甲基-4-苯基-吡啶离子(1-methyl-4-phenylpyridinium,MPP+)诱导的PC12细胞损伤的影响,并且探讨其作用机制。方法 MTT法检测细胞存活率,Annexin V/PI染色流式细胞术检测PC12细胞凋亡,JC-1染色倒置显微镜检测细胞线粒体膜电位(mitochondrial membrane potential,MMP),Western blot检测Caspase-3蛋白的水平。结果 500μmol.L-1MPP+作用PC12细胞48 h,能明显抑制细胞生长(P<0.01),诱导细胞发生凋亡,同时降低MMP,增加活性Caspase-3的蛋白水平。同时给予不同浓度PS-F处理,PC12细胞存活率增加(P<0.01);凋亡细胞量减少;MMP增高;活性Caspase-3蛋白水平降低(P<0.01)。结论 PS-F能抑制MPP+诱导的PC12细胞的凋亡,其作用机制可能与维持线粒体正常膜电位,稳定线粒体功能,降低活性Caspase-3蛋白水平有关。     

人参皂苷Rg1抗黑质神经元凋亡的可能机制

目的研究人参皂苷Rg1抗1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)诱导的小鼠黑质神经元凋亡的作用及其机制。方法MPTP制备的帕金森病(Parkinson′s disease,PD)小鼠模型,经人参皂苷Rg1预处理后,用尼氏(Nissl)染色和TH组化染色观察黑质神经元的损害情况,借助TUNEL染色了解黑质神经元的凋亡情况,并用免疫组织化学方法检测黑质神经元caspase-3的活化以及iNOS和nNOS的表达情况。结果人参皂苷Rg1预处理能减少PD鼠模型黑质致密带Nissl阳性神经元和TH阳性神经元的脱失现象,降低黑质神经元TUNEL染色的阳性率。结论人参皂苷Rg1预处理对MPTP诱导的小鼠黑质神经元凋亡有明显的保护作用。     

侧脑室注射DJ-1蛋白对MPTP致帕金森病小鼠的神经保护作用

目的:观察DJ-1蛋白对1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahy-dropyridine,MPTP)致帕金森病(Parkinson’s disease,PD)小鼠是否具有神经保护作用。方法:分别采用SDS-PAGE和生物质谱仪对DJ-1蛋白的纯度和活性位点进行检测。然后将DJ-1蛋白注射进入小鼠侧脑室内,24 h后小鼠腹腔注射MPTP造模,通过滚筒实验、自主活动实验和竖直网格实验观察行为学变化,使用HPLC-ECD对纹状体内神经递质含量进行测定,通过酪氨酸羟化酶(tyroxine hydroxylase,TH)免疫组化染色观察SN区域多巴胺能神经元的存活状态。结果:SDS-PAGE和质谱实验表明DJ-1蛋白纯度较高,且活性位点未产生氧化;将DJ-1蛋白注射进入PD小鼠侧脑室后,小鼠行为学明显改善,纹状体内神经递质含量降低有所恢复,黑质区域多巴胺能神经元细胞死亡显著减少。结论:侧脑室注射DJ-1蛋白能够显著改善MPTP致的小鼠帕金森病症状,具有一定的神经保护作用。     

MPTP诱导小鼠肝脏帕金森病样病理变化研究

目的 研究1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)诱导的帕金森病(Parkinson's disease,PD)小鼠模型中肝脏生理功能变化和病理改变.方法 将雄性C57BL/6小鼠随机分为空白对照组和模型组,皮下注...     

基于PKA信号通路探讨胆南星对MPTP诱导帕金森病模型小鼠的保护作用

目的 探讨胆南星对帕金森病（PD）模型小鼠的改善作用及可能机制。方法 将60只雄性C57BL/6J小鼠随机分为正常组、模型组、胆南星低剂量组[0.39 g/（kg·d）]、胆南星高剂量组[1.56 g/（kg·d）]和阳性对照药左旋多巴片组[80 mg/（kg·d）]，每组12只。除正常组小鼠注射等体积生理盐水外，其余各组连续5 d腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶[MPTP,35 mg/（kg·d）]建立亚急性PD模型；造模完成后连续给药治疗7 d，于造模前1 d、造模第5天和末次给药后进行爬杆实验和线悬挂测试。采用免疫荧光法检测小鼠脑黑质中酪氨酸羟化酶（TH）阳性神经元数量；采用酶联免疫吸附法检测小鼠血清中白细胞介素1β(IL-1β)和肿瘤坏死因子α(TNF-α)水平以及脑黑质中IL-1β、TNF-α、环氧合酶2(COX-2)和诱导型一氧化氮合酶（iNOS）水平；采用Western blot法检测小鼠脑黑质中cAMP依赖的蛋白激酶催化亚单位α(PKA C-α)、谷胱甘肽过氧化物酶4(GPX4)以及铁蛋白重链多肽1(FTH1)蛋白的表达。结果 末次给药后，与正常组比...     

MPTP诱导野生型和A53T转基因型小鼠帕金森病模型纹状体中神经递质变化

目的 探究帕金森病(Parkinson's disease,PD)小鼠模型纹状体中多巴胺等神经递质的变化.方法 通过腹腔注射丙磺舒(probenecid)、皮下注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)制备PD野...     

1-甲基-4-苯基吡啶离子诱导大鼠肾上腺嗜铬细胞瘤PC12细胞发生铁死亡的实验观察

目的 进行1-甲基-4-苯基吡啶离子(1-methyl-4-phenyl pyridine,MPP+)诱导大鼠肾上腺嗜铬细胞瘤PC12细胞铁死亡(Ferroptosis)的研究.方法 采用噻唑蓝法(MTT)检测细胞存活率和筛选铁死亡抑制剂(Ferrostatin-1)的最佳作用浓度;倒置显微镜观察Ferrostatin-1对PC12细胞的保护作用;MDC染色检测细胞自噬;ELISA法检测caspase-3的酶活性;流式细胞术检测活性氧ROS.结果 1 mmol·L-1 MPP+对PC12细胞有明显抑制作用;5 μmol·L-1 Ferrostatin-1能够明显提高PC12细胞的存活率;倒置显微镜观察结果表明Ferrostatin-1预保护后,PC12细胞损伤明显减少;MDC染色检测细胞自噬和ELISA法检测caspase-3的酶活性结果显示Ferrostatin-1对MPP+诱导的PC12细胞自噬和凋亡的保护作用不明显;ROS活性氧检测结果显示ROS在胞内增加,可能发生氧化应激,加Ferrostatin-1后ROS荧光强度减弱.结论 Ferroptosis能够显著抑制MPP+诱导的PC12细胞损伤,且Ferrostatin-1对细胞的自噬和凋亡作用不明显,推测出MPP+诱导PC12细胞的损伤可能有Ferroptosis的存在.     

Acute electrophysiological and neurochemical effects of administration of MPTP in mice

The changes occurring during the first few hours after subcutaneous administration of the catecholaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were investigated. Injections of MPTP (30-60 mg/kg s.c.) reduced the impulse rate by 12-45% in all dopaminergic neurones tested in the pars compacta of the substantia nigra. Depressions were maximal at 11 min and remained present for more than 2 hr after injection. This effect was completely abolished by prior administration of the catecholamine uptake inhibitor, nomifensine (13-69 mg/kg s.c.), which prevents the toxic metabolite of MPTP 1-methyl-4-phenylpyridine (MPP+) from entering dopaminergic neurones. These results suggest an intraneuronal mechanism underlying the observed depressions in impulse rate. Levels of dopamine (DA) were decreased at 3 hr after administration of MPTP (50 mg/kg s.c.) by 60% and 54% in the striatum and substantia nigra, respectively. Pretreatment with nomifensine (25 mg/kg, intraperitoneally) prevented the decrease in DA only in the striatum. This suggests an acute DA-releasing effect of MPTP in the striatum, mediated by intracellular accumulation of MPP+, while not explaining the depression of activity of DA neurones occurring with a different time course.     

Neuroprotective mechanism of modafinil on Parkinson disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine

AIM: To observe the neuroprotective mechanism of modafinil on Parkinson disease (PD) models induced by 1-methyl-4-phenyl- 1, 2, 3, 6-tetrahydropyridine (MPTP). METHODS: The model of PD was induced by intraperitoneally injecting MPTP into C57BL/6J mice for 4 d. Modafinil ( ip, 50 or 100 mg.kg^-1.d^-1 ) was administered at 30min following MPTP for 4 d and for another 10 d continuously. The contents of dopamine (DA), noradrenaline(NA), 5-hydroxytryptamine (5-HT), γ-aminobutyric acid (GABA), glutamine (Glu) in the striatum, and the contents of GABA, Glu, malondialdehyde (MDA), and glutathione (GSH) in the substantia nigra (SN) of model mice were determined. RESULTS: Modafinil (50 and 100 mg/kg) prevented against the decrease of the contents of DA,5-HT, and NA in the striatum and GSH, GABA in the SN induced by MPTP, but reduced the increase of MDA in the SN and GABA in the striatum induced by MPTP. Modafinil preferentially inhibited striatal GABA release, but it did not change the increase of nigrostriatal Glu release induced by MPTP. CONCLUSION: The anti-oxidation and the modulation of nigrostriatal GABA and striatal NA and 5-HT release contributed to the neuroprotective effects of modafinil on PD induced by MPTP.     

Attenuation of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity by the novel selective dopamine D3-receptor partial agonist FAUC 329 predominantly in the nucleus accumbens of mice

We previously synthesised a novel dopamine (DA) partial agonist FAUC 329 with high affinity and selectivity for the DA D(3) receptor. This is the first in vivo study to investigate the protective effects of FAUC 329 in a MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) mouse model of Parkinson's disease. Adult male C57bl/6 mice were injected with FAUC 329 (0, 0.1, 0.5, 0.75, or 1 mg/kg) 30 min before MPTP (2 x 30 mg/kg, 4 hr apart). One week later, accumbal and striatal tissue was processed for DA and metabolite HPLC determination as well as immunohistochemical analysis of DA transporter positive neurons in the substantia nigra pars compacta and ventral tegmental area was carried out. FAUC 329 showed a significant attenuation of MPTP-induced DA reduction in the nucleus accumbens (0.5, 0.75 and 1 mg/kg) in a dose-dependent manner. FAUC 329 (0.75 mg/kg) partly protected against DA depletion in the dorsal striatum as well as protected against loss of DA transporter immunoreactivity in the substantia nigra pars compacta. The highest dose of FAUC 329 (1 mg/kg), however, showed a non-significant tendency to augment the MPTP-induced striatal DA reduction. The protective effect of FAUC 329 against MPTP-induced DA depletion was most pronounced in the nucleus accumbens and appears to be linked to the preferential abundance of D(3) receptors in this region. Targeting the mesolimbic DA system may have implications for improvement of impaired motor behaviour and particularly non-motor functions related to the nucleus accumbens.     

Cell death induced by MPTP, a substrate for monoamine oxidase B

MPTP is known to cause PD symptoms in primates and in rodents. In order to exert its neurotoxicity MPTP must be converted by monoamine oxidase B into MPP(+) which is the true toxic agent. MPP(+) is taken up by the dopaminergic neurons of the substantia nigra in which it induces cell death. The present work reviews and discusses papers in which specific methods were used to determine whether cell death induced by MPTP/MPP(+) should be considered as apoptosis or necrosis. These two cell death modes may be distinguished using morphological and biochemical criteria. The effect of MPTP/MPP(+) was studied in vitro and in vivo. The results show that no univocal answer is possible. The most widespread interpretation is that MPTP/MPP(+) causes apoptosis when its neurotoxic effect is only sligh and necrosis when it is stronger. Similar considerations may be made also concerning the type of cell death occurring in the dopaminergic neurons in the substantia nigra of PD patients.     

Astaxanthin protects against MPTP/MPP+-induced mitochondrial dysfunction and ROS production in vivo and in vitro

Astaxanthin (AST) is a powerful antioxidant that occurs naturally in a wide variety of living organisms. We have investigated the role of AST in preventing 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced apoptosis of the substantia nigra (SN) neurons in the mouse model of Parkinson’s disease (PD) and 1-methyl-4-phenylpyridinium (MPP+)-induced cytotoxicity of SH-SY5Y human neuroblastoma cells. In in vitro study, AST inhibits MPP+-induced production of intracellular reactive oxygen species (ROS) and cytotoxicity in SH-SY5Y human neuroblastoma cells. Preincubation of AST (50 μM) significantly attenuates MPP+-induced oxidative damage. Furthermore, AST is able to enhance the expression of Bcl-2 protein but reduce the expression of α-synuclein and Bax, and suppress the cleavage of caspase-3. Our results suggest that the protective effects of AST on MPP+-induced apoptosis may be due to its anti-oxidative properties and anti-apoptotic activity via induction of expression of superoxide dismutase (SOD) and catalase and regulating the expression of Bcl-2 and Bax. Pretreatment with AST (30 mg/kg) markedly increases tyrosine hydroxylase (TH)-positive neurons and decreases the argyrophilic neurons compared with the MPTP model group. In summary, AST shows protection from MPP+/MPTP-induced apoptosis in the SH-SY5Y cells and PD model mouse SN neurons, and this effect may be attributable to upregulation of the expression of Bcl-2 protein, downregulation of the expression of Bax and α-synuclein, and inhibition of the activation of caspase-3. These data indicate that AST may provide a valuable therapeutic strategy for the treatment of progressive neurodegenerative disease such as Parkinson’s disease.     

白藜芦醇对慢性帕金森病6-OHDA模型大鼠iNOS mRNA及HO-1 mRNA表达的影响

目的观察白藜芦醇能否通过抑制诱导型一氧化氮合成酶(iNOS)mRNA及血红素加氧酶-1(HO-1)mRNA的表达对慢性帕金森病(PD)6-羟基多巴胺(6-OHDA)模型大鼠产生保护效应。方法经筛选无旋转行为的SD大鼠60只,随机选20只分为假手术组及正常给药组(白藜芦醇20 mg.kg-1.d-1);应用6-OHDA纹状体内注射制作PD模型大鼠40只,随机分为模型组和白藜芦醇10、20和40 mg.kg-1.d-1组,每日灌胃给药1次,连续10 wk。电镜下观察黑质神经元超微结构的改变,real-time PCR法检测大鼠黑质部iNOS mRNA及HO-1 mRNA的表达。结果电镜结果显示白藜芦醇治疗组能改善6-OHDA导致的大鼠黑质多巴胺能神经元超微结构的损伤。与模型组比较,白藜芦醇治疗组iNOS mRNA、HO-1 mRNA的表达均明显降低(P<0.01)。结论白藜芦醇对慢性帕金森病6-OHDA模型大鼠具有保护作用,其机制与抑制iNOS mRNA和HO-1 mRNA的表达有关。     

Asiaticoside: attenuation of neurotoxicity induced by MPTP in a rat model of Parkinsonism via maintaining redox balance and up-regulating the ratio of Bcl-2/Bax

In this study, we investigated the neuroprotective effects of asiaticoside, a triterpenoid saponin isolated from the Chinese medicinal herb Centella asiatica, in the rats model of Parkinsonism induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Rats were first injected with MPTP. One day after surgery, asiaticoside was administered and the behavioral tests were assessed. On 14th day, the rats were sacrificed, substantia nigra (SN) and striatum were dissected, and then dopamine (DA) and its metabolites in striatum and malonyldialdehyde (MDA) contents, reduced glutathione (GSH) level and gene expression level in SN were estimated. Treatment with asiaticoside was found to protect dopaminergic neuron by antagonizing MPTP induced neurotoxicity and to improve locomotor dysfunction. Asiaticoside significantly attenuated the MPTP-induced reduction of dopamine in the striatum. The content of MDA was significantly decreased while the GSH level was significantly increased in asiaticoside-treated groups. In addition, asiaticoside increased the Bcl-2/Bax ratio. These results indicated that asiaticoside was effective in reversing MPTP induced Parkinsonism via its neuroprotective effects including antioxidant activity, maintaining the metabolic balance of DA, and increasing ratio of Bcl-2/Bax.     

Long non‐coding RNA NEAT1 mediates the toxic of Parkinson's disease induced by MPTP/MPP+ via regulation of gene expression

Parkinson's disease (PD) is a result of the loss of dopaminergic neurons in the substantia nigra and is expected to increase the economic burden on patients’ families and societies. NEAT1, a long non‐coding RNA, is known as a cancer‐related gene, however, the role of it in PD remains unclear. The aims of this study are to detect the NEAT1‐mediated effects in PD and explore the mechanism of NEAT1 in PD. One group (n = 6) of C57BL/6 model mice were intraperitoneal injected with 1‐Methyl‐4‐phenyl‐2, 3, 6‐tetrahydropyridine (MPTP), while another group (n = 6) was treated with saline and served as control. Human neuroblastoma cell line SH‐SY5Y was pretreated with 1‐Methyl‐4‐phenylpyridinium (MPP+). Cell viability and apoptosis, as well as gene expression with different treatments were examined. Up‐regulated NEAT1 was found in MPTP‐induced PD mice. Moreover, the NEAT1 expression was positively correlated with the concentration of MPP+. In SH‐SY5Y cells stimulated by MPP+, NEAT1 knockdown dramatically promoted cell viability and suppressed cell apoptosis. Additionally, down‐regulation of NEAT1 also decreased the ratio of Bax/Bcl‐2, the activity of caspase‐3, as well as the expression of α‐synuclein. Moreover, α‐synuclein overexpression could significantly reverse the increase in cell viability and the decrease in cell apoptosis induced by NEAT1 knockdown. The results suggested that the knockdown of NEAT1 will have a protective effect on MPTP‐induced PD mice. The mechanism may be related to the dysregulation of α‐synuclein.     

Protective role of group-II metabotropic glutamate receptors against nigro-striatal degeneration induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine in mice

To examine how mGlu2/3 metabotropic glutamate receptors affect nigro-striatal degeneration, we used the agonist, LY379268, and the antagonist, LY341495, in mice challenged with the nigro-striatal toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In control mice, high doses of MPTP (20 mg/kg, i.p., injected four times with 2 h of interval) induced a nearly total degeneration of the nigro-striatal pathway, as shown by measurements of striatal dopamine (DA) levels and by immunohistochemical analysis of tyrosine hydroxylase, high affinity dopamine transporter, and glial fibrillary acidic protein in the corpus striatum and substantia nigra. Lower cumulative doses of MPTP (30 mg/kg, i.p., injected only once) produced a partial lesion of the nigro-striatal pathway (about 50% reduction of striatal DA content). Systemic injection of LY379268 (1 mg/kg, i.p., 30 min prior to each injection of MPTP) partially reduced the extent of nigro-striatal degeneration induced by high doses of MPTP. Similar results were obtained by continuously delivering LY379268 (1 mg/kg/d for 7 d) by means of a subcutaneous osmotic minipump. The protective effect of LY379268 was antagonized by LY341495 (also delivered by the osmotic minipump). In mice challenged with the lower cumulative dose of MPTP, injection of LY379268 did not produce a significant neuroprotective effect. In contrast, the lesion was amplified by the antagonist, LY341495. Neither LY379268 nor LY341495 influenced the central bioavailability and the local half-life of MPTP, as shown by measurements of the toxin and its active metabolite, MPP(+), in the striatum. We conclude that mGlu2/3 receptors play a protective role against MPTP toxicity, and that the efficacy of the agonist, LY379268, critically depends on the extent of the nigro-striatal lesion.     

The PPARgamma agonist pioglitazone is effective in the MPTP mouse model of Parkinson's disease through inhibition of monoamine oxidase B

BACKGROUND AND PURPOSE: The peroxisome proliferator-activated receptor-gamma (PPARgamma) agonist pioglitazone has previously been shown to attenuate dopaminergic cell loss in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of Parkinson's disease, an effect attributed to its anti-inflammatory properties. In the present investigation, we provide evidence that pioglitazone is effective in the MPTP mouse model, not via an anti-inflammatory action, but through inhibition of MAO-B, the enzyme required to biotransform MPTP to its active neurotoxic metabolite 1-methyl-4-phenylpyridinium (MPP+). EXPERIMENTAL APPROACH: Mice were treated with pioglitazone (20 mg kg(-1) b.i.d. (twice a day), p.o., for 7 days), prior and post or post-MPTP (30 mg kg(-1) s.c.) treatment. Mice were then assessed for motor impairments on a beam-walking apparatus and for reductions in TH immunoreactivity in the substantia nigra and depletions in striatal dopamine. The effects of pioglitazone on striatal MPP+ levels and MAO-B activity were also assessed. KEY RESULTS: Mice treated with MPTP showed deficits in motor performance, marked depletions in striatal dopamine levels and a concomitant reduction in TH immunoreactivity in the substantia nigra. Pretreatment with pioglitazone completely prevented these effects of MPTP. However, pretreatment with pioglitazone also significantly inhibited the MPTP-induced production of striatal MPP+ and the activity of MAO-B in the striatum. CONCLUSIONS AND IMPLICATIONS: The neuroprotection observed with pioglitazone pretreatment in the MPTP mouse model was due to the blockade of the conversion of MPTP to its active toxic metabolite MPP+, via inhibition of MAO-B.