GDNF reduces oxidative stress in a 6-hydroxydopamine model of Parkinson's disease

Many current theories of Parkinson's disease (PD) suggest that oxidative stress is involved in the neurodegenerative process. Potential neuroprotective agents could protect neurons through inherent antioxidant properties or through the upregulation of the brain's antioxidant defenses. Glial cell line-derived neurotrophic factor (GDNF) has been shown to protect and restore dopamine neurons in experimental models of PD and to improve motor function in human patients. This study was designed to investigate GDNF's effect on oxidative stress in a model of PD. GDNF or vehicle was injected into the right striatum of male Fischer-344 rats. Three days later 6-OHDA or saline was injected into the same striatum. The striatum and substantia nigra from both sides of the brain were removed 24h after 6-OHDA or saline injection and analyzed for the oxidative stress markers protein carbonyls and 4-hydroxynonenal. Both markers were significantly reduced in GDNF+6-OHDA treated animals compared to vehicle+6-OHDA treated animals. In addition, in animals allowed to recover for 3.5-4 weeks after the 6-OHDA administration, the GDNF led to significant protection against loss of striatal and nigral tissue levels of dopamine. These results suggest that the protective effects of GDNF against 6-OHDA involve a reduction in oxidative stress.     

肌酸对帕金森病模型大鼠黑质多巴胺能神经元保护作用的研究

目的:观察肌酸对帕金森病模型大鼠黑质多巴胺能神经元的保护作用及其机制。方法:30只雄性SD大鼠随机分成3组:对照组(A组),6-羟多巴胺(6-OHDA)组(B组),肌酸+6-OHDA组(C组),每组各10只。A组不注射6-OHDA,B组进行6-OHDA造模,C组在造模前5天每天给予肌酸(100 mg/kg)灌胃,连续两周,B组给予生理盐水4 ml灌胃。分别观察各组动物行为学、黑质多巴胺能神经元数量及氧化应激指标谷胱甘肽(GSH)和丙二醛(MDA)水平变化。结果:6-OHDA立体定向注射后,实验大鼠出现阿朴吗啡诱导的旋转行为,黑质致密部多巴胺能神经元显著减少,GSH含量降低、MDA水平升高;肌酸能够减轻动物行为学异常(P0.01)、显著增加黑质致密部多巴胺神经元数量(P0.01),拮抗6-OHDA诱导的氧化应激水平升高(P0.01)。结论:肌酸对6-OHDA诱导的多巴胺神经元损伤具有明显保护作用,其机制与抑制氧化应激损伤有关。     

The effect of intrastriatal single injection of GDNF on the nigrostriatal dopaminergic system in hemiparkinsonian rats: behavioral and histological studies using two different dosages

Glial cell line-derived neurotrophic factor (GDNF) is a member of the transforming growth factor-beta superfamily and acts as a neurotrophic factor for the nigrostriatal dopamine (DA) system. Although previous studies have shown that pretreatment with GDNF could prevent degenerative changes of nigrostriatal DA system by DA neurotoxin 6-hydroxydopamine (6-OHDA), it is not really known whether GDNF can induce recovery of nigrostriatal DA system after partial lesioning by 6-OHDA. Substantia nigra has been commonly chosen as injection site for GDNF but a limited number of studies have used striatum as injection site where neural transplantation is commonly performed. Unilateral intrastriatal administration of 6-OHDA was performed in Sprague-Dawley rats to create partial lesion of the nigrostriatal DA system. These hemiparkinsonian model rats received a 10- or 100-microg single injection of human recombinant GDNF into the same portion of the striatum 4 weeks after 6-OHDA treatment. Both animals that received a 10- or 100-microg single injection of GDNF showed decreased apomorphine-induced rotation at 2 weeks after injection. More potent and prolonged functional recovery was observed in animals receiving 100 microg of GDNF than in those receiving 10 microg of GDNF. Tyrosine hydroxylase (TH) immunocytochemistry revealed that TH positive DA fiber density in the striatum and the number of DA cell bodies in the substantia nigra were greater in animals receiving 10 or 100 microg of GDNF than those receiving saline. These immunocytochemical results have also shown that 100 microg of GDNF was more potent than 10 microg of GDNF. These morphological and functional results indicate that GDNF treatment 4 weeks after 6-OHDA lesioning could induce recovery of nigrostriatal DA system. Striatum was a good site for GDNF administration for hemiparkinsonian rats and a single injection of 100 microg of GDNF was more potent than 10 microg of GDNF.     

帕金森病大鼠模型的建立及MRI分析

目的:从行为学和MRI表现上评价6-OHDA分别毁损大鼠黑质及纹状体制备的偏侧帕金森病模型。方法:40只Wistar雄性大鼠随机分为3组:黑质毁损组20只,纹状体毁损组18只,假手术组2只。应用立体定向仪,分别作单点黑质毁损与两点纹状体毁损术。观察术后不同时期阿朴吗啡诱导的大鼠旋转行为,并进一步用高场强MRI活体检测帕金森病大鼠黑质、纹状体的毁损情况。结果:黑质毁损后第2周内有7只大鼠诱发出明显的旋转行为,且旋转次数>7转/min,模型成功率为35％。纹状体毁损后第2周有11只大鼠诱发出旋转行为,旋转次数<4转/min,第3周内旋转次数<5转/min,至术后第5周达到7转/min以上并保持稳定,模型成功率为61.1％。MRI显示:模型大鼠第3周内毁损侧黑质和纹状体较对侧出现了明显的MRI低信号区,且随着时间的延长低信号区逐渐减小,至第5周已基本消失。结论:应用6-OHDA小剂量两点毁损纹状体制备的偏侧帕金森病大鼠模型更加符合临床帕金森病病人的病程进展并具有较高的成功率,是帕金森病研究较为理想的模型。MRI扫描可以活体连续观察帕金森病大鼠模型的毁损情况,是客观评价和检测帕金森病大鼠模型的一种有效工具。     

Neuroprotective effect of silymarin in 6-hydroxydopamine hemi-parkinsonian rat: Involvement of estrogen receptors and oxidative stress

This study examined neuroprotective effect of silymarin (SM) in a model of Parkinson's disease (PD). Unilateral intrastriatal 6-hydroxydopamine (6-OHDA)-lesioned rats were pretreated i.p. with SM (100 and 200 mg/kg) 1 h before neurotoxin injection. Fulvestrant was used to evaluate the involvement of estrogen receptors. Net apomorphine-induced rotations and number of Nissl-stained neurons of substantia nigra pars compacta (SNC) were counted in addition to measurement of oxidative stress markers. SM administration only at a dose of 200 mg/kg attenuated the rotational behavior in 6-OHDA-lesioned rats and protected the neurons of SNC against its toxicity and fulvestrant partially attenuated this beneficial effect of SM. In addition, pretreatment with SM at a dose of 200 mg/kg significantly decreased the 6-OHDA-induced thiobarbituric acid reactive substances (TBARS) formation. SM exhibits a dose-dependent neuroprotective effect against 6-OHDA toxicity, partly through attenuating oxidative stress and via an estrogenic pathway.     

中药龟板对Parkinson病大鼠模型BMP4表达的影响

为研究益肾中药龟板对Parkinson病(PD)模型大鼠骨形成蛋白4(BMP4)表达的影响,本研究将6-羟基多巴胺注入大鼠黑质建立PD大鼠模型,对模型大鼠行高、低剂量龟板水煎液口服治疗45d后,采用ELISA和RT-PCR方法进行血清中BMP4酶联免疫试验和脑黑质、纹状体中BMP4mRNA的检测。结果显示:PD模型组的BMP4表达明显降低,用龟板治疗后可以显著阻碍此趋势,而且高剂量组比低剂量组效果更为明显(P<0.05)。本研究结果提示,龟板有明显的促进BMP4及BMP4mRNA表达的作用。     

6-羟基多巴胺帕金森病大鼠模型的制作和行为学评价

6 羟基多巴胺能与多巴胺竞争性结合多巴胺转运体而进入细胞,通过诱发氧化应激反应、抑制 线粒体功能等选择性地损害多巴胺能神经元。将这种神经毒素于大鼠中脑黑质注射,神经元发生损伤至多巴 胺耗竭;于纹状体注射神经元损伤较慢呈渐进性过程。在这些情况下,神经元丢失程度都与注射部位相关。 在大鼠第三脑室注射能诱发出与人类极为相似的神经元退变模式,即中脑内不同区域的DA能神经元因敏感 性不同损伤程度也不同。大鼠模型的行为学评估包括药物诱发试验和非药物诱发试验,前者使用最多,而后 者种类较多。两种方法结合使用能使评估结果更有效、可靠。     

Aging-related dysregulation of dopamine and angiotensin receptor interaction

It is not known whether the aging-related decrease in dopaminergic function leads to the aging-related higher vulnerability of dopaminergic neurons and risk for Parkinson's disease. The renin-angiotensin system (RAS) plays a major role in the inflammatory response, neuronal oxidative stress, and dopaminergic vulnerability via type 1 (AT1) receptors. In the present study, we observed a counterregulatory interaction between dopamine and angiotensin receptors. We observed overexpression of AT1 receptors in the striatum and substantia nigra of young adult dopamine D1 and D2 receptor-deficient mice and young dopamine-depleted rats, together with compensatory overexpression of AT2 receptors or compensatory downregulation of angiotensinogen and/or angiotensin. In aged rats, we observed downregulation of dopamine and dopamine receptors and overexpression of AT1 receptors in aged rats, without compensatory changes observed in young animals. L-Dopa therapy inhibited RAS overactivity in young dopamine-depleted rats, but was ineffective in aged rats. The results suggest that dopamine may play an important role in modulating oxidative stress and inflammation in the substantia nigra and striatum via the RAS, which is impaired by aging.     

ATP敏感性钾通道亚基Kir6.1、Kir6.2在MPTP诱导帕金森病小鼠纹状体和黑质内的改变

为探讨ATP敏感性钾通道(KATP)亚基Kir6.1、Kir6.2在帕金森病(PD)病理生理机制中的可能作用。本研究采用蛋白免疫印迹分析(Western blot)对1-甲基-4-苯基-1,2,3,6-四氢吡啶(MPTP)诱导的PD小鼠模型黑质、纹状体Kir6.1、Kir6.2在不同时间点表达变化进行检测,并与酪氨酸羟化酶(TH)的变化进行比较。结果发现:(1)与正常对照组相比,黑质、纹状体TH蛋白的表达在给药后第1d即开始下降,且呈时间依赖性下降(P<0.01);(2)黑质Kir6.1蛋白的表达在给药后第5d才开始下降(P<0.01);而纹状体Kir6.1蛋白的表达在给药后第5d才开始升高(P<0.01);(3)黑质Kir6.2蛋白的表达在给药后第5d才开始明显升高(P<0.01);而纹状体Kir6.2蛋白的表达在给药后第3d轻度升高(P<0.05),第5d又明显降低(P<0.01)。以上结果提示作为KATP通道亚基的Kir6.1、Kir6.2在MPTP的作用下,可能通过参与星形胶质细胞的活化、胆碱能突触传递的抑制以及自身代偿和修复在PD的病理生理过程中发挥了重要的角色。     

Expression of FasL and its interaction with Fas are mediated by c-Jun N-terminal kinase (JNK) pathway in 6-OHDA-induced rat model of Parkinson disease

Our previous studies and those of others have strongly suggested that c-Jun N-terminal kinase (JNK) signaling pathway plays a critical role in 6-hydroxydopamine (6-OHDA)-induced dopaminergic neuron injury in the substantia nigra. However, the downstream mechanism that accounts for the proapoptotic actions of JNK in 6-OHDA lesion remains to be investigated in detail. Fas, a member of the tumor necrosis factor receptor family with proapoptotic functions, was reported to be elevated within the striatum and substantia nigra pars compacta (SNc) of Parkinson's disease (PD) patients. In the present study, we examined the changes in the protein level of Fas ligand (FasL) and its interaction with Fas in a rat model of PD. We demonstrate that the expression of FasL and not Fas was increased after 6-OHDA lesion; additionally, the interaction of FasL and Fas was increased due to 6-OHDA lesion. This indicates that the 6-OHDA-induced activation of Fas signaling pathway is mediated by JNK and that FasL may be a promising target in the therapeutic approach for PD patients.     

Losartan pretreatment reduces neurodegeneration and behavioural symptoms in 6-hydroxydopamine induced unilateral rat model of Parkinson's disease

Losartan is an angiotensin II receptor antagonist which is mainly used to treat hypertension. It has been shown that angiotensin II involves in NADPH-dependent oxidase activation. In this study, the effect of losartan in 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease was investigated. The rats were daily pre-treated i.p. with losartan (90 mg/kg), for the duration of six days before the 6-OHDA injection in the left substantia nigra pars compacta (SNC), until one day afterwards. Losartan administration caused a significant decrease in the rotational and rigidity score in the lesioned rats after 2 weeks. Furthermore, the pretreatment with losartan significantly lowered the value of the markers of oxidative stress after 24 h. Moreover, losartan protected SNC dopaminergic neurons against toxicity of 6-OHDA. The results therefore suggested that losartan pretreatment attenuated the symptoms of Parkinson's disease probably by preventing 6-OHDA induced oxidative stress and neurodegeneration.     

胚腹侧中脑移植入震颤麻痹症模型鼠靶区与非靶区的实验研究

用６－羟基多巴胺注入ＳＤ鼠右侧被盖腹侧区黑质内侧端，制成震颤麻痹症动物模型．毁损后３～５周，用胚龄１５ｄ的胚鼠腹侧中脑混悬液植入模型鼠靶区──纹状体与非靶区──黑质、丘脑等部位．动物存活８～１２周后处死，于尾壳核、黑质及丘脑均可见有存活的移植区．移植区内均可见ＴＨ免疫阳性细胞．本实验表明，用胚腹侧中脑移植入震颤麻痹症模型鼠靶区及非靶区，移植物均能存活、生长并发挥其功能效应．     

慢病毒介导核受体相关因子1基因修饰骨髓间充质干细胞移植治疗帕金森病模型大鼠

目的探讨慢病毒介导核受体相关因子1(Nurrl)基因修饰骨髓间充质干细胞(BMSCs)移植至帕金森病(PD)模型大鼠纹状体后对PD大鼠的治疗作用。方法采用神经毒素6-羟多巴胺(6-OHDA)纹状体注射成功制备PD大鼠模型18只,将携带绿色荧光的慢病毒GV287-Nurr1感染大鼠BMSCs,然后随机移植入6只PD模型大鼠的纹状体内(实验组),设生理盐水组(假移植组)6只及感染空慢病毒GV287的BMSCs组(对照组)6只;术后第1、2、4周观察大鼠的行为改善情况;免疫组织化学染色法检测纹状体及黑质中Nurrl和酪氨酸羟化酶(TH)蛋白的表达变化;RT-PCR法检测黑质Nurrl mRNA和TH mRNA的表达变化。结果慢病毒感染后的BMSCs及上清中均检测到Nurr1蛋白;对照组与实验组大鼠在移植后第1、2、4周的旋转行为较假移植组均有所改善,且实验组比对照组改善更明显;实验组纹状体Nurr1阳性细胞有效存活并沿胼胝体向皮质及对侧脑组织迁移;实验组纹状体及黑质损毁侧Nurrl和TH蛋白及mRNA的表达较假移植组和对照组明显增高,差异均有统计学意义(P0.05)。结论慢病毒介导Nurr1基因修饰大鼠BMSCs移植治疗PD大鼠,能有效地改善PD模型大鼠的行为学症状,增加大鼠脑内纹状体和黑质区Nurr1和TH的表达。     

硫化氢对帕金森病模型大鼠多巴胺神经元的保护作用

目的:观察硫化氢对帕金森病(Parkinson’s disease,PD)大鼠神经行为学、氧化应激以及多巴胺及其代谢产物的影响。方法:采用6-羟基多巴胺(6-OHDA)注射于脑右侧黑质造成偏侧PD模型。将模型动物随机分为模型组、硫化氢组(硫氢化钠做供体),每组10只;另分别取10只正常大鼠为正常组及假手术组(以抗坏血酸注射)。观察PD大鼠经过硫化氢处理后神经行为学、脑组织丙二醛(MDA)、谷胱甘肽(GSH)、超氧化物歧化酶(SOD)含量以及多巴胺代谢产物的变化。结果:与模型组比较硫化氢组大鼠行为学明显改善(P<0.01),同时脑组织中GSH、SOD含量均升高,MDA含量降低,多巴胺及其代谢产物升高。结论:硫化氢对PD模型大鼠多巴胺神经元具有保护作用。     

Intrastriatal administration of erythropoietin protects dopaminergic neurons and improves neurobehavioral outcome in a rat model of Parkinson's disease

Erythropoietin (EPO), a hematopoietic cytokine, has recently been demonstrated to protect nigral dopaminergic neurons in a mouse model of Parkinson's disease (PD). In the present study, we tested the hypothesis that recombinant human erythropoietin (rhEPO) could protect dopaminergic neurons and improve neurobehavioral outcome in a rat model of PD. rhEPO (20 units in 2 microl of vehicle) was stereotaxically injected into one side of the striatum. 6-hydroxydopamine (6-OHDA) was injected into the same side 1 day later. Another group of rats received rhEPO (5000 u/kg, i.p.) daily for 8 days, and unilateral injection of 6-OHDA in the striatum 3 days after systemic administration of rhEPO. We observed that intrastriatal administration, but not systemic administration of rhEPO significantly reduced the degree of rotational asymmetry. The rhEPO-treated rats also showed an improvement in skilled forelimb use when compared with control rats. The number of tyrosine hydroxylase (TH)-immunoreactive (IR) neurons in the ipsilateral substantia nigra (SN) was significantly larger in intrastriatal rhEPO-treated rats than that in control rats. TH-IR fibers in the 6-OHDA-lesioned striatum were also increased in the intrastriatal rhEPO-treated rats when compared with control rats. In addition, there were lower levels of expression of major histocompatibility complex (MHC) class II antigens and a smaller number of activated microglia in the ipsilateral SN in intrastriatal rhEPO-treated rats than that in control rats at 2 weeks, suggesting that intrastriatal injection of rhEPO attenuated 6-OHDA-induced inflammation in the ipsilateral SN. Our results suggest that intrastriatal administration of rhEPO can protect nigral dopaminergic neurons from cell death induced by 6-OHDA and improve neurobehavioral outcome in a rat model of PD. Anti-inflammation may be one of mechanisms responsible for rhEPO neuroprotection.     

Immunohistochemical detection of L-DOPA-derived dopamine within serotonergic fibers in the striatum and the substantia nigra pars reticulata in Parkinsonian model rats

On the basis of our previous studies in the normal rat [Arai, R., Karasawa, N., Geffard, M., Nagatsu, I., 1995. L-DOPA is converted to dopamine in serotonergic fibers of the striatum of the rat: a double-labeling immunofluorescence study. Neurosci. Lett. 195, 195-198; Arai, R., Karasawa, N., Nagatsu, I., 1996a. Aromatic L-amino acid decarboxylase is present in serotonergic fibers of the striatum of the rat. A double-labeling immunofluorescence study. Brain Res. 706, 177-179; Arai, R., Karasawa, N., Nagatsu, I., 1996b. Dopamine produced from L-DOPA is degraded by endogenous monoamine oxidase in neurons of the dorsal raphe nucleus of the rat: an immunohistochemical study. Brain Res. 722, 181-184] we have assumed that exogenously administered L-dihydroxyphenylalanine (L-DOPA) is converted into dopamine (DA) in serotonergic (5-HT) fibers within the striatum (ST) and the substantia nigra pars reticulata (SNR). In the present study, an attempt was made to confirm the assumptions in Parkinsonian rats, which were produced by unilateral injections of 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNC). The rats exhibiting more than 150 total controversial circles were regarded as satisfactory models of Parkinson disease (PD). Using a dual immunofluorescence histochemistry, we examined DA-immunoreactivity in the 5-HT fibers within the ST and the SNR of the PD model rats after L-DOPA was injected intraperitoneally. In experimental cases with the L-DOPA administration, DA-immunoreactivity was detected in 5-HT fibers in both the ST and the SNR on the 6-OHDA injection side; no DA-immunoreactivity was found in 5-HT fibers in the ST or the SNR in control cases without the L-DOPA administration. The results support the assumption that exogenously administered L-DOPA may be converted into DA within the 5-HT fibers in the ST and SNR of the PD model rats.     

龟板促进帕金森病大鼠黑质神经生长因子信号分子的表达

目的:进一步探讨神经生长因子(NGF)/酪氨酸受体激酶A(TrkA)通路是否为龟板抗帕金森病(PD)大鼠多巴胺能神经元凋亡中的机制.方法:采用大鼠左侧黑质致密带注射6-羟基多巴胺(6-OHDA,0 2%)2μl造成PD模型,同时设立龟板组、模型组和正常对照组,用免疫组织化学显色方法观察PD大鼠中脑黑质NGF、 TrkA和磷酸化的糖原合成酶激酶-3β(p-GSK-3β)阳性神经元数目.免疫印迹法检测NGF、 TrkA、 p-GSK-3β蛋白表达水平的变化.结果:免疫组织化学显色显示龟板组PD大鼠中脑黑质致密部NGF、 TrkA的阳性细胞数明显多于模型组.免疫印迹法结果显示龟板组PD大鼠中脑黑质致密部NGF、 TrkA的蛋白表达水平高于模型组.结论:龟板能上调6-OHDA诱导的PD大鼠中脑黑质NGF、 TrkA和p-GSK-3β的表达,这可能是其抗PD大鼠多巴胺能神经元凋亡的分子机制.     

Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress

Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E₂ (PGE₂) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD.     

Prostaglandin receptor EP2 protects dopaminergic neurons against 6-OHDA-mediated low oxidative stress

Dopaminergic neurons in the substantia nigra (SN) selectively die in Parkinson's disease (PD), but it is unclear how and why this occurs. Recent findings implicate prostaglandin E(2) (PGE(2)) and two of its four receptors, namely EP1 and EP2, as mediators of degenerative and protective events in situations of acute and chronic neuronal death. EP1 activation can exacerbate excitotoxic damage in stroke models and our recent study showed that EP1 activation may explain the selective sensitivity of dopaminergic neurons to oxidative stress. Conversely, EP2 activation may be neuroprotective, although toxic effects have also been demonstrated. Here we investigated if and how EP2 activation might alter the survival of dopaminergic neurons following selective low-level oxidative injury evoked by the neurotoxin 6-hydroxydopamine (6-OHDA) in primary neuronal cultures prepared from embryonic rat midbrain. We found that cultured dopaminergic neurons displayed EP2 receptors. Butaprost, a selective EP2 agonist, significantly reduced 6-OHDA neurotoxicity. EP2 receptors are coupled to stimulatory G-proteins (Gs), which activate adenylate cyclase, increasing cAMP synthesis, which then activates protein kinase A (PKA). Both dibutyryl cAMP and forskolin reduced dopaminergic cell loss after 6-OHDA exposure. Conversely, KT5720 and H-89, two structurally distinct high-affinity PKA inhibitors, abolished the protective effect of butaprost, implicating cAMP-dependent PKA activity in the neuroprotection by EP2 activation. Finally, we show that melanized dopaminergic neurons in the human SN express EP2. This pathway warrants consideration as a neuroprotective strategy for PD.     

Dopamine neurotoxicity: age-dependent behavioral and histological effects

The oxidative stress (OS) theory has implicated the involvement of reactive oxygen species (ROS) in both aging and age-dependent neurodegenerative diseases. The dopaminergic system is particularly vulnerable to ROS, and dopamine (DA) itself can be an endogenous source of ROS. The present study evaluated the hypothesis that DA-induced toxicity is age-dependent, and tested the behavioral and histological correlates of DA neurotoxicity in aging. Young (6 months) and middle-aged (15 months) rats were chronically treated with DA in the substantia nigra (SN, 1 micromol/2 microl vehicle per side/day/5 days) and were subsequently examined for changes in motor function and histology. The neurotoxic effect of DA treatment was an age-dependent effect, as middle-aged animals that received DA infusions in the SN were more impaired than their age-matched controls, especially on tasks that involved greater sensory-motor coordination, whereas young animals that received DA behaved similarly to their age-matched controls. The behavioral effects noted were accompanied by a loss of the tyrosine hydroxylase phenotype in substantia nigra. However, selective neurodegeneration was not noted in the SN of the treated animals, nor was a selective iron deposition noted at the site of injection. These results suggest that a neurochemical deficit and not cell loss per se within the nigrostriatal system underlies the motor behavioral deficits observed in the middle-aged rats.