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)

Brain-derived neurotrophic factor (BDNF), present in minute amounts in the adult central nervous system, is a member of the nerve growth factor (NGF) family, which includes neurotrophin-3 (NT-3). NGF, BDNF and NT-3 all support survival of subpopulations of neural crest-derived sensory neurons; most sympathetic neurons are responsive to NGF, but not to BDNF; NT-3 and BDNF, but not NGF, promote survival of sensory neurons of the nodose ganglion. BDNF, but not NGF, supports the survival of cultured retinal ganglion cells but both NGF and BDNF promote the survival of septal cholinergic neurons in vitro. However, knowledge of their precise physiological role in development and maintenance of the nervous system neurons is still limited. The BDNF gene is expressed in many regions of the adult CNS, including the striatum. A protein partially purified from bovine striatum, a target of nigral dopaminergic neurons, with characteristics apparently similar to those of BDNF, can enhance the survival of dopaminergic neurons in mesencephalic cultures. BDNF seems to be a trophic factor for mesencephalic dopaminergic neurons, increasing their survival, including that of neuronal cells which degenerate in Parkinson's disease. Here we report the effects of BDNF on the survival of dopaminergic neurons of the developing substantia nigra.
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PMID:BDNF is a neurotrophic factor for dopaminergic neurons of the substantia nigra. 200 78

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

Studies of the trophic activities of brain-derived neurotrophic factor and neurotrophin-3 indicate that both molecules support the survival of a number of different embryonic cell types in culture. We have shown that mRNAs for brain-derived neurotrophic factor and neurotrophin-3 are localized to specific ventral mesencephalic regions containing dopaminergic cell bodies, including the substantia nigra and ventral tegmental area. In the present study, in situ hybridization with 35S-labeled cRNA probes for the neurotrophin mRNAs was combined with neurotoxin lesions or with immunocytochemistry for the catecholamine-synthesizing enzyme tyrosine hydroxylase to determine whether the dopaminergic neurons, themselves, synthesize the neurotrophins in adult rat midbrain. Following unilateral destruction of the midbrain dopamine cells with 6-hydroxydopamine, a substantial, but incomplete, depletion of brain-derived neurotrophic factor and neurotrophin-3 mRNA-containing cells was observed in the ipsilateral substantia nigra pars compacta and ventral tegmental area. In other rats, combined in situ hybridization and tyrosine hydroxylase immunocytochemistry demonstrated that the vast majority of the neurotrophin mRNA-containing neurons in the substantia nigra and ventral tegmental area were tyrosine hydroxylase immunoreactive. Of the total population of tyrosine hydroxylase-positive cells, double-labeled neurons constituted 25-50% in the ventral tegmental area and 10-30% in the substantia nigra pars compacta, with the proportion being greater in medial pars compacta. In addition, tyrosine hydroxylase/neurotrophin mRNA coexistence was observed in neurons in other mesencephalic regions including the retrorubral field, interfascicular nucleus, rostral and central linear nuclei, dorsal raphe nucleus, and supramammillary region. The present results demonstrate brain-derived neurotrophic factor and neurotrophin-3 expression by adult midbrain dopamine neurons and support the suggestion that these neurotrophins influence dopamine neurons via autocrine or paracrine mechanisms. These data raise the additional possibility that inappropriate expression of the neurotrophins by dopaminergic neurons could contribute to the neuropathology of disease states such as Parkinson's disease and schizophrenia.
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PMID:Dopaminergic neurons in rat ventral midbrain express brain-derived neurotrophic factor and neurotrophin-3 mRNAs. 791 99

A pathology of brain serotonergic (5-HT) systems has been found in psychiatric disturbances, normal aging and in neurodegenerative disorders including Alzheimer's and Parkinson's disease. Despite the clinical importance of 5-HT, little is known about the endogenous factors that have neurotrophic influences upon 5-HT neurons. The present study examined whether chronic pain parenchymal administration of the neurotrophins brain-derived neurotrophic factor (BDNF), neurotrophin-3 (NT-3) or NGF could prevent the severe degenerative loss of serotonergic axons normally caused by the selective 5-HT neurotoxin p-chloroamphetamine (PCA). The neurotrophins (5-12 micrograms/d) or the control substances (cytochrome c or PBS vehicle) were continuously infused into the rat frontoparietal cortex using an osmotic minipump. One week later, rats were subcutaneously administered PCA (10 mg/kg) or vehicle, and the 5-HT innervation was evaluated after two more weeks of neurotrophin infusion. As revealed with 5-HT immunocytochemistry, BDNF infusions into the neocortex of intact (non-PCA-lesioned) rats caused a substantial increase in 5-HT axon density in a 3 mm diameter region surrounding the cannula tip. In PCA-lesioned rats, intracortical infusions of BDNF completely prevented the severe neurotoxin-induced loss of 5-HT axons near the infusion cannula. In contrast, cortical infusions of vehicle or the control protein cytochrome c did not alter the density of serotonergic axons in intact animals, nor did control infusions prevent the loss of 5-HT axons in PCA-treated rats. NT-3 caused only a modest sparing of the 5-HT innervation in PCA-treated rats, and NGF failed to prevent the loss of 5-HT axon density. The immunocytochemical data were supported by neurochemical evaluations which showed that BDNF attenuated the PCA-induced loss of 5-HT and 5-HIAA contents and 3H-5-HT uptake near the infusion cannula. Thus, BDNF can promote the sprouting of mature, uninjured serotonergic axons and dramatically enhance the survival or sprouting of 5-HT axons normally damaged by the serotonergic neurotoxin PCA.
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PMID:Brain-derived neurotrophic factor promotes the survival and sprouting of serotonergic axons in rat brain. 861 31

Parkinson's disease (PD) is characterized by the degeneration of the mesencephalic dopaminergic (mesDA) neurons innervating the striatum. Neurotrophic factor(s) that prevents the degeneration and increases the functional activity of the remaining mesDA neurons are of substantial clinical interest. The origin and development of mesDA neurons were characterized in the human mesencephalon from 5.0 to 12 Postconception (PC) weeks. Tyrosine Hydroxylase (TH) immunoreactive cells were first demonstrated at 5.5 PC weeks next to the ventricular zone. In primary culture, TH immunoreactive neurons represent 3 to 5% of the total cells at days 7 in vitro and basic Fibroblast growth factor (bFGF) was demonstrated to induce a significant increase of both TH immunoreactive cell number and TH enzymatic activity. This effect was mediated by proliferating glial fibrillary acidic protein immunoreactive cells. Nerve growth factor treatment did not have any appreciable effect. The effect of bFGF on TH positive cells described in this human bioassay is only a preliminary evidence that, if confirmed by experiments in vivo, may provide a starting rationale for investigating alternative strategies in the treatment of PD.
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PMID:Molecules with neurotrophic effects on the human developing mesencephalic dopaminergic neurons. 874 37

Among the pathogenetic phenomena of Parkinson's disease, the character of the selective degeneration of nigrostriatal system with severe gliosis is not fully understood. Here, we have shown that dopaminergic neurons may be exclusively sensitive to elevated acidity elicited after the addition of glial mitogenic factors such as epidermal growth factor and basic fibroblast growth factor or after the direct treatment with hydrochloric acid. The acid sensitivity was specific to dopaminergic neurons. The neurons other than dopaminergic neurons in culture from the ventral mesencephalon were not sensitive to acidity and the neurons from several brain areas were the same as above, except for the hippocampal neurons which had slight acid vulnerability. Choline acetyltransferase assay studies demonstrated that the cholinergic neuronal population in the septum and corpus striatum had no acid sensitivity. The vulnerability of dopaminergic neurons either elicited by glial mitogenic factor or derived from the direct acid exposure was inhibited by the addition of brain-derived neurotrophic factor (BDNF), but not by neurotrophin-3 or nerve growth factor. These findings suggest that dopaminergic neurons have selective acid vulnerability on which BDNF has a pronounced protective effect.
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PMID:Selective acid vulnerability of dopaminergic neurons and its recovery by brain-derived neurotrophic factor. 878 12

This review focuses on two restorative strategies against Parkinson's disease: (1) intrastriatal implantation of fetal dopamine producing cells and (2) application of neurotrophic factors. (1) Neuronal transplantation of dopaminergic embryonic ventral mesencephalic cells aims at compensating the striatal dopamine deficit in Parkinson's disease. Clinically, dopaminergic ventral mesencephalic grafts have been demonstrated to ameliorate rigidity, bradykinesia, and efficacy of L-DOPA therapy, for instance reduction of L-DOPA-induced dyskinesias and ON-OFF-fluctuations. Future experimental refinements predominantly concern the improvement of survival of the transplanted fetal dopaminergic neurons and the use of genetically modified cells. (2) Neurotrophic factor therapy relates to the prevention and/or restoration of the progressing nigral cell loss in Parkinson's disease. In this regard special emphasis is put on the newly characterized glial cell line-derived neurotrophic factor (GDNF). More recent results and perspectives of this concept are discussed.
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PMID:Neuronal transplantation and neurotrophic factors in the treatment of Parkinson's disease--update February 1995. 882 Oct 56

The tyrosine kinase receptors trkB and trkC are essential components of the high-affinity receptors for members of the neurotrophin family, including brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3). Both neurotrophin receptor mRNAs are broadly distributed throughout the caudate-putamen. In animal models of Parkinson's disease, loss of the ventral mesencephalic dopamine projection to the striatum has been shown to alter the expression of several striatal peptides, neurotransmitter-synthesizing enzymes and receptors. To determine if expression of trkB and/or trkC striatal mRNAs is also regulated by the integrity of the dopaminergic afferents, adult rats were given unilateral injections of 6-hydroxydopamine (6-OHDA), a selective catecholamine neurotoxin, or vehicle into the right ascending medial forebrain bundle. Following a 2 week survival period, in situ hybridization with 35S-labelled cRNA probes for the kinase-specific, full-length form of trkB mRNA and all forms of trkC mRNA was performed in striatal sections. A significant increase in the hybridization density for trkB mRNA was observed in the caudate-putamen ipsilateral to the 6-OHDA injection, compared with the uninjected control side (P < 0.001). In contrast, no alteration in the hybridization density for trkC mRNA was observed in the striatum of 6-OHDA-treated rats. No alterations in trkB or trkC mRNA levels were observed in the striata of vehicle-treated animals. These data suggest that midbrain dopaminergic afferents regulate the expression of trkB mRNA in the caudate-putamen. Alternatively, since dopaminergic neurons of the ventral mesencephalon express BDNF mRNA, the up-regulation of striatal trkB mRNA may reflect a compensatory response by striatal neurons due to a loss of anterogradely and/or retrogradely derived trophic support from the ventral midbrain.
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PMID:Increased expression of trkB mRNA in rat caudate--putamen following 6-OHDA lesions of the nigrostriatal pathway. 910 91

GABAergic neurons in the rat substantia nigra die after inhibitory inputs to the nigra have been killed, and glutamatergic inputs disinhibited, by striatal-pallidal injections of ibotenic acid. This delayed transneuronal injury model imitates the neuron loss observed in Huntington's disease, and may also imitate neuron loss distant from the primary injury in stroke and Parkinson's disease. Because the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 can prevent excitotoxic killing of cultured GABA neurons, we tested whether either factor could protect nigral neurons from transneuronal degeneration. A continuous, three week supranigral infusion of brain-derived neurotrophic factor completely prevented the loss of nigral neurons caused by the ibotenic acid-induced destruction of the caudate-putamen and globus pallidus, and brain-derived neurotrophic factor increased nigral neuron size by 25%. These effects were specific to the TrkB tyrosine kinase receptor that mediates brain-derived neurotrophic factor actions, since supranigral infusions of saline or the TrkC preferring neurotrophin-3, did not prevent nigral neuron loss or induce a hypertrophic response. Neither trophic factor influenced the ibotenic acid destruction of striatal or pallidal neurons. These results demonstrate that exogenously supplied brain-derived neurotrophic factor can prevent delayed, transneuronal loss, and implicate decreased excitatory amino acid transmission or diminished nigral neuron susceptibility to glutamate inputs in the protective effect of brain-derived neurotrophic factor.
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PMID:Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions. 948 58

Adenovirus is an efficient vector for neuronal gene therapy due to its ability to infect post-mitotic cells, its high efficacy of cell transduction and its low pathogenicity. Recombinant adenoviruses encoding for therapeutical agents can be delivered in vivo after direct intracerebral injection into specific brain areas. They can be transported in a retrograde manner from the injection site to the projection cell bodies offering promising applications for the specific targeting of selected neuronal populations not easily accessible by direct injection, such as the motor neurons in the spinal cord. Adenoviral vectors are also efficient tools for the ex vivo gene therapy, that is, the genetical modification of cells prior to their transplantation into the nervous system. Recently, the efficacy of the adenovirus as a gene vector system has been demonstrated in several models of neurodegenerative diseases including Parkinson's disease (PD) and motor neuron diseases. In rat models of PD, adenoviruses encoding for either tyrosine hydroxylase, superoxide dismutase or glial-derived neurotrophic factor improved the survival and the functional efficacy of dopaminergic cells. Similarly, the intramuscular injection of an adenovirus encoding for neurotrophin-3 had substantial therapeutic effects in a mutant mouse model of motor neuron degenerative disease. However, although adenoviruses are highly attractive for neuronal gene transfer, they can trigger a strong inflammatory reaction leading in particular to the destruction of infected cells. The recent development of new generations of adenoviral vectors could shed light on the nature of the immune reaction caused by adenoviral vectors in the brain. The use of these new vectors, combined with that of neurospecific and regulatable promoters, should improve adenovirus gene transfer into the central nervous system.
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PMID:Adenovirus in the brain: recent advances of gene therapy for neurodegenerative diseases. 965 83


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