Neurochemical correlates of sparing from motor deficits in rats depleted of striatal dopamine as weanlings

The behavioral and neurochemical effects of striatal DA depletions were investigated in rats lesioned as weanlings (Day 27) or as adults (250-300 g). Administration of 6-OHDA into the medial forebrain bundle resulted in comparably large (> or = 95%) depletions of tissue levels of DA in both age groups. As expected, rats depleted of DA as adults exhibited marked deficits in motoric behavior and body weight regulation that persisted for the 8 days of postsurgical observation. In contrast, rats depleted of DA as weanlings were spared from such deficits, and their behavior closely resembled that of age-matched controls. Microdialysis studies revealed dialysate levels of striatal DA that paralleled these age-dependent behavioral differences. At a time when age-related behavioral differences were still quite pronounced (5-6 days postsurgery), basal DA levels were reduced by 80% of control values in rats lesioned as adults whereas basal DA levels in rats lesioned as weanlings were unchanged relative to their controls. Finally, adults depleted of striatal DA as weanlings were no more sensitive to the movement-impairing effects of intrastriatal sulpiride (3.0 or 10.0 micrograms/hemisphere) infusions than were control rats. These data suggest that weanlings compensate for large, but incomplete, denervation of striatal DA with markedly enhanced release and turnover from residual terminals. This developmental plasticity may prevent the occurrence of behavioral deficits soon after the lesion and also the supersensitivity to the challenging effects of DA antagonists as animals grow into adulthood.     

损毁单侧黑质-纹状体通路的大鼠SVZ、纹状体和黑质神经前体细胞的变化

研究成年大鼠脑室下区 (SVZ)神经前体细胞 (neural precursors)在黑质 -纹状体通路损伤后的反应 ,本研究用 6-羟多巴胺单侧纹状体注射以损毁黑质 -纹状体通路 ,损毁 10 d后腹腔注射 Brd U ,连续 4d,每日两次 ;在 SVZ、纹状体和黑质部位用免疫组化方法检测 Brd U、nestin以及 GFAP阳性细胞。结果显示 :(1) 6-羟多巴胺损毁黑质 -纹状体通路后 ,伤侧 SVZ的 Brd U阳性细胞数明显增多 ,并成簇分布 ;nestin和 GFAP阳性细胞数也增多 ,但以 GF AP阳性细胞增多明显 ;(2 )伤侧纹状体可见大量 Br-d U、GFAP以及少量 nestin阳性细胞分布 ,而健侧只有少量 GFAP阳性细胞 ;(3 )伤侧可见 Brd U阳性细胞在 SVZ和纹状体之间呈条带样分布 ;(4 )伤侧黑质除酪氨酸羟化酶阳性神经元减少外 ,未见 Brd U、GFAP和 nestin阳性细胞表达。上述结果表明 ,6-羟多巴胺损毁黑质 -纹状体通路后 ,SVZ神经前体细胞活动增强 ,有向纹状体迁移的趋势。     

6-羟基多巴胺对帕金森病大鼠GDNF表达影响的实验研究

目的 :研究 6 -羟基多巴胺 (6 - OHDA)诱发的大鼠帕金森 (PD)模型 GNDF表达。方法 :通过脑内立体定向术注射 6 -羟基多巴胺建立大鼠 PD模型。采用免疫组化的方法观察损伤侧脑胶质细胞源性神经营养因子 (GDNF)表达。结果 :6 - OHDA诱发的 PD鼠 GDNF蛋白表达减低 (P <0 . 0 5 )。结论 :神经营养因子表达减少可能是 6 - OHDA诱发的 PD大鼠发病机制之一     

Eugenol and its association with levodopa in 6‐hydroxydopamine‐induced hemiparkinsonian rats: Behavioural and neurochemical alterations

Parkinson's disease is a neurodegenerative disorder that affects the central nervous system and is mainly characterized by the loss of dopaminergic neurons and pro‐oxidant mechanisms. Eugenol has been widely studied due to its anti‐inflammatory and antioxidant activities, making it a promising neuroprotective agent. This study aimed to investigate the effects of eugenol and its combined action with levodopa in the 6‐hydroxydopamine‐induced Parkinson's disease model. Wistar rats were subjected to intrastriatal injection of 6‐hydroxydopamine (21 μg) and then treated with eugenol (0.1, 1, or 10 mg/kg), levodopa (25 mg/kg) or their combination (eugenol 10 mg/kg + levodopa 12.5 mg/kg) orally for 14 days. On the 14th day, the animals were subjected to behavioural tests, and after euthanization and dissection of the brain areas, neurochemical analyses were performed. The results showed that eugenol reduced the oxidative stress and behavioural disturbances induced by 6‐hydroxydopamine. The eugenol and levodopa combination was more effective in some behavioural parameters and body‐weight gain in addition to promoting an increase in reduced glutathione levels compared to levodopa alone. Thus, the neuroprotective activity of eugenol was observed against motor and neurochemical disorders. Additionally, the eugenol and levodopa combination was promising when compared to conventional treatment.     

Doxycycline restrains glia and confers neuroprotection in a 6‐OHDA Parkinson model

Neuron–glia interactions play a key role in maintaining and regulating the central nervous system. Glial cells are implicated in the function of dopamine neurons and regulate their survival and resistance to injury. Parkinson's disease is characterized by the loss of dopamine neurons in the substantia nigra pars compacta, decreased striatal dopamine levels and consequent onset of extrapyramidal motor dysfunction. Parkinson's disease is a common chronic, neurodegenerative disorder with no effective protective treatment. In the 6‐OHDA mouse model of Parkinson's disease, doxycycline administered at a dose that both induces/represses conditional transgene expression in the tetracycline system, mitigates the loss of dopaminergic neurons in the substantia nigra compacta and nerve terminals in the striatum. This protective effect was associated with: (1) a reduction of microglia in normal mice as a result of doxycycline administration per se; (2) a decrease in the astrocyte and microglia response to the neurotoxin 6‐OHDA in the globus pallidus and substantia nigra compacta, and (3) the astrocyte reaction in the striatum. Our results suggest that doxycycline blocks 6‐OHDA neurotoxicity in vivo by inhibiting microglial and astrocyte expression. This action of doxycycline in nigrostriatal dopaminergic neuron protection is consistent with a role of glial cells in Parkinson's disease neurodegeneration. The neuroprotective effect of doxycycline may be useful in preventing or slowing the progression of Parkinson's disease and other neurodegenerative diseases linked to glia function.     

1,25-Dihydroxyvitamin D3 administration to 6-hydroxydopamine-lesioned rats increases glial cell line-derived neurotrophic factor and partially restores tyrosine hydroxylase expression in substantia nigra and striatum

It has previously been demonstrated that 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] administration, whether in cell cultures or in vivo to rats, increases glial cell line-derived neurotrophic factor (GDNF) expression levels, suggesting that this hormone may have beneficial effects in neurodegenerative disorders. This study was carried out to explore the effects of 1,25(OH)(2)D(3) administration in a 6-OHDA-lesioned rat model of Parkinson's disease on GDNF and tyrosine hydroxylase (TH) expression in substantia nigra (SN) and striatum. Two groups of animals received 1,25(OH)(2)D(3) intraperitoneally, the first group 7 days before the unilateral injection of 6-OHDA into the medial forebrain bundle (MFB) and the second group 21 days (days 21-28) after the unilateral injection of 6-OHDA. Animals of both groups were sacrificed on day 28. In addition, two other groups received a unilateral injection of either saline or 6-OHDA into the MFB. Rats were killed, and the SN and striatum were then removed for GDNF and TH determination. Striatal GDNF protein expression was increased on the ipsilateral with respect to the contralateral side after 6-OHDA injection alone as well as in 1,25(OH)(2)D(3)-treated rats before or after 6-OHDA administration. As expected, 6-OHDA injection induced an ipsilateral decrease in TH-immunopositive neuronal cell bodies and axonal terminals in the SN and striatum. However, treatment with 1,25(OH)(2)D(3) before and after 6-OHDA injection partially restored TH expression in SN. These data suggest that 1,25(OH)(2)D(3) may help to prevent dopaminergic neuron damage.     

Alterations in dendritic morphology of the prefrontal cortical and striatum neurons in the unilateral 6-OHDA-rat model of Parkinson's disease

We have studied the morphological changes of the dendrites of the pyramidal neurons of the prefrontal cortex (PFC) and the medium spiny neurons of the caudate-putamen (CPu) and nucleus accumbens (NAcc) induced by the injection of 6-hydroxydopamine (6-OHDA) into the substantia nigra pars compacta (SNc). The unilateral 6-OHDA-induced lesion of the SNc was made in Wistar rats to produce the Parkinson model lesion. Two weeks after the injection, the testing of rotational behavior caused by amphetamine injection was done to assess the animals with lesions. Four weeks after the 6-OHDA injection, the morphology of the pyramidal cells of Layer 5 of the PFC and the medium spiny neurons of the CPu and NAcc were quantified by modified Golgi-Cox staining. The results showed that the length of dendrites, the branching, and the density of dendritic spines on the medium spiny neurons of the same side of the caudate-putamen lesion were significantly decreased in rats with the unilateral 6-OHDA-induced lesion of the SNc. The pyramidal neurons of the PFC and medium spiny neurons of the NAcc showed a decrease in the density of dendritic spines without significant changes in dendritic length or arborization. Our data suggest that the SNc lesion with the 6-OHDA, Hemiparkinsonism animal model may lead to altered neuronal plasticity in the CPu, NAcc, and PFC that may have participated in the emergence of the behavioral changes observed in these animals.     

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。