Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Rats with unilateral 6-hydroxydopamine lesions (6-OHDA) of the mesencephalon and vehicle controls (SHAM) were chronically treated with carbidopa (CD) or CD plus levodopa (CD/LD) for 18 days. Seventy-two hours following the last treatment, ipsilateral striata, contralateral striata, and cerebellums from each treatment group were homogenized separately and the supernatant extracts were incubated with rostral mesencephalic tegmentum cultures. As indices of growth-promoting activity (GPA), number of viable neurons and their process lengths were measured 40 h later. In all cultures exposed to striatal extracts, the 6-OHDA lesion was associated with greater GPA than the SHAM extracts. CD/LD consumption reduced this GPA in a dose-dependent fashion in both the lesioned and the SHAM animals. These data suggest that denervation of the striatum enhances the production of a striatally derived neurotrophic factor, the production of which is sensitive to levodopa. Chronic levodopa treatment in Parkinson's disease may therefore contribute to disease progression by reducing the compensating effects of this neurotrophic factor on remaining mesencephalic neurons.
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PMID:Levodopa reduces the growth promoting effects of striatal extracts on rostral mesencephalic tegmentum cultures. 191 32

A recently cloned neurotrophic factor, Glial Cell Line-Derived Neurotrophic Factor (GDNF), has been implicated in the survival and morphological and functional differentiation of midbrain dopaminergic neurones in vitro. GDNF has therefore been proposed as a factor which may have utility in the treatment of Parkinson's disease. In the present study, we have used RT-PCR to analyse the distribution of GDNF mRNA throughout the newborn rat (P0). We show that GDNF transcripts are present in kidney, lung, bone, heart, liver, spleen, sciatic nerve and blood. Two separate GDNF transcripts are present in different ratios in each tissue investigated. Sequence analysis of both these mRNA species revealed that the shorter transcript (sGDNF) contains a deletion of 78 bp in comparison to the published sequence for GDNF. We speculate that this shorter mRNA arose due to alternative splicing.
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PMID:GDNF is expressed in two forms in many tissues outside the CNS. 769 86

Glial-cell-line-derived neurotrophic factor (GDNF), a recently cloned new member of the transforming growth factor-beta superfamily, promotes survival of cultured fetal mesencephalic dopamine neurons and is expressed in the developing striatum. There have, however, been no reports about effects of GDNF in situ. We have used the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which produces parkinsonian symptoms in man, to determine whether GDNF might exert protective or regenerative effects in vivo in the adult nigrostriatal dopamine system in C57/B1 mice. GDNF injected over the substantia nigra or in striatum before MPTP potently protects the dopamine system, as shown by numbers of mesencephalic dopamine nerve cell bodies, dopamine nerve terminal densities and dopamine levels. When GDNF is given after MPTP, dopamine levels and fibre densities are significantly restored. In both cases, motor behaviour is increased above normal levels. We conclude that intracerebral GDNF administration exerts both protective and reparative effects on the nigrostriatal dopamine system, which may have implications for the development of new treatment strategies for Parkinson's disease.
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PMID:Protection and repair of the nigrostriatal dopaminergic system by GDNF in vivo. 783 Jul 62

Glial-cell-line-derived neurotrophic factor (GDNF) promotes survival of embryonic dopaminergic neurons in culture, and its expression pattern suggests a role as a transient target-derived trophic factor for dopaminergic neurons of the substantia nigra. These neurons participate in the control of motor activity, emotional status and cognition, and they degenerate in Parkinson's disease for unknown reasons. To test whether GDNF has a trophic effect on dopaminergic neurons in the adult brain, we used a rat model in which these neurons are induced to degenerate by transecting their axons within the medial forebrain bundle. We report here that axotomy resulted in loss of half the tyrosine hydroxylase-expressing neurons in the substantia nigra. This loss was largely prevented by repeated injections of GDNF adjacent to the substantia nigra. Our findings suggest that GDNF or related molecules may be useful for the treatment of Parkinson's disease.
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PMID:Mesencephalic dopaminergic neurons protected by GDNF from axotomy-induced degeneration in the adult brain. 783 Jul 62

The ability of neurotrophic factors to regulate developmental neuronal survival and adult nervous system plasticity suggests the use of these molecules to treat neurodegeneration associated with human diseases. Solid rationales exist for the use of NGF and neurotrophin-3 in the treatment of neuropathies of the peripheral sensory system, insulin-like growth factor and ciliary neurotrophic factor in motor neuron atrophy, and NGF in Alzheimer's disease. Growth factors have been identified for neurons affected in Parkinson's disease, Huntington's disease, and acute brain and spinal cord injury. Various strategies are actively pursued to deliver neurotrophic factors to the brain, and develop therapeutically useful molecules that mimic neurotrophic factor actions or stimulate their production or receptor mechanisms.
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PMID:Neurotrophic factor therapy for nervous system degenerative diseases. 785 95

Recent findings emphasize the significance of oxidative mechanisms, involving the activity of monoamine oxidase (MAO) and the formation of free radicals, in the pathogenesis of Parkinson's disease. The possible role of such mechanisms in the degeneration of neurones in the substantia nigra has led to clinical trials aimed at preventing or slowing the progressively disabling course of the disease. However, conclusive clinical evidence of a neuroprotective effect in PD is still lacking. In this paper, we discuss possible mechanisms by which selegiline manifests neuroprotective effects in experimental and clinical situations. Besides MAO-B inhibition, which above all explains the prevention of protoxin activation and substrate oxidation by MAO-B, selegiline appears to exhibit other mechanisms of action (induction of superoxide dismutase, stimulation of neurotrophic factor synthesis, antagonistic modulation of the polyamine binding site of the NMDA-receptor) which are independent of its action on MAO-B.
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PMID:Is selegiline neuroprotective in Parkinson's disease? 793 Dec 25

A recently cloned neurotrophic factor, termed glial cell line-derived neurotrophic factor (GDNF), has been reported to exhibit selective neurotrophic properties on ventral mesencephalon dopaminergic neurons, which degenerate in patients with Parkinson's disease. In the present study, we used reverse transcriptase followed by polymerase chain reaction (PCR) and in situ hybridization to study the expression of GDNF messenger RNA (mRNA) in the adult rat and human central nervous system (CNS). GDNF transcripts were identified using PCR in all regions of the rat CNS analyzed including striatum, hippocampus, cortex, cerebellum, and spinal cord. Interestingly, the rat hippocampal formation contained two transcripts, i.e., a larger form in addition to the amplified GDNF cDNA found in all other areas analyzed. GDNF PCR products also were observed in human striatum, hippocampus, cortex, and spinal cord, but not cerebellum, and both the striatum and hippocampal formation contained two GDNF transcripts. Finally, GDNF transcripts were detected in a rat Schwann cell line previously shown to secrete a factor that exerts a neurotrophic effect on dopaminergic neurons. In situ hybridization experiments using a cRNA probe hybridized to adult rat brain sections demonstrated no positive GDNF mRNA signal. However, intense GDNF mRNA hybridization signal was found to be associated with dorsal root ganglia in Postnatal Day 1 rats. These findings provide evidence that GDNF is detectable using PCR in a number of nervous system structures and, in some areas, GDNF is expressed in more than one form.
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PMID:Expression of GDNF mRNA in rat and human nervous tissue. 803 59

Fibroblast growth factor (FGF) is synthesized and stored by astroglial cells and regulates their proliferation and differentiation in vitro. Its implication in the transformation of quiescent astrocytes into reactive astroglia has been discussed. Using a mouse model of Parkinson's disease, in which FGF-2 has been shown to exert marked neuroprotection of nigrostriatal dopaminergic neurons, we have studied striatal levels of glial fibrillary acidic protein (GFAP), an established marker for astrocytes, and the distribution and morphologies of GFAP-immunoreactive cells following treatments with the neurotoxic drug 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), the growth factor FGF-2, and the non-trophic control protein cytochrome C (cyt C). Systemic injections of MPTP (30 mg/kg) on 3 consecutive days, which we have previously shown to cause profound and long-lasting damage to the nigrostriatal system, induced an approximate 20% transient increase in striatal GFAP, determined by enzyme-linked immunosorbent assay (ELISA), 1 day after the final MPTP injection (= day 4), with subsequent normalization at day 7, which lasted until the end of the experiment (day 18). Morphologically, MPTP elicited a marked increase in number, size, arborization, and stainability of GFAP-immunoreactive cells at day 4 in a striatal area adjacent to the corpus callosum, which was evaluated throughout all experiments. Even on day 18, astrocytes were still apparently larger and more branched than in unlesioned controls. Administration of 4 micrograms of either FGF-2 or cyt C (soaked into a piece of Gelfoam unilaterally to the right striatum in either MPTP- or saline-injected controls) increased striatal GFAP levels bilaterally about 2- to 2.5-fold at 14 days, when FGF-2 showed marked protection of dopaminergic parameters. Likewise, GFAP immunocytochemistry revealed increased numbers of intensely immunoreactive astrocytes under any experimental situation. Differences in the morphologies of astrocytes in FGF-2- and cyt C-treated animals were very subtle and only noted at greater distances away from the site of application of the factors. We conclude that FGF-2, a potent neurotrophic factor for the neurotoxically lesioned nigrostriatal system, does not cause a marked astrogliotic reaction, which might be expected from previous in vitro and in vivo studies in other neural systems. This may limit concerns regarding potential applicability of FGF-2 to the parkinsonian striatum.
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PMID:FGF-2 in the MPTP model of Parkinson's disease: effects on astroglial cells. 807 Aug 94

The caudate, putamen, and cerebellum from five patients with Parkinson's disease (PD) and five normal, aged controls were studied to determine if cell-free extracts from these tissues influenced dopamine neuron growth in culture. Cultures incubated with extracts of the caudate and putamen, but not the cerebellum, from PD patients contained more tyrosine hydroxylase immunoreactive neurons than aged controls. These data suggest that the parkinsonian striatum compensates for dopamine loss by increasing neurotrophic factor production.
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PMID:Striatal extracts from patients with Parkinson's disease promote dopamine neuron growth in mesencephalic cultures. 809 75

A large body of experimental data suggests that neurotrophic molecules and/or substances that facilitate their action could be pharmaceutical agents for neurodegenerative pathologies. In particular, it has been demonstrated that nerve growth factor (NGF) exerts a physiological role for forebrain cholinergic neurons, while brain-derived neurotrophic factor (BDNF) seems to play a relevant role in rescuing dopaminergic neurons following damage. In addition, gangliosides are reported to potentiate neurotrophic factor effects in vitro as well as in vivo. In this study we examined the effects of the monosialoganglioside GM1 in different experimental models. The responsiveness of forebrain cholinergic neurons following NGF +/- GM1 was evaluated by assessing choline acetyltransferase (ChAT) activity in hippocampus, septal area and striatum of behaviorally impaired 24-month-old rats. NGF was intracerebroventricularly (i.c.v.) infused for 2 weeks while GM1 was given systemically for 3 weeks, starting from the beginning of NGF infusion. Moreover, the possible protective effects of GM1 were assessed following exposure of cultured cerebellar granule cells and dopaminergic mesencephalic neurons to different doses of 6-OH-DOPA, a metabolite of the dopamine pathway which has excitotoxic properties and has been hypothesized to participate in the pathology of Parkinson's disease. GM1 treatment to aged rats was seen to potentiate the NGF-induced increase of ChAT activity in the striatum ipsilateral to the NGF infusion. Moreover, in the striatum contralateral to the NGF infusion, GM1 increased ChAT activity above the control values, whereas NGF treatment alone did not affect enzymatic activity. GM1 treatment of cerebellar granule cells and mesencephalic neurons counteracted the dose- and time-dependent neurotoxicity of 6-OH-DOPA. These data support the notion that GM1 might prove useful in treating those pathological conditions where trophic factor deficits and/or excitotoxin-related toxicity play an important role.
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PMID:Gangliosides and neurotrophic factors in neurodegenerative diseases: from experimental findings to clinical perspectives. 823 3


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