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1.
人胚神经干细胞定向诱导分化为多巴胺能神经元的实验研究   总被引:17,自引:3,他引:14  
目的 建立神经干细胞与骨髓基质细胞的共培养系统,根据该系统的条件性培养液诱导多巴胺能神经元的分化。方法 来源于胎脑海马、纹状体、额叶、中脑的神经干细胞与骨髓基质细胞建立起各自的共培养系统,并根据数种条件性培养液诱导神经干细胞的分化,以免疫细胞化学检测神经元的总体分化率及多巴胺能神经元的诱导率。结果 骨髓基质细胞及CO-BMSC能显著提高不同来源的神经干细胞的神经元分化率,同时只有中脑神经干细胞能被有效地进行多巴胺能神经元的诱导。结论 共培养系统诱发了神经干细胞与骨髓基质细胞的自/旁分泌作用,该作用可根据神经干细胞的区域特异性有效的定向诱导中脑神经干细胞的分化。  相似文献
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GM1 enhances dopaminergic markers in the brain of aged rats   总被引:13,自引:0,他引:13  
A number of presynaptic markers are compromised in the dopaminergic neurons of aged Sprague-Dawley rats (22 months old) compared with young rats (3 months old). Indeed, in the striatum of the aged rats there is a diminished capacity to transport dopamine (DA), to bind the dopamine transporter (DAT) marker mazindol, to bind the vesicular monoamine transporter 2 (VMAT2) marker dihydrotetrabenazine, and to release DA under basal conditions or after induction by K(+) or amphetamine. Furthermore, the expression of DAT and VMAT2 mRNA in the midbrain is suppressed. GM1 ganglioside, 30 mg/kg ip daily, administered for 30 days, restores the afore-mentioned markers to values approaching those for young rats. Taken together with our published observations that GM1 partially restores tyrosine hydroxylase activity and DA metabolism in aged nigrostriatal and mesoaccumbal neurons and improves their morphology, our work suggests that GM1 might act as a dopaminergic neurotrophic factor in the aged brain and be a useful adjuvant for treating age-associated dopaminergic deficits.  相似文献
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Extracts from dopamine (DA)-depleted striatal tissue (lesion extract) and from intact striatal tissue (intact extract) were prepared, and trophic activities in these extracts were evaluated using survival and neurite extension of DAergic neurons as indices. Levels of brain-derived neurotrophic factor (BDNF), basic fibroblast growth factor (bFGF), glial cell-line derived neurotrophic factor (GDNF) and neurotrophin-3 (NT-3) in extracts were measured using enzyme-linked immunosorbent assay (ELISA). The lesion extract exhibited a stronger trophic activity on survival and neurite extension of DAergic neurons than intact extract. In lesion extract, bFGF was slightly and GDNF was significantly increased, while BDNF and NT-3 were the same level in each extract. The peak increase of bFGF and GDNF was during 2 to 3 weeks after DA depletion. Trophic activity of extract was strongly attenuated after immunoprecipitation of GDNF and partly attenuated after immunoprecipitation of bFGF. In parallel immunohistological study, no significant variations were found for striatal microtubule-associated protein-2 (MAP-2)- nor OX-41-immunoreactive cells, while the number of strongly labeled glial fibrillary acidic protein (GFAP)-immunoreactive cells were increased in DA-depleted striatum, suggesting reactive gliosis. Data suggest that bFGF is a minor, while GDNF is a major component of trophic activity for DAergic neurons in DA-depleted striatum, and increased bFGF and GDNF levels may be mediated partly by reactive gliosis.  相似文献
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Nicotinic acetylcholine receptors (nAChRs) are expressed in the midbrain ascending dopaminergic system, a target of many addictive drugs. Here we assessed the intracellular Ca2+ level by imaging fura-2-loaded cells in substantia nigra pars compacta in mouse brain slices, and we examined the influence on this level of prolonged exposures to nicotine using mice lacking the nAChR beta2-subunit. In control cells, superfusion with nicotine (10-100 microM) caused a long-lasting rise of intracellular Ca2+ level which depended on extracellular Ca2+. This nicotinic response was almost completely absent in beta2-/- mutant mice, leaving a small residual response to a high concentration (100 microM) of nicotine which was inhibited by the alpha7-subunit-selective antagonist, methyllycaconitine. Conversely, the alpha7-subunit-selective agonist choline (10 mM) caused a methyllycaconitine-sensitive increase in intracellular Ca2+ level both in wild-type and beta2-/- mutant mice. Nicotine-elicited Ca2+ mobilization was reduced by the Na+ channel blocker tetrodotoxin (TTX) and by T-type Ca2+ channel blocking agents, whereas the choline-elicited Ca2+ increase was insensitive to TTX. Neither nicotine nor choline produced Ca2+ increase following inhibition of the release of Ca2+ from intracellular stores by dantrolene. These results demonstrate that in nigral dopaminergic neurons, nicotine can elicit Ca2+ mobilization via activation of two distinct nAChR subtypes: that of beta2-subunit-containing nAChR followed by activation of Na+ channel and T-type Ca2+ channels, and/or activation of alpha7-subunit-containing nAChR. The Ca2+ influx due to nAChR activation is subsequently amplified by the recruitment of intracellular Ca2+ stores. This Ca2+ mobilization may possibly contribute to the long-term effects of nicotine on the dopaminergic system.  相似文献
6.
Simultaneous electrical and chemical recordings have been made of dopamine neuronal activity in the rat brain during electrical stimulation of the medial forebrain bundle. Tungsten recording electrodes were placed at the level of the substantia nigra and carbon-fiber, Nafion-coated, voltammetric electrodes were placed in the neostriatum. Dopamine units, verified by histology to be in the zona compacta of the substantia nigra, were identified by previously established electrophysiological criteria. Dopamine release was detected by fast-scan cyclic voltammetry, a technique which allows dopamine to be determined in vivo on a sub-second time scale. The majority of dopamine cells examined (7 out of 10) were antidromically activated by 60 Hz stimulation of the medial forebrain bundle. The same stimulus also elicits dopamine overflow in the caudate nucleus. Following stimulation, dopamine concentrations in the extracellular fluid of the neostriatum rapidly declined to prestimulus levels. In addition, impulse flow in dopaminergic neurons was inhibited for 20 s following stimulation. These measurements represent the first direct observation from a neuronal tract of simultaneous unit activity and chemical release of a neurotransmitter in real time.  相似文献
7.
Prior studies suggest that prolactin (PRL) stimulates release of dopamine (DA) from tuberoinfundibular dopaminergic (TIDA) neurons. In the present study, the time course over which PRL exerts its effects on all three populations of neuroendocrine dopaminergic (DAergic) neuron populations [TIDA, tuberohypophyseal (THDA) and periventricular-hypophyseal (PHDA)] was determined. Ten days following ovariectomy (OVX), groups of female rats were injected either with 15 microg of ovine PRL (oPRL) or saline at 0900 h. Rats were decapitated every 30 min from 0830 h-1100 h and hourly from 1200 h-1500 h. Trunk blood was assayed for rat PRL (rPRL) and oPRL using species-specific radioimmunoassays (RIAs). The concentration of DA and 3,4-dihydroxyphenylacetic acid (DOPAC) in the median eminence (ME), as well as the anterior (AL), intermediate (IL) and neural (NL) lobes of the pituitary gland were determined by HPLC-EC. The concentration of rPRL in oPRL-treated animals, compared to saline-treated animals, was diminished by 1000 h and again between 1200 h-1500 h. DOPAC/DA ratio, an indicator of dopaminergic neuronal activity, increased spontaneously in the ME, IL, and NL during the afternoon in OVX rats. In animals injected with oPRL at 0900 h, the DOPAC/DA ratio increased in the ME, IL and NL within 1 h. Moreover, a secondary increase in the DOPAC/DA ratio in the IL and NL occurred during the afternoon in oPRL-treated rats. However, the second increase of DA turnover present in the ME of control animals never occurred in oPRL-treated animals. Furthermore, there were two increases in the concentration of DA in the AL: the first coincided with the increased turnover of DA in all three terminal areas and the second with increased DA turnover in the IL and NL. These data suggest that all three populations of hypothalamic neuroendocrine DAergic neurons are activated by PRL and that PHDA/THDA neurons have a second 'delayed' activation.  相似文献
8.
We have generated embryonic stem (ES) cells and transgenic mice with green fluorescent protein (GFP) inserted into the Pitx3 locus via homologous recombination. In the central nervous system, Pitx3-directed GFP was visualized in dopaminergic (DA) neurons in the substantia nigra and ventral tegmental area. Live primary DA neurons can be isolated by fluorescence-activated cell sorting from these transgenic mouse embryos. In culture, Pitx3-GFP is coexpressed in a proportion of ES-derived DA neurons. Furthermore, ES cell-derived Pitx3-GFP expressing DA neurons responded to neurotrophic factors and were sensitive to DA-specific neurotoxin N-4-methyl-1, 2, 3, 6-tetrahydropyridine. We anticipate that the Pitx3-GFP ES cells could be used as a powerful model system for functional identification of molecules governing mDA neuron differentiation and for preclinical research including pharmaceutical drug screening and transplantation. The Pitx3 knock-in mice, on the other hand, could be used for purifying primary neurons for molecular studies associated with the midbrain-specific DA phenotype at a level not previously feasible. These mice would also provide a useful tool to study DA fate determination from embryo- or adult-derived neural stem cells.  相似文献
9.
Primary astrocytes were genetically modified ex vivo to express recombinant glial cell line-derived neurotrophic factor (GDNF) and subsequently were tested for their ability to provide neuroprotection to dopaminergic neurons in a 6-hydroxydopamine (6-OHDA) mouse model of Parkinson's disease. A replication-defective retrovirus was constructed, which contained the rat GDNF sequence and a sequence encoding a beta-galactosidase (beta-gal)/neomycin phosphotransferase fusion protein, linked via an internal ribosomal entry site. Murine astrocytes transduced with this vector secreted GDNF into the culture media at the rate of 115 +/- 34 pg/24 h/10(5) cells and expressed cytoplasmic beta-gal, whereas control nontransduced astrocytes were negative for GDNF production and cytoplasmic beta-gal expression. Mice that received implants of GDNF-producing astrocytes into the striatum or nigra displayed elevated levels of GDNF compared to mice that received control nontransduced astrocytes. In addition, tissue content of GDNF was increased bilaterally and in brain regions both proximal and distal to the graft, even though astrocyte migration away from the graft site did not occur. Importantly, GDNF-producing astrocytes provided marked neuroprotection of nigral dopaminergic perikarya, and partial protection of striatal dopaminergic fibers, when implanted into the midbrain 6 days prior to a retrograde 6-OHDA lesion, as assessed by tyrosine hydroxylase immunohistochemistry. Similarly, GDNF-producing astrocytes prevented the acquisition of amphetamine-induced rotational behavior in 6-OHDA-treated mice and completely prevented dopamine depletion within the substantia nigra, as assessed by high-performance liquid chromatography. These results indicate that continuous exposure to low levels of GDNF provided by transgenic astrocytes provides marked neuroprotection of nigral dopaminergic neurons. (c)2002 Elsevier Science (USA).  相似文献
10.
帕金森病与细胞凋亡的新进展   总被引:6,自引:0,他引:6  
帕金森病的病因和发病机理尚不十分清楚。最近的研究表明细胞凋亡可能在帕金森病的黑质多巴胺能神经元死亡中起重要作用,本综述了近年的研究进展。  相似文献
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