低分子肝素对MPTP帕金森小鼠的治疗作用及可能机制

目的：研究1．甲基4-苯基-1,2,3,6-四氢吡啶（1-methy-4-phenyl-1,2,3,6-tetrahy-dropyridine,MPTP）帕金森病（PD）模型中小胶质细胞的激活情况,探讨低分子肝素对MPTP导致的小胶质细胞活化的抑制作用。方法：C57BL随机分成正常对照组、MPTP组、低分子肝素＋MPTP组。MPTP组腹腔注射MPTP（30mg／kgx7d）同时腹部皮下注射生理盐水,低分子肝素＋MPTP组在注射MPTP同时腹部皮下注射低分子肝素（1501U／kg·12hx7d）。各组于末次给药后予行为学测试,7d后免疫组化检测酪氨酸羟化酶（TyrosineHydroxylase,TH）阳性细胞。镀银染色观察小胶质细胞激活情况。结果：MPTP组较低分子肝素＋MPTP组爬竿时间明显延长,并出现更多非随意动作。低分子肝素＋MPTP组黑质部位TH阳性细胞数量高于MPTP组。MPTP组活化的小胶质细胞数量高于低分子肝素＋MPTP组。结论：低分子肝素通过抑制小胶质细胞的激活减少MPTP帕金森小鼠多巴胺能神经元的损伤,提示低分子肝素可能有延缓PD进程的作用。     

MPTP诱导小鼠黑质区铁摄取和DMT1表达增加

铁在帕金森病(Parkinson‘s disease,PD)的发病机制中起着非常关键的作用,为了探讨PD中铁升高的机制,本实验观察了1-甲基4-苯基—1,2,3,6-四氢吡啶(MPTP)处理小鼠黑质(substantia nigra,SN)内铁摄取及新的铁转运蛋白二价金属离子转运蛋白1(DMT1)的表达变化。结果表明：(1)MPTP处理组小鼠SN内铁染色增高,注射MPTP7d组明显高于3d组。(2)MPTP处理组小鼠,酪氨酸羟化酶(TH)免疫阳性细胞数目显著减少。(3)MPTP处理组小鼠,“-IRE”型DMT1表达在各组中均增加,而“ IRE”型DMT1仅在MPTP处理后7d才出现变化。上述结果提示,这种新发现的哺乳动物跨膜铁转运蛋白表达增加可能是引起MPTP处理小鼠SN中铁升高的关键因素,铁的升高进一步导致DA神经元的死亡。     

环加氧酶-2对帕金森病小鼠黑质多巴胺能神经元的影响

目的和方法 :选用C5 7BL种系环加氧酶 2 (cyclooxygenase 2 ,COX 2 )缺陷小鼠 ,腹腔注射 1 甲基 4 苯基 1,2 ,3,6 四氢吡啶 (MPTP)制备帕金森病小鼠模型 ,用免疫组织化学方法观察COX 2对帕金森病小鼠黑质多巴胺能神经元的影响。结果 :行为学及免疫组织化学观察显示 ,野生型帕金森病小鼠的死亡率明显高于COX 2缺陷杂合子帕金森病小鼠 (P <0 .0 1) ,野生型帕金森病小鼠黑质致密部酪氨酸羟化酶 (tyrosinehydroxylase,TH)免疫反应阳性神经元数目较杂合子帕金森病小鼠明显减少 (P <0 .0 1)。结论 :COX 2可能与帕金森病时黑质多巴胺能神经元的损伤有关     

脂多糖联合MPTP诱导的小鼠慢性帕金森病模型的评价

目的建立脂多糖(lipopolysaccharide,LPS)联合1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)诱导的慢性小鼠帕金森病模型,探讨其行为学和黒质多巴胺能神经元细胞的变化情况。方法将20只C57BL/6小鼠随机分为模型组和对照组,模型组每日腹腔注射LPS(0.25 mg/kg)一次,连续3 d,最后一次注射LPS 4 h后,每日腹腔注射MPTP(25 mg/kg)一次,连续2 d,对照组腹腔注射相同量的生理盐水。8周后用步态分析和转棒实验评价小鼠的行为学能力,免疫组化法观察黑质酪氨酸羟化酶(TH)阳性细胞变化情况。结果模型组小鼠行为学变化较对照组差异有显著性(P0.05),模型组小鼠中脑黒质区显示出严重的神经元细胞损伤。结论 LPS联合MPTP腹腔注射可成功诱导出慢性小鼠帕金森病模型,提示该模型可用于帕金森病的发病机制及药物治疗效果等相关研究。     

帕金森病小鼠模型行为学检测方法的比较研究

目的比较目前常用的5种帕金森病(PD)小鼠模型行为学检测方法在PD研究中的作用。方法用MPTP建立C57BL小鼠PD模型,通过行为学检测(自主活动计数、滚轴实验、游泳实验、爬杆实验、悬挂实验)、免疫组织化学和荧光分光光度法,对比5种行为学检测方法的平均数与变异系数,观察MPTP对PD小鼠模型的行为学、黑质多巴胺(DA)神经元和纹状体酪氨酸羟化酶免疫反应阳性(TH-ir)神经纤维以及纹状体DA水平的影响。结果给与MPTP后,小鼠行为学计数降低,爬杆实验未能得到检测结果,悬挂实验变异系数很高,结果有明显的偶然性,滚轴实验结果变异系数中等,平均数呈现一定的上升趋势,自主活动计数中移动与站立和游泳实验的平均数则呈现明显的下降趋势,变异系数很低,而黑质DA神经元数目减少约58%,纹状体TH-ir神经纤维密度减低,纹状体DA水平明显降低约88%,两组相比差异有显著性(P<0.01)。结论MPTP所致的C57BL小鼠的神经病理、生化改变与PD患者近似,自主活动计数和游泳实验优于其他行为学检测方法。     

小鼠帕金森病模型的行为学及组织病理学改变的观察分析

目的:观察1-甲基4苯基-1,2,3,6-四氢吡啶(MPTP)诱导的帕金森病小鼠模型的行为学及组织学变化.方法:C57/BL小鼠腹腔注射MPTP 25 mg/kg,每周2次,连续5周.通过旷场实验和强迫游泳实验检测小鼠的行为变化,分别使用抗酪氨酸羟化酶(TH)单克隆抗体和抗诱生型一氧化氮合酶(iN0S)单克隆抗体、抗精氨酸酶Ⅰ(Arg1)多克隆抗体作为多巴胺能神经元和小胶质细胞M1、M2两种极化表型的分子标志进行免疫荧光染色.结果:旷场实验中,模型组小鼠的活动总路程较对照组小鼠有减少趋势,但无明显统计学差异(P＞0.05),而其中央活动时间较正常对照组明显缩短(P＜0.05);强迫游泳实验中,模型组小鼠在水中的不动时间较对照组显著延长(P＜0.05).与对照组相比,模型组小鼠中脑黑质致密部TH阳性神经细胞数目减少约87％,两组TH阳性神经细胞计数比较差异显著(P＜0.01).模型组iNOS所染M1型小胶质细胞数量较对照组增加约54％,有显著性差异(P＜0.05),而Arg1标志的M2型细胞数量,虽较对照组有减少趋势,但无明显统计学差异(P＞0.05).结论:MPTP所致的C57/BL小鼠行为学及神经病理学改变与临床PD患者类似,脑内黑质区小胶质细胞两种极化表型混合存在,但M1型极化较正常有所改变,M2型变化不明显.     

尼古丁对帕金森病小鼠多巴胺能神经元的保护作用

目的：观察尼古丁对多巴胺能神经元的作用并探讨其作用机制。方法：采用1-甲基-4-苯基-1,2,3,6-四氢吡啶（1-methyl-4-phenyl—1,2,3,6-tetrahydmpyridine,MPTP）小鼠模型,通过行为学方法、免疫组织化学、电镜观察尼古丁预处理对帕金森病（parkinson’s disease,PD）小鼠的影响。结果：尼古丁预处理可以明显缩短PD小鼠的爬杆时间,提高悬挂的得分。免疫组化结果显示尼古丁显著减少多巴胺（doparnine,DA）能神经元变性（P〈0．01）和γ-氨基丁酸（γ-aminobutyric acid,GABA）能神经元的脱失（P〈0．05）,并可减轻尾核超微结构的损伤。结论：尼古丁可减轻MPTP小鼠多巴胺能神经元的损伤,对多巴胺能神经元有保护作用。     

MPTP损伤的小鼠PD模型的制作与评价

帕金森病(Parkinson!sdisease,PD)动物模型研究的目的是揭示多巴胺能神经元特异性损伤的机制,进而探索针对这种损伤的神经保护方法或治疗方法.由神经毒素MPTP损伤的小鼠PD模型,广泛应用于散发性PD的研究中.根据注射总剂量、两次注射间隔时间、注射方式的不同,制成了适合于不同研究目的的各种小鼠PD模型.关于MPTP导致的PD模型动物神经损伤的评价方式也是多层面、多指标并存的.对MPTP动物模型的起源和MPTP导致多巴胺能神经元损伤途径进行了较为系统的概述,并对MPTP小鼠PD模型的制作方法与评价指标进行较为详细的归纳.     

色钉菇粗多糖对小鼠DA能神经元MPTP损伤的保护作用

以C57BL/6J小鼠为实验材料,研究色钉菇粗多糖对多巴胺能神经元损伤的保护作用,并用体外实验方法测定其抗氧化活性。用MPTP（1-甲基-4-苯基-1,2,3,6-四氢吡啶）方法复制了帕金森病小鼠模型,模型复制前,预先给予小鼠100mg/kg、200mg/kg、400mg/kg不同剂量的色钉菇粗多糖,通过行为学检测方法和免疫组化技术观察小鼠的行为变化以及黑质中多巴胺能神经元的数量变化;用抑制小鼠肝脂质过氧化能力的方法测定色钉菇粗多糖的抗氧化活性。结果显示,预先给予200mg/kg和400mg/kg剂量的色钉菇粗多糖能显著地改善帕金森病模型小鼠的行为症状,并能显著地降低MPTP所致的小鼠多巴胺能神经元的凋亡,这可能与该多糖的抗氧化活性有关。提示色钉菇多糖有开发成防治帕金森病药物的应用前景。     

纹状体内移植胚胎干细胞来源的神经前体细胞可升高帕金森病小鼠纹状体内多巴胺含量

目的探讨胚胎干细胞来源的神经前体细胞移植治疗帕金森病(Parkinson's disease,PD)的疗效及作用机制。方法以小鼠腹腔注射1-甲基-4-苯基-1,2,3,6-四氢吡啶(1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine,MPTP)建立PD小鼠模型;于体外将小鼠胚胎干细胞(embryonic stem cells,ESCs)向神经前体细胞(neural precursor cells,NPC)方向分化,经PCR与免疫荧光染色分析鉴定后将高纯度的NPC移植入PD小鼠纹状体内,2周和4周分别取纹状体制作冰冻切片并进行免疫荧光染色,用高效液相色谱法测定纹状体多巴胺的含量;对移植后死亡小鼠,取其脑进行常规石蜡切片、HE染色。结果移植的NPC可在移植部位存活,并分化为表达酪氨酸羟化酶(TH)的多巴胺能神经元;高效液相色谱法检测显示,PD小鼠纹状体内多巴胺含量明显降低,移植NPC 2周后的PD小鼠纹状体内多巴胺含量较未移植小鼠明显升高,但仍低于正常对照小鼠;移植4周后PD小鼠纹状体内多巴胺含量与未移植小鼠接近;有18.75%的PD小鼠移植NPC后形成畸胎瘤而死亡。结论 ESCs来源的NPC移植因可补充病变处多巴胺含量而对PD有一定治疗作用。     

Modulatory Effects of Testosterone on 1-Methyl-4-Phenyl- 1, 2, 3, 6-Tetrahydropyridine-Induced Neurotoxicity

Abstract: In this experiment, we examined the modulatory effects of testosterone on the parkinsonism-inducing drug 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) in two strains of mice. Orchidectomized male CD-1 and C57/BI mice were implanted with either empty Silastic capsules or capsules containing testosterone and subsequently treated with MPTP. A small area of the corpus striatum was removed for determination of dopamine (DA) content, whereas the remainder was superfused and used to measure L-DOPA (5 μ M )-evoked DA release. In animals treated with MPTP, L-DOPA-evoked DA release was reduced significantly in CD-1 mice, but not in C57/BI mice, treated with testosterone. No differences in L-DOPA-stimulated DA release between MPTP- versus vehicle-treated mice was observed in either the CD-1 or C57/BI mice receiving empty Silastic capsules. Corpus striatum DA contents were more severely depleted in the MPTP-sensitive C57/BI versus the CD-1 mouse strain irrespective of hormone treatment. These results confirm previous results demonstrating differences in these two mouse strains in response to the neurotoxic effects of MPTP upon corpus striatum DA content. More interestingly, they show an important differential modulatory effect of testosterone upon L-DOPA-evoked DA release as a function of MPTP treatment and indicate that testosterone significantly alters the neurotoxic effects of MPTP in the CD-1 mouse.     

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) neurotoxicity in mice is enhanced by ethanol or acetaldehyde

Persistent neurochemical changes consistent with parkinsonism have been reported in brains of mice treated with repeated high doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We now report that ethanol or acetaldehyde potentiate MPTP-induced damage to mouse striatum. One hour after the combined treatments (ethanol and MPTP or acetaldehyde and MPTP), the animals exhibited a marked and long-lasting catatonic posture and then returned gradually to apparently normal locomotion. Seven days after MPTP administration, depletion of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) in mouse striatum were further potentiated in the group of animals treated with ethanol. This effect was more evident when the treatment was repeated twice and was dose-dependent. Acetaldehyde was more potent than ethanol in enhancing MPTP neurotoxicity. A single exposure to acetaldehyde before and during MPTP treatment produced a very consistent fall of DA, DOPAC and HVA but not serotonin (5HT) or 5-hydroxyindoleacetic acid (5HIAA) in the striatum. This suggests that ethanol effects on MPTP neurotoxicity might be related to acetaldehyde formation.     

Treatment with GM1 Ganglioside Restores Striatal Dopamine in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine-Treated Mouse

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), 30 mg/kg i.p. daily for 7 days, was administered to mice. This dosage regimen resulted in an approximately 50% reduction of striatal dopamine (DA) level. Chronic administration of GM1 ganglioside (II3NeuAc-GgOse Cer), beginning between 1 to 4 days after terminating MPTP dosing, resulted in partial restoration of the striatal DA level. From dose- and time-response studies, it appeared that 30 mg/kg i.p. of GM1 administered daily for approximately 23 days resulted in an approximately 80% restoration of the DA level and complete restoration of the 3,4-dihydroxyphenylacetic acid (DOPAC) content. This dosage of GM1 also restored the turnover rate of DA in the striatum to near normal. Discontinuing GM1 treatment resulted in a fall of DA and DOPAC levels to values found in mice treated with MPTP alone. There was no evidence for regeneration of nerve terminal amine reuptake in the GM1-treated mice as evaluated by DA uptake into synaptosomes. Our biochemical findings in animals suggest that early GM1 ganglioside treatment of individuals with degenerative diseases of dopaminergic nigrostriatal neurons might be fruitful.     

Dopamine Transporter Is Required for In Vivo MPTP Neurotoxicity: Evidence from Mice Lacking the Transporter

Abstract: The neurotoxic effect of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) was tested on mice lacking the dopamine (DA) transporter (DAT−/− mice). Striatal tissue DA content and glial fibrillary acidic protein (GFAP) mRNA expression were assessed as markers of MPTP neurotoxicity. MPTP (30 mg/kg, s.c., b.i.d.) produced an 87% decrease in tissue DA levels and a 29-fold increase in the level of GFAP mRNA in the striatum of wild-type animals 48 h after administration. Conversely, there were no significant changes in either parameter in DAT−/− mice. Heterozygotes demonstrated partial sensitivity to MPTP administration as shown by an intermediate value (48%) of tissue DA loss. Direct intrastriatal infusion of the active metabolite of MPTP, 1-methyl-4-phenylpyridinium (MPP⁺; 10 m M ), via a microdialysis probe produced a massive efflux of DA in wild-type mice (>320-fold). In the DAT−/− mice the same treatment produced a much smaller increase in extracellular DA (sixfold), which is likely secondary to tissue damage due to the implantation of the dialysis probe. These observations show that the DAT is a mandatory component for expression of MPTP toxicity in vivo.     

Prolonged Alterations in Canine Striatal Dopamine Metabolism Following Subtoxic Doses of l-Methyl-4-Phenyl- 1,2,3,6-Tetrahydropyridine (MPTP) and 4''-Amino-MPTP Are Linked to the Persistence of Pyridinium Metabolites

Single toxic doses of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP).HCl (2.5 mg/kg i.v.) and 4'-amino-MPTP.2HCl (22.5 mg/kg) induce loss of striatal dopamine (DA) and tyrosine hydroxylase (TH) activity and of nigral DA neurons in the dog. To examine the subacute neurochemical changes induced by low doses of MPTP and 4'-amino-MPTP, dose-response studies of these compounds were carried out in the dog, using 6- and 3-week survival times for these two compounds, respectively. Low single doses of MPTP (1.0, 0.5, and 0.1 mg/kg i.v.) and 4'-amino-MPTP (15, 7.5, and 3.75 mg/kg i.v.) did not cause depletion of canine striatal DA or TH or a loss of nigral neurons. However, levels of the DA metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were decreased in a dose-related fashion, with significant loss of DOPAC being evident 6 weeks after the lowest administered dose of MPTP and 3 weeks after 4'-amino-MPTP. This selective loss of DA metabolites following nontoxic doses of MPTP and 4'-amino-MPTP led to a shift in the ratio of DA to DOPAC or HVA, which was characteristic for each compound. The measurement of striatal 1-methyl-4-phenylpyridinium (MPP+) and 4'-amino-MPP+ levels revealed that high concentrations (up to 150 microM) persist in the striatum for weeks following administration of a single nontoxic dose of MPTP or 4'-amino-MPTP. A causal relationship between the striatal concentration of MPP+ or 4'-amino-MPP+ and the change in DA metabolism as reflected in the DA/DOPAC ratio is suggested by a significant correlation between these measures. It is suggested that presynaptic sequestration and retention of MPP+ and 4'-amino-MPP+ by striatal DA terminals result in the inhibition of the monoamine oxidase contained within these terminals.     

Chronic D1 and D2 dopaminomimetic treatment of MPTP-denervated monkeys: effects on basal ganglia GABA(A)/benzodiazepine receptor complex and GABA content.

The effect of various chronic dopaminergic treatments in 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) monkeys on the brain gamma-aminobutyric acid type A (GABA(A)) /benzodiazepine receptor complex and GABA content was investigated in order to assess the GABAergic involvement in dopaminomimetic-induced dyskinesia. Three MPTP monkeys received for one month pulsatile administrations of the D1 dopamine (DA) receptor agonist SKF 82958 whereas three others received the same dose of SKF 82958 by continuous infusion. A long acting D2 DA receptor agonist, cabergoline, was given to another three animals. Untreated MPTP as well as naive control animals were also included. Pulsatile SKF 82958 relieved parkinsonian symptoms but was also associated with dyskinesia in two of the three animals whereas animals treated continuously with SKF 82958 remained as untreated MPTP monkeys. Chronic cabergoline administration improved motor response with no persistent dyskinesia. MPTP treatment induced a decrease of 3H-flunitrazepam binding in the medial anterior part of caudate-putamen and an increase in the internal segment of globus pallidus (GPi) which was in general unchanged by pulsatile or continuous SKF 82958 administration. Throughout the striatum, binding of 3H-flunitrazepam remained reduced in MPTP monkeys treated with cabergoline but was not significantly lower than untreated MPTP monkeys. Moreover, cabergoline treatment reversed the MPTP-induced increase in 3H-flunitrazepam binding in the GPi. GABA concentrations remained unchanged in the striatum, external segment of globus pallidus and GPi following MPTP denervation. Pulsatile but not continuous SKF 82958 administration decreased putamen GABA content whereas cabergoline treatment decreased caudate GABA. No alteration in GABA levels were observed in the GPe and GPi following the experimental treatments. These results suggest that: (1) D2-like receptor stimulation with cabergoline modulates GABA(A) receptor density in striatal subregions anatomically related to associative cortical afferent and (2) the absence of dyskinesia in dopaminomimetic-treated monkeys might be associated with the reversal of the MPTP-induced upregulation of the GABA(A)/benzodiazepine receptor complex in the Gpi.     

Neurochemical and Histochemical Characterization of Neurotoxic Effects of 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine on Brain Catecholamine Neurones in the Mouse

Systemic administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) caused a rapid and long-lasting reduction of both 3,4-dihydroxyphenylalanine (dopamine, DA) and noradrenaline (NA) in mouse brain, as observed histo- and neurochemically. The depleting effects were more pronounced after repeated MPTP administration and the most marked reductions were observed after 2 X 50 mg MPTP/kg s.c., when DA in striatum and NA in frontal cortex were reduced by greater than 90% 1 week after MPTP. Mice with such catecholamine depletions were markedly sedated and almost completely immobilized. The behavioural syndrome after MPTP resembled that seen after reserpine, a monoamine-depleting drug. MPTP also caused a long-lasting reduction of catecholamine uptake in striatal DA and cortical NA nerve terminals and reduced tyrosine hydroxylase activity in these regions. There was no evidence that MPTP caused any marked DA and NA cell body death. MPTP given acutely transiently elevated serotonin levels. The results are compatible with a neurotoxic action of MPTP on both DA and NA nerve terminals. The nigro-striatal DA and the locus coeruleus NA neurone systems appeared to be most susceptible. Synthesis and utilization of residual striatal DA and cortical NA were increased, as often observed in partially denervated monoamine-innervated brain regions. Both DA and NA showed a gradual recovery, which took months to become complete and may have been related to a regrowth of catecholamine nerve terminals.     

Trace dosages of the neurotoxins MPTP and MPP+ may affect brain dopamine in vivo.

The present study has examined the effects of systemically administered MPTP and MPP+ upon striatal DA and Dopac of C57 mice, also treated concurrently with either saline or reserpine. MPTP followed by saline did not affect DA level but decreased that of Dopac only at 5.0 mg/kg and higher dosages. The potency of MPTP affecting DA increased greatly when the neurotoxicant was followed by either 5.0 or 10.0 mg/kg reserpine; MPTP at 0.10 mg/kg and higher dosages significantly reversed the DA depleting effects of reserpine. MPP+ (1.0 or 10.0 mg/kg) with saline did not affect either DA or Dopac. In contrast, MPP+ at 0.10 mg/kg and higher dosages, when followed by 10.0 mg/kg reserpine, dose-dependently enhanced the DA depleting effects of reserpine. In agreement with the earlier results obtained in vitro, the present study indicates that MPTP administration at trace level dosages may lead to an inhibition of MAO in vivo. The effect of systemically given MPP+ on DA, however, appears to be more complex in nature, conceivably comprised of actions at the striatal neurones including the intraneuronal vesicles and, possibly, at the substantia nigra which may affect striatum in turn. That MPP+ may have reached brain areas in these experiments is also indicated by the observation of a significant striatal level of 3H-MPP+ after its systemic administration. In conclusion, irrespective of MPTP and MPP+ action mechanisms, trace levels of these neurotoxicants appear to affect brain dopamine neurons.     

Nei-like 1 inhibition results in motor dysfunction and promotes inflammation in Parkinson’s disease mice model

Parkinson’s disease (PD) is well known as a neurodegenerative disorder with progressive loss of dopaminergic (DA) neurons. Nei-like 1 (NEIL1) is one of four mammalian DNA glycosylases involved in the progression of various diseases, including neuroinflammation. However, it is still unknown if the expression changes of NEIL1 could contribute to PD progression. In the present study, we established mouse model with PD using 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to explore the effects of NEIL1 on PD development. Here, we found that NEIL1 deletion significantly promoted the motor dysfunction in the wild type mice treated with 6-OHDA. Furthermore, DA neuronal loss was further accelerated by NEIL1 deletion in 6-OHDA-injected mice, as evidenced by the significantly reduced expression of tyrosine hydroxylase (TH) and dopamine transporter (DAT). Furthermore, in PD mice induced by MPTP, remarkably reduced expression of NEIL1 was observed in nigra and striatum of mice. A strong positive correlation was detected in the expression of NEIL1 and the survival rate of DA neurons. Also, NEIL1 ablation further elevated the DA neuronal loss in MPTP-treated mice, accompanied with higher glial activation, as evidenced by the obvious up-regulation of glial fibrillary acidic protein (GFAP) and Ionized calcium-Binding Adapter molecule 1 (Iba1). Moreover, MPTP-triggered inflammation was highly aggravated by the loss of NEIL1 through inducing the expression of pro-inflammatory cytokines and chemokines. In contrast, promoting NEIL1 expression effectively reversedPD progression induced by MPTP in mice. Together, these results demonstrated that NEIL1 insufficiency might be a contributing factor for the progression of PD, which therefore could be considered as a novel candidate to develop effective treatments against PD progression.