重组人促红细胞生成素预处理对帕金森病大鼠胶质细胞源性炎症因子表达的影响

目的探讨重组人促红细胞生成素(rhEPO)预处理对帕金森病(PD)大鼠胶质细胞源性炎症因子表达的影响。方法 40只SD大鼠随机分为4组,A组:右侧纹状体内注射rhEPO 24 h后,同侧黑质内注射6-羟基多巴胺(6-OHDA);B组:右侧纹状体内立体定向注射与rhEPO等量的生理盐水,24 h后同侧黑质内立体定向注射6-OHDA;C组:右侧黑质内立体定向注射6-OHDA;D组:右侧黑质内立体定向注射与6-OHDA等量的生理盐水。4周后采用酶联免疫吸附法检测血清诱导型一氧化氮合酶(iNOS)和肿瘤坏死因子(TNF)-α含量;逆转录(RT)-PCR法检测黑质iNOS和TNF-αmRNA的表达。结果与D组比较,A、B、C组大鼠血清iNOS、TNF-α含量增多,黑质iNOS、TNF-αmRNA表达增高(均P<0.05);与B组和C组比较,A组大鼠血清iNOS、TNF-α含量显著减少,黑质iNOS、TNF-αmRNA表达显著降低(均P<0.05)。结论 rhEPO可能通过抑制黑质TNF-α、iNOS表达,减轻6-OHDA对多巴胺能神经元的毒性损害,具有神经保护作用。     

酪氨酸羟化酶cDNA移植治疗帕金森病的实验研究

帕金森病(PD)的主要病因是黑质多巴胺能神经元损伤,表达的酪氨酸羟化酶(TH)减少。本文在应用6-羟多巴胺(6-OHDA)制备偏侧PD大鼠模型的前提下,首次将TH cDNA移植到PD大鼠纹状体内,模型动物的旋转行为明显改善,用免疫组化法及PCR法证实了外源性THcDNA可以进入脑细胞内,并表达出有生物活性的TH。     

帕金森病大鼠模型黑质白介素-6表达的实验研究

目的探讨白介素-6(IL-6)和小胶质细胞在帕金森病发病机制中作用,阐述小胶质细胞激活后作用的合理模式。方法采用立体定向术将神经毒素6-羟基多巴(6-OHDA)注入大鼠右侧纹状体制作偏侧帕金森病大鼠模型。造模2月后,计数黑质致密部神经元和小胶质细胞数目,观察黑质致密部病理形态学变化,并采用免疫组织化学方法观察黑质致密部IL-6表达水平的变化。结果光镜下观察模型组右侧黑质致密部多巴胺能神经元几乎消失,小胶质细胞数目明显增多,与假手术组及正常对照组相比,差异有显著性(P<0.05)。免疫组化染色显示模型组右侧黑质致密部可见明显的小胶质细胞核周的棕褐色阳性表达,而模型组左侧与假手术组及正常对照组右侧黑质均未见明显阳性着染区。结论神经毒素6-OHDA可导致神经元释放小胶质细胞激活态物质,激活小胶质细胞释放IL-6介导细胞毒作用,促进神经元的慢性变性坏死。     

N-乙酰半胱氨酸对帕金森病模型大鼠黑质氧化应激相关指标的影响

目的观察抗氧化剂N-乙酰半胱氨酸(N-acetylcysteine,NAC)对帕金森病(Parkinson's disease,PD)模型大鼠黑质氧化应激相关指标的影响。方法 36只健康雄性SD大鼠随机分为假手术组(sham组)、帕金森病模型组(PD组)和抗氧化剂NAC组(NAC组),每组又分为模型制备成功后4d和8d两个亚组,每个亚组6只。采用颈背部皮下注射鱼藤酮制作帕金森病大鼠模型,微量酶标法检测大鼠黑质谷胱甘肽(GSH)、谷胱甘肽过氧化物酶(GSH-Px)、超氧化物歧化酶(SOD)和丙二醛(MDA)的含量。结果 (1)与sham组相比,PD组各时间点大鼠黑质中GSH、GSH-Px、SOD含量降低(均P0.01),8d组低于4d组(均P0.05);与PD组相比,NAC组大鼠黑质中GSH、GSH-Px、SOD含量增多(均P0.01),8d组高于4d组(均P0.05)。(2)与sham组相比,PD组大鼠黑质中MDA含量增多(均P0.01),8d组高于4d组(P0.05);与PD组相比,NAC组大鼠黑质中MDA含量降低(均P0.01),8d组低于4d组(P0.05)。结论 N-乙酰半胱氨酸可减轻帕金森病模型大鼠的氧化应激损伤,具有神经保护作用。     

脑源性神经营养因子对帕金森病大鼠多巴胺能神经元的影响

目的观察脑源性神经营养因子对帕金森病(Parkinson’s disease,PD)大鼠模型黑质多巴胺能神经元的影响。方法选用Wistar种系大白鼠30只,体质量230~250g,随机分3组,通过左侧中脑黑质立体定向注射法,组1为生理盐水对照组(简称对照组)10只,注射相应量(5μL)的生理盐水;组2为注射6-OHDA制作帕金森病模型组(简称6-OHDA组)10只,注射6-OHDA,5μL(2μg/μL);组3为(6-OHDA+BDNF)组,在制成帕金森病模型后再向同侧中脑黑质注射BDNF 5μL(3μg/5μL),连续6d,1次/d。分别观察动物的旋转行为,免疫组化染色方法观察黑质酪氨酸羟化酶(tyrosine hydroxylase,TH)阳性神经元的数量,高效液相法测定纹状体部多巴胺(dopamine,DA)含量的变化。结果单侧黑质内注入6-OHDA制成帕金森病大鼠模型后,6-OHDA组与对照组比较,产生旋转行为,(6-OHDA+BDNF)组在观察旋转行为时,症状明显改善;镜下见TH阳性神经元主要见于对照组的黑质致密部,数量为(42.3±7.56)个/μm2,模型组黑质致密部TH阳性神经元数明显减少为(2.41±1.07)个/μm2,(6-OHDA+BDNF)组黑质致密部TH阳性神经元数为(15.36+3.04)个/μm2;纹状体部多巴胺含量:生理盐水组为(11.4±1.2)μg/g,6-OHDA组(3.6±0.5)μg/g,(6-OHDA+BDNF)组(5.5±0.6)μg/g。结论 BDNF能改善6-OHDA所致的帕金森病大鼠黑质多巴胺能神经元数目的减少;明显抑制6-OHDA引起的纹状体部多巴胺含量降低;并可抑制6-OHDA对黑质多巴胺能神经元的毒性作用。     

镁对帕金森病大鼠黑质多巴胺神经元的影响

目的观察镁对帕金森病(PD)大鼠黑质多巴胺神经元影响及其作用机制。方法应用6-羟基多巴胺(6-OHDA)制备偏侧PD大鼠模型后分为硫酸镁组、美多巴组、混合组(硫酸镁+美多巴)和对照组(生理盐水),并给予相应药物灌胃治疗28d。观察治疗后各组大鼠旋转行为的变化;免疫组化法检测黑质酪氨酸羟化酶(TH)阳性神经元数量;生化法测定损毁侧纹状体超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-Px)活性及丙二醛(MDA)含量;逆转录聚合酶链反应检测损毁侧黑质caspase-3 mRNA表达;Western Blot法检测核因子(NF)-кBP65水平。结果治疗后仅混合组出现较稳定的向对侧的旋转行为;TH阳性神经元数混合组较其他各组明显增加(均P<0.05);与对照组和美多巴组比较,硫酸镁组和混合组SOD、GSH-Px活性显著增高,MDA、caspase-3 mRNA、NF-кBP65水平显著降低(均P<0.05);硫酸镁组与混合组间差异无统计学意义。结论镁及美多巴联合治疗可提高PD模型脑内多巴胺神经元存活、降低氧化应激损伤、减少神经元凋亡,改善PD大鼠症状。     

托吡酯对多巴胺能神经元保护作用研究

目的研究托吡酯对帕金森病大鼠多巴胺能神经元的保护作用。方法将48只雄性Sprague-Dawley大鼠随机分成4组:生理盐水组(A组),6-OHDA组(B组),造模前托吡酯预处理组(C组)和造模后托吡酯处理组(D组),每组各12只;第1～3dA、B、D组分别行生理盐水灌胃,C组用托吡酯稀释后灌胃;第4dB、C、D组分别向右侧纹状体注入6-OHDA,A组注入生理盐水;第5～7dA、B、C组行生理盐水灌胃,D组用托吡酯(剂量同前)稀释后灌胃;分别于造模后第4、28d断头处死,用免疫组织化学方法观察黑质区域内酪氨酸羟化酶(TH)阳性细胞数量,用分光光度计测定纹状体内超氧化物歧化酶(SOD)、谷胱甘肽过氧化物酶(GSH-PX)和丙二醛(MDA)含量。结果与B组损毁侧比较,C、D组损毁侧黑质TH阳性细胞计数明显增多(P<0.01),纹状体内SOD及GSH-Px活性显著增高,MDA含量明显降低,同时C、D组比较差异有显著性(P<0.01)。结论托吡酯对多巴胺能神经元具有保护作用,其保护机制可能与降低脂质过氧化水平及毒性产物的作用和减少自由基的产生有关。     

帕金森病大鼠模型神经元型一氧化氮合酶(nNOS)阳性神经元的实验研究

目的 观察研究帕金森病(PD)大鼠模型纹状体神经元型一氧化氮合酶(nNOS)阳性神经元，探讨一氧化氮(NO)在PD发病机制中所起作用。方法 应用立体定向技术建立6-OHDA毁损的大鼠PD模型，通过多巴胺受体激动剂阿扑吗啡(APO)测试大鼠旋转行为，免疫组化方法观察黑质酪氨酸羟化酶(TH)阳性神经元和纹状体nNOS阳性神经元的变化。结果 大鼠6-OHDA损毁侧黑质TH阳性神经元数目较对侧明显减少，双侧纹状体nNOS阳性神经元数目无显著差异。结论 6-OHDA对TH阳性神经元有损伤作用，而NOS阳性神经元对其具有抵抗作用。NO可能参与了PD发病机制。     

神经胶质细胞在帕金森病发病机制中的作用

目的　探讨胶质细胞在帕金森病 ( Parkinson's disease,PD)发病机制中的作用。方法　采用立体定向术将神经毒素 6 -羟基多巴 ( 6 - hydroxydopamine,6 - OHDA)注入大鼠右侧纹状体内 ,制备经典的帕金森病动物模型。观察黑质致密带内多巴胺 ( dopamine,DA)能神经元缺失、胶质细胞的增生和肿瘤坏死因子 ( tumor necrosis factor-alpha,TNF- α)表达水平。结果　模型组右侧黑质 DA能神经元的数量明显减少 ,同时伴有星形胶质细胞和小胶质细胞的数量明显增高 ( P<0 .0 5 ) ,TNF- α在模型组右侧黑质和纹状体内有阳性表达 ,且主要分布在激活的小胶质细胞上。结论　神经胶质细胞可能是通过 TNF- α等细胞因子 ,导致或参与 DA能神经元的大量的变性、死亡。以抑制小胶质细胞的激活作为靶点的药物研究有可能为 PD的治疗提供新的思路。     

6-羟基多巴定向注射建立帕金森病大鼠模型的实验研究

目的探讨立体定向间隔注射6-羟基多巴(6-OHDA)毁损黑质致密部(SNc)和中脑腹侧被盖(VTA)建立类似于人类帕金森病(PD)中晚期的PD大鼠模型方法。方法近交系Wistar大鼠50只,脑立体定向将6-OHDA注入大鼠右侧VTA及SNc,间隔两周,对阿朴吗啡(Apo)诱发旋转后旋转不明显或无稳定左侧旋转模型再次制模,并观察大鼠行为学改变,免疫组化检测黑质多巴胺(DA)能神经元的数量以及高效液相-荧光法检测黑质纹状体中DA含量的变化。结果(1)50只大鼠中有41只经APO诱导表现为恒定左侧旋转且结果稳定,旋转圈数>210r/30min,视为成功PD大鼠模型,部分大鼠伴有震颤、活动迟缓、嗅探、觅食、竖尾等异常行为改变,并且可持续存在16周;(2)免疫组化结果:PD大鼠模型毁损侧黑质区多巴胺能神经元较对侧及对照组减少大于90%;(3)PD大鼠右侧黑质纹状体中DA含量较左侧及对照组减少90%以上。结论6-OHDA毁损SNc及VTA间隔注射法可有效建立模拟人类PD中晚期的大鼠PD模型。     

PD模型中GDNF与星形胶质细胞对黑质DA能神经元的影响

目的探讨星形胶质细胞和胶质细胞源性神经营养因子(glial cell line-derived neurotrophic factor,GDNF)在帕金森病(Parkinson's disease,PD)中对多巴胺(dopamine neurons,DA)能神经元损伤的影响。方法成年大鼠右侧前脑侧束注射6羟多巴胺(6-OHDA)制备PD模型。PD模型右侧黑质内注射GDNF,于注射后第6周采用免疫组织化学方法观察星形胶质细胞神经纤维酸性蛋白(glial fibrillary acidic protein,GFAP)以及多巴胺能神经元酪氨酸羟化酶(tyrosine hydroxylasa,TH)的变化。结果模型组、PBS和GDNF组注射侧与非注射侧星形胶质细胞相比,均发现GFAP阳性细胞明显增多,DA能神经元数量明显减少(P<0.05)。GDNF组与模型组相比,发现GFAP阳性细胞明显增多,同时残存的DA能神经元数量有所增加(P<0.05)。结论黑质内注射GDNF可能通过激活的星形胶质细胞保护PD大鼠模型黑质DA能神经元。     

尼古丁对帕金森病大鼠纹状体GDNF和多巴胺含量的影响

目的 研究尼古丁对帕金森病（PD）大鼠纹状体脑胶质细胞源性神经营养因子(GDNF)和多巴胺（DA）含量的影响。方法 将6－羟多巴胺（6－OHDA）立体定向注射到大鼠右侧中脑腹侧背盖部（VTA）和黑质致密部（SNpc)，建立PD大鼠模型。采用生化、免疫组织化学方法观察不同剂量尼古丁对PD大鼠的作用，检测纹状体GDNF表达及DA含量的变化。结果 造模前及造模后皮下注射尼古丁的PD大鼠，纹状体GDNF表达及DA含量较PD组有明显改善（P＜0．05）。结论 尼古丁可减轻6－OHDA对黑质DA能神经元的损伤，对PD大鼠具有保护作用。     

Delivery of a GDNF gene into the substantia nigra after a progressive 6-OHDA lesion maintains functional nigrostriatal connections

The effects of delivering GDNF via an adenoviral vector (AdGDNF) 1 week after lesioning dopaminergic neurons in the rat substantia nigra (SN) with 6-hydroxydopamine (6-OHDA) were examined. Rats were unilaterally lesioned by injection of 6-OHDA into the striatum, resulting in progressive degeneration of dopaminergic neurons in the SN. One week later, when substantial damage had already occurred, AdGDNF or a control vector harboring beta-galactosidase (AdLacZ) was injected into either the striatum or SN (3.2 x 10(7) PFU/microl in 2 microl). Rats were examined behaviorally with the amphetamine-induced rotation test and for forelimb use for weight-bearing movements. On day 30 postlesion, the extent of nigrostriatal tract degeneration was determined by injecting a retrograde tracer (FluoroGold) bilaterally into the lesioned striatum. Five days later, rats were sacrificed within 2 h of amphetamine injection to examine amphetamine-induced Fos expression in the striatum, a measure of dopaminergic-dependent function in target neurons. AdGDNF injection in the SN rescued dopaminergic neurons in the SN and increased the number of dopaminergic neurons that maintained a connection to the striatum, compared to rats injected with AdLacZ. Further support that these spared SN cells maintained functional connections to the striatum was evidenced by increased Fos expression in striatal target neurons and a decrease in amphetamine-induced rotation. In contrast to the effects observed in rats injected with AdGDNF in the SN, rats injected with AdGDNF in the striatum did not exhibit significant ameliorative effects. This study demonstrates that experimentally increasing levels of GDNF biosynthesis near the dopaminergic neuronal soma is effective in protecting the survival of these neurons and their function even when therapy is begun after 6-OHDA-induced degeneration has commenced. Thus, GDNF gene therapy may ameliorate the consequences of Parkinson's disease through rescuing compromised dopaminergic neurons.     

重组人促红细胞生成素预处理对黑质多巴胺能神经元凋亡的影响

目的研究重组人促红细胞生成素(rhEPO)对离体帕金森病模型中黑质多巴胺神经元凋亡的影响。方法以6-羟基多巴胺(6-OHDA)为毁损剂建立大鼠离体帕金森病(PD)模型。用6u/mlrhEPO预处理黑质多巴胺神经元,然后用免疫组化方法观察黑质中酪氨酸羟化酶(TH)免疫反应阳性细胞数和半胱天冬酶-3(Caspase-3)免疫反应阳性细胞数的变化,TUNEL法观察黑质中多巴胺神经元的凋亡情况。结果与6-OHDA组(44.2±5.0)相比,rhEPO预处理组TH免疫反应阳性细胞(63.8±6.2,P<0.01)增多;与6-OHDA组(22.3±2.8)相比,rhEPO预处理组多巴胺神经元中Caspase-3表达减少,Caspase-3免疫反应阳性细胞染色较淡,数量减少(13.7±1.8,P<0.01);与6-OHDA组(20.3±3.1)相比,rhEPO预处理组TUNEL阳性细胞染色较淡,数量减少(10.7±1.5,P<0.01)。结论rhEPO预处理可以减轻6-OHDA对离体帕金森病模型中多巴胺神经元的损伤,其机制可能与rhEPO抑制黑质多巴胺神经元凋亡有关。     

提高帕金森病动物模型制作成功率的方法学探讨及模型综合评价

目的探讨提高6-OHDA帕金森病(PD)大鼠模型制作成功率的方法,并对模型进行综合评价。方法取SD大鼠90只,将6-OHDA立体定向注射于左侧黑质区及中脑腹侧被盖,观察大鼠的行为、黑质抗氧化指标、线粒体呼吸链及黑质细胞形态学的变化。结果①经阿朴吗啡诱导后共筛选出成功模型64只,成功率为71%;②模型大鼠黑质区ROS、MDA水平均明显升高,而GSH-Px活性则明显降低;③模型大鼠黑质区存在线粒体呼吸链功能障碍;④免疫组化发现注射侧黑质区多巴胺能神经元较对侧明显减少(P<0.001);⑤电镜观察发现模型大鼠黑质细胞同时存在凋亡、变性和坏死样改变。结论应用本方法可较快建立稳定的成功率较高的PD大鼠模型,该方法是通过增强氧化应激、干扰线粒体呼吸链功能、诱导凋亡甚至引发坏死等不同机制损毁多巴胺能神经元的,同PD的发病机制基本一致。     

被动吸烟对大鼠纹状体多巴胺及黑质自由基含量的影响

目的研究被动吸烟对帕金森病(PD)大鼠的影响,探讨其作用机制。方法通过6-羟多巴胺(6-O-HDA)脑立体定向注射术建立大鼠PD模型。术前4周开始被动吸烟及术后持续2周为预防组;术后3周给予被动吸烟持续2周为治疗组。采用生化的方法观察PD大鼠纹状体黑质自由基、抗氧化剂及多巴胺含量的变化。结果吸烟治疗组和吸烟预防组大鼠黑质自由基及抗自由基酶较对照组有明显改善(P<0.05);吸烟预防组PD大鼠纹状体DA含量较对照组有明显改善(P<0.05);吸烟治疗组PD大鼠纹状体DA含量较对照组无变化(P>0.05)。结论被动吸烟能减轻黑质纹状体DA能神经元的损伤。     

双靶点注射6-OHDA建立帕金森病大鼠模型并提高成功率

目的建立大鼠帕金森病模型,观测其行为学、中脑黑质多巴胺能神经元及超微结构的变化。方法利用立体定向技术,注射6-OHDA至大鼠中脑黑质SNc和中脑腹侧被盖区VTA,于注射后2、4、6、8周观测阿朴吗啡诱导的大鼠旋转行为学变化;采用免疫组化染色检测TH的表达,了解中脑黑质多巴胺能阳性神经元变化;利用透射电镜了解黑质区超微结构的变化。结果所有大鼠进行阿朴吗啡诱导旋转行为测试,旋转圈数>7r/min,并且>210r/30min,为合格的PD大鼠模型。大鼠模型于第4、6和8周时,大鼠行为学变化较为恒定。第8周时,50只大鼠中出现32只大鼠大鼠旋转次数平均为11.5±1.2/分,造模成功率为64%。PD模型大鼠超微结构观察,黑质神经元数目明显减少,线粒体肿胀,粗面内质网囊性扩张、脱颗粒,髓鞘扩张。免疫组化检测,成功模型光镜下分别计数双侧黑质TH阳性神经元,损毁侧黑质TH阳性神经元占正常侧的3.0%,即毁损侧TH阳性神经元减少97.0%。结论利用立体定向技术,选择黑质和中脑腹侧被盖区等双靶点,可建立6-OHDA大鼠PD模型,具有明确病理变化,提高模型成功率。     

KDI tripeptide of gamma1 laminin protects rat dopaminergic neurons from 6-OHDA induced toxicity

Our previous studies indicate that the KDI (Lys-Asp-Ile) tripeptide of gamma1 laminin protects central neurons from mechanical trauma and excitotoxicity. At least part of the neuroprotective effect of the KDI tripeptide may be mediated by its inhibitory function on ionotropic glutamate receptors. We studied the protective effect of the KDI tripeptide against 6-hydroxy-dopamine (6-OHDA) induced neurotoxicity in a rat experimental model of Parkinson's disease (PD). We found that a single unilateral injection of the KDI tripeptide into the substantia nigra before an injection of 6-OHDA protected the dopaminergic neurons from the neurotoxicity of 6-OHDA. Compared to rats treated with 6-OHDA alone, the KDI + 6-OHDA-treated substantia nigra was relatively intact with large numbers of dopaminergic neurons present at the injection side. In the rats treated with 6-OHDA alone, no dopaminergic neurons were detected, and the substantia nigra-area at the injection side was filled with blood-containing cavities. Quantification of the rescue effect of the KDI tripeptide indicated that, in animals receiving KDI before 6-OHDA, 33% of tyrosine hydroxylase-positive dopaminergic neurons of the substantia nigra were present as compared to the contralateral non-injected side. In animals receiving 6-OHDA alone, only 1.4% of the tyrosine hydroxylase expressing dopaminergic neurons could be verified. If this much protection were achieved in humans, it would be sufficient to diminish or greatly alleviate the clinical symptoms of PD. We propose that the KDI tripeptide or its derivatives might offer a neuroprotective biological alternative for treatment of PD.     

Behavioral and Cellular Protection of Rat Dopaminergic Neurons by an Adenoviral Vector Encoding Glial Cell Line-Derived Neurotrophic Factor

Previously, we observed that an adenoviral (Ad) vector encoding human glial cell line-derived neurotrophic factor (GDNF), injected near the rat substantia nigra (SN), protects SN dopaminergic (DA) neuronal soma from 6-hydroxydopamine (6-OHDA)-induced degeneration. In the present study, the effects of Ad GDNF injected into the striatum, the site of DA nerve terminals, were assessed in the same lesion model. So that effects on cell survival could be assessed without relying on DA phenotypic markers, fluorogold (FG) was infused bilaterally into striatae to retrogradely label DA neurons. Ad GDNF or control treatment (Ad mGDNF, encoding a deletion mutant GDNF, Ad lacZ, vehicle, or no injection) was injected unilaterally into the striatum near one FG site. Progressive degeneration of DA neurons was initiated 7 days later by unilateral injection of 6-OHDA at this FG site. At 42 days after 6-OHDA, Ad GDNF prevented the death of 40% of susceptible DA neurons that projected to the lesion site. Ad GDNF prevented the development of behavioral asymmetries which depend on striatal dopamine, including limb use asymmetries during spontaneous movements along vertical surfaces and amphetamine-induced rotation. Both behavioral asymmetries were exhibited by control-treated, lesioned rats. Interestingly, these behavioral protections occurred in the absence of an increase in the density of DA nerve fibers in the striatum of Ad GDNF-treated rats. ELISA measurements of transgene proteins showed that nanogram quantities of GDNF and lacZ transgene were present in the striatum for 7 weeks, and picogram quantities of GDNF in the SN due to retrograde transport of vector and/or transgene protein. These studies demonstrate that Ad GDNF can sustain increased levels of biosynthesized GDNF in the terminal region of DA neurons for at least 7 weeks and that this GDNF slows the degeneration of DA neurons and prevents the appearance of dopamine dependent motor asymmetries in a rat model of Parkinson's disease (PD). GDNF gene therapy targeted to the striatum, a more surgically accessible site than the SN, may be clinically applicable to humans with PD.