6-羟多巴诱导大鼠黑质的持续胶质细胞反应

本研究将40μg6- 羟多巴注射到SD大鼠一侧纹状体制作Parkinson病动物模型,研究黑质反应性神经胶质增生在Par kinson病发病过程中的可能作用。筛选成功的模型大鼠,术后12周处死。应用免疫荧光双标记法检测模型大鼠黑质胶质细胞对多巴胺能神经元损伤的反应。结果显示:在注射后12周,损伤侧黑质仍然存在明显的星形胶质细胞反应和小胶质细胞激活。此外,小胶质小结和淋巴细胞浸润的存在提示在注射后12周的注射侧黑质内依然有多巴胺能神经元死亡。结论: 6 -羟多巴对大鼠黑质多巴胺能神经元的急性损伤可以通过胶质细胞反应从而对多巴胺能神经元产生长期的毒性作用。     

GDNF激活星形胶质细胞保护PD模型大鼠黑质多巴胺能神经元

探索在胶质细胞源性神经营养因子(GDNF)保护受损多巴胺(DA)能神经元过程中,星形胶质细胞的可能作用。成年大鼠右侧纹状体内注射6-羟多巴胺(6-OHDA)制备Parkinson病(PD)模型。动物模型右侧黑质内注射GDNF,于注射后第7、14和21d进行动物行为学分析,行黑质节段连续冠状石蜡切片,以抗酪氨酸羟化酶(TH)、胶质原纤维酸性蛋白(GFAP)抗体免疫组化染色,分别显示DA能神经元和激活的星形胶质细胞,光镜观察并进行细胞计数。用免疫印迹法分析注射后第21d黑质内TH、GFAP蛋白表达量,蛋白条带用图像处理仪扫描,LabWorks软件分析处理。结果显示:动物在注射GDNF后第21d,行为学功能出现显著性恢复;TH阳性神经元数量显著增加;在检测的各时间点均可观察到大量的GFAP阳性细胞;TH、GFAP的蛋白表达量显著高于对照组。以上结果提示,黑质内注射GDNF可能通过激活了的星形胶质细胞保护PD模型大鼠黑质DA能神经元。     

Degeneration of pre-labelled nigral neurons induced by intrastriatal 6-hydroxydopamine in the rat: behavioural and biochemical changes and pretreatment with the calcium-entry blocker nimodipine

Intrastriatal application of 6-hydroxydopamine (6-OHDA) initiates a delayed and progressive loss of nigral dopaminergic neurons and therefore may better resemble the slowly developing neuropathology of Parkinson’s disease. We investigated the anatomical, behavioural and biochemical consequences of intrastriatal 6-OHDA after prior labelling of nigral dopaminergic neurons in rats and whether the dihydropyridine L-type calcium channel blocker nimodipine protected from the induced deficits. Adult rats received bilateral intrastriatal injections of the retrograde fluorescence tracer fluorogold and nimodipine (n=12) or placebo (n=9) pellets implanted subcutaneously. One week later all rats were injected unilaterally with 6-OHDA (20 μg) at the same intrastriatal site. Placebo-treated rats displayed relatively few d-amphetamine-induced ipsilateral net rotations (R) (1.3±1.4 R/min; mean±SEM) 1 week after the lesion with a slight but non-significant decline thereafter (after 2, 3 and 4 weeks). In nimodipine-treated rats the rotation behaviour after 1 week was more prominent (3.5±0.8 R/min; mean±SEM) with a similar slight decline until week 4. Fluorescent and immunocytochemical analysis of the midbrain after 4 weeks revealed a 35% and 39% loss of tyrosine hydroxylase positive cells and a 62% and 56% (placebo and nimodipine, respectively) loss of fluorogold-labelled cells in the ipsilateral substantia nigra pars compacta. Striatal dopamine levels were reduced to 47% (placebo) and 43% (nimodipine) of the control side and the dopamine metabolites dihydroxyphenylacetic acid and homovanillic acid to about 50%. Pretreatment with nimodipine failed to antagonize or to ameliorate any of the lesion-induced deficits. We conclude that pretreatment with 80 mg nimodipine pellets does not prevent nigrostriatal damage induced by intrastriatal 6-OHDA. Received: 5 August 1996 / Accepted: 20 March 1997     

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.     

Neuroprotection induced by the adenosine A<Subscript>2A</Subscript> antagonist CSC in the 6-OHDA rat model of parkinsonism: effect on the activity of striatal output pathways

In Parkinsons disease (PD), the striatal dopamine depletion and the following overactivation of the indirect pathway of the basal ganglia leads to very early disinhibition of the subthalamic nucleus (STN) that may contribute to the progression of PD by glutamatergic overstimulation of the dopaminergic neurons in the substantia nigra. Adenosine A_2A antagonism has been demonstrated to attenuate the overactivity of the striatopallidal pathway. To investigate whether neuroprotection exerted by the A_2A antagonist 8-(3-chlorostyryl)caffeine (CSC) correlates with a diminution of the striatopallidal pathway activity, we have examined the changes in the mRNA encoding for enkephalin, dynorphin, and adenosine A_2A receptors by in situ hybridization induced by subacute systemic pretreatment with CSC in rats with striatal 6-hydroxydopamine(6-OHDA) administration. Animals received CSC for 7 days until 30 min before 6-OHDA intrastriatal administration. Vehicle-treated group received a solution of dimethyl sulfoxide. CSC pretreatment partially attenuated the decrease in nigral tyrosine hydroxylase immunoreactivity induced by 6-OHDA, whereas no modification of the increase in preproenkephalin mRNA expression in the dorsolateral striatum was observed. The neuroprotective effect of the adenosine A_2A antagonist CSC in striatal 6-OHDA-lesioned rats does not result from a normalization of the increase in striatal PPE mRNA expression in the DL striatum, suggesting that other different mechanisms may be involved.     

雌激素对去卵巢Parkinson病模型大鼠黑质-纹状体系统多巴胺能神经元的影响

本研究的目的是观察雌激素对多巴胺(DA)能神经元是否具有保护作用。去卵巢(OVX)大鼠分别给予生理盐水(NS)和苯甲酸雌二醇(EB)处理,1周后6OHDA造模,造模2周后灌注取材;利用免疫组化法观察黑质内DA阳性神经元的数量、纹状体中DA能末梢的变化;用TUNEL法观察黑质凋亡细胞的数目并对纹状体中胆碱能神经元进行乙酰胆碱酯酶(AChE)染色,观察其退变情况。结果显示和NS组相比,EB组黑质内DA能神经元数量多、凋亡细胞数少(P<0.05);NS组纹状体内DA能神经元末梢减少60%左右,胆碱能神经元退变明显。结果提示雌激素对DA能神经元具有保护作用,在很大程度上可能与抑制神经元凋亡有关。     

Sonic Hedgehog蛋白在帕金森病模型大鼠黑质中的表达

目的检测Sonic Hedgehog蛋白(Shh)在帕金森病(Parkinson's disease,PD)大鼠中脑黑质的表达。方法将健康SD大鼠(雌雄不拘)随机分成3组:正常组大鼠不实施任何处理;应用脑立体定位技术,在大鼠右侧纹状体两针道内4点定位注射含0.2g/L抗坏血酸的生理盐水4μL(假手术组)或6-羟基多巴(6-OHDA)12μg/4μL(模型组)。术后1、2、4、6周以阿朴吗啡检测其异常旋转行为,左侧旋转的圈数大于7r/min者为合格的帕金森病模型大鼠。6周后在激光共聚焦显微镜下观察黑质Shh及酪氨酸羟化酶(TH)的免疫荧光双重染色结果,用Leica Confocal Software对Shh的荧光强度进行定量分析。结果Shh蛋白在正常对照组和假手术组大鼠中脑黑质中无明显表达,而在模型组表达显著。结论PD模型大鼠黑质中Shh蛋白的明显表达,提示Shh在PD模型大鼠中脑多巴胺能神经元(DA神经元)修复过程中可能发挥着一定的作用。     

Nerve growth factor increases survival of dopaminergic graft, rescue nigral dopaminergic neurons and restores functional deficits in rat model of Parkinson's disease

In the present study, an attempt has been made to explore the neuroprotective and neurorescue effects of nerve growth factor (NGF) on grafted cells and on host nigral dopaminergic neurons, respectively. NGF was co-transplanted with fetal ventral mesencephalic cells (VMC) in the striatum of 6-hydroxydopamine (6-OHDA) lesioned rat model of Parkinson's disease (PD). In the other groups fetal VMC and NGF were transplanted alone. Twelve weeks post-transplantation, a significant restoration was observed in D-amphetamine induced rotations (stereotypy), spontaneous locomotor activity, striatal and nigral dopamine (DA) and 3,4-dihydroxy-phenyl acetic acid (DOPAC) levels in co-transplanted rats as compared to VMC alone transplanted rats. Higher number of surviving tyrosine hydroxylase immunoreactive (TH-ir) neurons and significantly increased fiber outgrowth from graft was evident in co-transplanted rats as compared to VMC alone transplanted rats. Further, a significant increase was also observed in substantia nigra TH-ir neurons count in co-transplanted rats, exhibiting a potential neuroprotective and neurorescue effects of NGF on nigrostriatal dopaminergic neurons. The results suggest that NGF at the time of transplantation exhibits neuroprotective effect on transplanted VMC as well as neurorescue effect on remaining host nigral dopaminergic neurons, leading to better functional restoration.     

Postmenopausal effects of intrastriatal estrogen on catalepsy and pallidal electroencephalogram in an animal model of Parkinson's disease

The main objective was to test the preventive and treatment effects of central injection of estrogen (ES) on muscular rigidity and pallidal EEG in menopausal rats' model of Parkinson's disease (PD). We hypothesized that intrastriatal pretreatment and post-lesion treatment by estrogen improve the pallidal local EEG and muscular stiffness in animal model of menopause with PD. Forty-eight female Wistar rats (300-350 g) were ovariectomized (OVX) and divided into two main groups: Non-pretreated subgroups; sham (S), lesioned (L), post-lesion treated (LT) and pretreated subgroups; pretreated (Pt), pretreated and then lesioned (PtL), pretreated and post-lesion treated (PtLT). Pallidal local EEG was recorded by a bipolar recording electrode and muscle stiffness was scored by Dekundy's test in freely moving rats. Muscle stiffness and pallidal local EEG were indicated as main outcome measures. In pretreated group the local pallidal EEG was decreased in sham-operated rats compared with non-pretreated group (P<0.01), and SNc lesioning decreased EEG in the non-pretreated (P<0.01), while it increased the EEG in the pretreated group (P<0.01). In both groups administration of ES restore the EEG to the respective sham-operated group (P<0.01). Regarding muscle stiffness, it increased after SNc lesioning in both pretreated and non-pretreated groups and ES administration decreased the rigidity significantly (P<0.05, P<0.001 respectively). However, the lesion-induced rigidity in pretreated groups was significantly less than non-pretreated groups (P<0.05). Because of its modulatory effect estrogen may protect dopaminergic neurons from injury and may interfere with the uptake of 6-hydroxydopamine (6-OHDA) into the nigral dopaminergic neurons or alter dopamine release and uptake in remaining neurons.     

Might deep brain stimulation of the subthalamic nucleus be neuroprotective in patients with Parkinson’s disease?

Parkinson’s disease (PD) is characterized by nigral degeneration of dopaminergic neurons in the pars compacta of the substantia nigra. Rather than treating only the symptomatic aspects of Parkinson’s disease, one may also consider treatments designed to retard, arrest, or even reverse this degenerative process. Such strategies could include preventive or restorative treatments instead of purely palliative treatments. A recent hypothesis states that glutamate output from the subthalamic nucleus (STN) to the substantia nigra contributes to the neurotoxic process underlying dopaminergic cell death in Parkinson’s disease. Furthermore, high-frequency stimulation (HFS) of the STN inhibits neurons resulting in the suppression of their glutamate output. Experiments in both rats and monkeys provide preliminary data supporting this hypothesis. Kainic acid (KA) lesions of the STN prevent the loss of dopaminergic neurons in the substantia nigra after intrastriatal injection of 6-hydroxydopamine (6-OHDA) in rats, and after systemic administration of MPTP in monkeys. In PD patients, the background level of their disease is evaluated in the off medication/off stimulation state (UPDRS III score), over a period of 5 years. Thirty percent of the patients are stabilized and 18% have persistent improvement of their disease-related impairment. Further experiments are needed, including controlled clinical trials utilizing functional imaging of the dopamine transporters and post-synaptic receptors.     

益精养血方对帕金森病大鼠多巴胺能神经元Bcl-2及caspase-3表达的影响

为了观察益精养血方对帕金森病(Parkinson’sdisease,PD)大鼠多巴胺能神经元Bcl-2及caspase-3表达的影响,本研究采用6-羟多巴胺注入右侧黑质制备的PD模型大鼠,实验分为模型组、实验(益精养血方)组和正常组。正常组和模型组大鼠用生理盐水灌胃,实验组大鼠用益精养血方灌胃,各30d。灌胃结束两周后进行旋转行为学检测,并用免疫荧光组织化学方法观察黑质酪氨酸羟化酶(TH)阳性神经元及神经纤维的变化,用免疫组织化学方法观测黑质神经元Bcl-2、caspase-3的表达。结果显示:(1)实验组大鼠的旋转圈数比治疗前明显减少(P<0.05);(2)实验组损毁侧与健侧黑质TH阳性神经元数量百分比和网状部TH阳性纤维面积百分比较模型组显著提高(P<0.05);(3)实验组损毁侧黑质神经元caspase-3表达的OD值比模型组显著降低(P<0.05),而Bcl-2的表达与caspase-3相反。以上结果提示益精养血方可使帕金森病大鼠黑质内多巴胺能神经元Bcl-2的表达升高,caspase-3的表达降低,进而明显抑制神经细胞的凋亡。     

Effects of orally administered levodopa on mesencephalic dopaminergic neurons undergoing a degenerative process

Although the issue of in vivo levodopa toxicity appears to be settled by now in the light of recent findings, a crucial aspect was not accounted for the experiments designed to tackle that question. Levodopa could in fact be non-toxic on surviving dopamine neurons, but that could not be the case when the drug is administered at the same time those neurons are undergoing degeneration, which is what happens in the clinical setting. Dopaminergic neurons could in that situation be more vulnerable to levodopa's potential toxic action. Our aim was to determine if oral administration of levodopa is toxic for mesencephalic dopaminergic neurons that are actively involved in a degenerative process. We induced delayed retrograde degeneration of the nigrostriatal system in rats by injecting 6-hydroxydopamine (6-OHDA) intrastriatally. Treatment was started the day after the injection. Dopaminergic markers were histologically studied at the striatal and nigral levels, to determine degree of damage of the nigrostriatal dopaminergic system in levodopa- and vehicle-treated rats. No significant differences between levodopa or vehicle-treated rats were found in: (i) striatal immunoautoradiographic labeling for tyrosine hydroxylase (TH) and the membrane dopamine transporter (DAT); (ii) cell counts of TH-immunoreactive (TH-ir) neurons remaining in the substantia nigra and ventral tegmental area (VTA); (iii) surface area of remaining TH-immunoreactive neurons in the substantia nigra. The present experiments demonstrate that levodopa does not enhance delayed retrograde degeneration of dopaminergic neurons induced by intrastriatal administration of 6-OHDA.     

Emotional, cognitive and neurochemical alterations in a premotor stage model of Parkinson's disease

In addition to classic motor symptoms, Parkinson's disease (PD) is characterized by cognitive and emotional deficits, which have been demonstrated to precede motor impairments. The present study addresses the question of whether a partial degeneration of dopaminergic neurons using 6-hydroxydopamine (6-OHDA) in rats is able to induce premotor behavioral signs. The time-course of nigrostriatal damage was evaluated by tyrosine hydroxylase immunohistochemistry and the levels of dopamine, noradrenaline, and 5-HT in various brain regions were analyzed by high performance liquid chromatography (HPLC). Behavioral tests that assessed a variety of psychological functions, including locomotor activity, emotional reactivity and depression, anxiety and memory were conducted on 6-OHDA lesioned rats. Bilateral infusion of 6-OHDA in the striatum of rats caused early (1 week) damage of dopaminergic terminals in striatum and in cell bodies in substantia nigra pars compacta. The nigrostriatal lesion was accompanied by early loss of dopamine in the striatum, which remained stable through a 3-week period of observation. In addition, a late (3 weeks) loss of dopamine in the prefrontal cortex, but not in the hippocampus, was seen. Additional noradrenergic and serotonergic alterations were observed after 6-OHDA administration. The results indicated that 6-OHDA lesioned rats show decreased sucrose consumption and an increased immobility time in the forced swimming test, an anhedonic-depressive-like effect. In addition, an anxiogenic-like activity in the elevated plus maze test and cognitive impairments were observed on the cued version of the Morris water maze and social recognition tests. These findings suggest that partial striatal dopaminergic degeneration and parallel dopaminergic, noradrenergic and serotonergic alterations in striatum and prefrontal cortex may have caused the emotional and cognitive deficits observed in this rat model of early phase PD.     

The flavanoide caffeic acid phenethyl ester blocks 6-hydroxydopamine-induced neurotoxicity

Parkinson's disease (PD) is a neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons of the substantia nigra pars compacta. 6-Hydroxydopamine (6-OHDA) is specific to dopaminergic neurons in intrastriatal rodent models. It induces neuronal death either via uncoupling mitochondrial oxidative phosphorylation resulting in energy deprivation or alternatively, is associated with its ability to produce hydrogen peroxide, hydroxyl and superoxide radicals. Caffeic acid phenethyl ester (CAPE), an antioxidant flavanoid, has antiviral, anti-inflammatory, antioxidant, and immunomodulatory properties. Recent studies have shown that CAPE has also a neuroprotective effects in ischemia and low potassium-induced neuronal apoptotic models. In cerebellar granule neurons CAPE significantly blocks 6-OHDA mediated cell death (70 microM) in a dose-dependent manner. Furthermore, CAPE was able to modulate the Ca(2+)-induced release of cyctochrome c in isolated liver mitochondria. Caspase-3 activation following 6-OHDA treatment was markedly inhibited in the presence of CAPE. Although the molecular mechanisms associated with CAPE's neuroprotective effects remain to be elucidated in more detail, our results clearly demonstrate a considerable neuroprotective effect of CAPE. Since a mitochondrial insult is a major cause for the degeneration of nigral neurons in PD, we hypothesize that propolis derivatives, in particular CAPE, may have a neuroprotective effect on those cells and may be a promising drug candidate to be taken into in vivo models of PD.     

The effects of intranigral injections of picrotoxin and carbachol in cats with a lesioned nigrostriatal pathway.

Picrotoxin, carbachol and atropine were injected intranigrally through chronically implanted crannulae in cats. The drug-induced behavioural syndromes, mainly asymmetric behaviour, were analyzed. The changes in these syndromes after 6-hydroxydopamine (6-OHDA) lesion of the substantia nigra (SN) indicate that, in addition to the dopaminergic (DA), a non-catecholaminergic (non-CA) nigral output exists, both being responsible for asymmetric behaviour. It is further suggested that gamma-aminobutyric acid (GABA) receptors are present on both dopaminergic and non-CA nigral output neurons, while acetylcholine (ACh) receptors, responsible for asymmetric behaviour, are almost exclusively located on non-CA nigral output neurons.     

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。     

6-OHDA所致PD大鼠模型黑质多巴胺能神经元与胶质细胞的变化

目的 应用6-羟多巴(6.OHDA)建立帕金森病(PD)大鼠模型。方法将6-OHDA立体注入大鼠前脑内侧束,应用免疫组织化学法检测6-OHDA注射后第3、7及14天后多巴胺能神经元、小胶质细胞与星形胶质细胞数量及形态的变化。用显微镜专业摄像头采集图像,计算机图像分析软件测量平均灰度值。结果 损伤侧与对侧相比,TH阳性多巴胺能神经元数量减少,损伤侧平均灰度值增加;小胶质细胞与星形胶质细胞显著增生,二者损伤侧的平均灰度值下降,经配对t检验,各组内比较差异均具有显著性意义(P<0.01);增生活化的小胶质细胞与星形胶质细胞形态发生明显的改变。结论 6-OHDA能成功建立PD大鼠模型。     

阿扑吗啡对6-羟基多巴胺毁损纹状体鼠的神经保护和神经营养作用

目的在6-羟基多巴胺毁损纹状体鼠模型上,探讨阿扑吗啡的神经保护和神经营养作用。方法用6-羟基多巴胺毁损大鼠单侧纹状体,在毁损前15 m in注射阿扑吗啡(10 mg/kg,s.c.),连续注射11 d。毁损2周后,分别进行行为学(苯丙胺引起的旋转数目)、组织学(黑质和腹侧被盖区的酪氨酸羟化酶阳性细胞计数)的观察。结果阿扑吗啡降低苯丙胺引起的向损伤侧旋转的次数,显著降低黑质神经元的损伤(从50%降至30%)。且多巴胺细胞形状可恢复到类似正常组;阿扑吗啡对正常鼠黑质细胞数无影响,但可使腹侧被盖区细胞数显著增高37%。结论阿扑吗啡对6-羟基多巴胺毁损纹状体模型鼠的黑质和腹侧被盖区神经细胞具有显著的保护作用,且改善运动功能。同时,对正常鼠的腹侧被盖区也显示神经营养作用。     

Kainic acid lesion-induced nigral neuronal death

Parkinson's disease (PD) is characterized by progressive death of dopamine (DA) neurons in the substantia nigra pars compacta. We report a rat model that exhibits progressive death of nigral neurons following unilateral injection of kainic acid in the striatum. In situ end-labeling revealed significant numbers of dying nigral neurons ipsilateral to the lesion during the first 3 weeks following injection. An indication of the gradual nature of death was that similar small numbers of cells were detected at each time point. These early morphological markers of neuronal death led to a significant reduction (20%) at 5 months of tyrosine hydroxylase-positive neurons and total number of neurons in the ipsilateral substantia nigra compared with the contralateral control. To examine the role of nigrostriatal DA metabolism in the observed nigral neuronal death, we manipulated DA metabolism during the initial 2 weeks following kainic acid lesion. Neurons in the ventral tier of the substantia nigra pars compacta were protected from death by treatment with 2,4-diamino-6-hydroxy-pyrimidine (DAHP), an inhibitor of GTP cyclohydrolase, the initial enzyme in the synthesis of the tyrosine hydroxylase co-substrate, tetrahydrobiopterin (BH(4)). Neurons in both the dorsal and ventral tier of substantia nigra pars compacta were protected from death by treatment with DAHP and L-DOPA. These experiments suggest that intrastriatal kainic acid lesion is an in vivo model of trophic support withdrawal. This experimental procedure is useful for studying mechanisms underlying protracted death of nigral DA neurons and may provide valuable mechanistic information relevant to understanding the etiology of PD.     

Bromodeoxyuridine and methylazoxymethanol exposure during brain development affects behavior in rats: consideration for a role of nerve growth factor and brain derived neurotrophic factor

Extensive unilateral striatal deafferentation was produced by intranigral 6-hydroxydopamine (6-OHDA) in rats. Beginning 60 days after 6-OHDA injection animals received a 14-day course of treatment with either the small molecule FKBP ligand GPI 1046 (10 mg/kg) or its vehicle alone. Striatal dopaminergic innervation density was determined from high power image analysis of striatal tyrosine hydroxylase (TH) immunohistochemistry. GPI 1046 treatment did not alter TH fiber density in the contralateral striatum but did produce significantly higher striatal TH fiber density in the ipsilateral caudate-putamen. This striatal re-innervation occurred in the absence of increased nigral sparing, and appears to reflect the GPI 1046 induced sprouting of residual TH+ fibers spared by the 6-OHDA lesion.