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)

Transplantation of fetal nigral dopamine neurons into the caudate and putamen of Parkinson's disease patients produces limited symptomatic relief. One approach to augment the outgrowth and function of nigral grafts includes exposure of the graphs to neurotrophic factors; however, the temporal requirements for optimizing these actions are unknown. The present study characterized the ontogeny of brain-derived neurotrophic factor (BDNF) in the rat striatum and used this information to define and evaluate three distinct periods of BDNF infusion into fetal nigral grafts transplanted into the striatum of rats with experimental Parkinson's disease. At postnatal day 1 (P1), BDNF and dopamine were measured at 17 and 27% of peak levels, respectively, that occurred at P27 for both. Both compounds showed their greatest surge between P7 and P20, increasing from 40% to approximately 95% of peak levels. Exogenous BDNF infused into transplants during weeks 1 and 2 after the transplantation, which coincide with the developmental period embryonic day 14 (E14)-P7 for transplanted tissue, did not improve rotational behavior or enhance fiber outgrowth of transplanted dopamine neurons. Delaying the BDNF infusion until transplanted tissue was approximately P8-P21 greatly enhanced the effect on rotational behavior and doubled the area of dopamine fiber outgrowth from the transplants. Delaying the infusion until transplanted tissue was approximately P36-P49 failed to augment fiber outgrowth and decreased the behavioral function of transplants. Thus, the optimal effect of exogenous BDNF on the development of dopamine neurons in fetal nigral transplants occurs at a postnatal age when endogenous dopamine and BDNF show the greatest increases during the normal development of the striatum.
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PMID:Optimal effectiveness of BDNF for fetal nigral transplants coincides with the ontogenic appearance of BDNF in the striatum. 967 88

trkB is a high-affinity receptor for brain-derived neurotrophic factor, a neurotrophin acting on numerous cells, including dopaminergic neurons. Yet, little is known of its expression in the human brain. We report an in situ hybridization analysis of trkB messenger RNA, encoding the catalytic form of the receptor, in the human brain post mortem. Its expression was found to be widespread but heterogeneous among all the cerebral structures studied, the highest level being found in the cerebral cortex and the cerebellum. A strong but less intense staining was observed in the striatum, nucleus basalis of Meynert, hippocampus, tegmental pedonculopontinus nucleus and substantia nigra pars compacta. Combined immunohistochemistry for tyrosine hydroxylase and in situ hybridization for trkB messenger RNA showed that within the substantia nigra pars compacta a major proportion of dopaminergic neurons expressed trkB messenger RNA. Furthermore, we compared trkB messenger RNA expression in the mesencephalon of six control subjects and five patients with Parkinson's disease, a neurodegenerative disorder characterized by a severe loss of dopaminergic neurons. Despite the fact that the number of trkB messenger RNA-containing neurons was dramatically reduced in the substantia nigra pars compacta and ventral tegmental area of patients with Parkinson's disease, the level of trkB messenger RNA was unchanged in the remaining neurons in diseased brains. These results suggests that trkB is not involved in the process of neuronal death in Parkinson's disease. Furthermore, expression of brain-derived neurotrophic factor high-affinity receptor in patients could allow this neurotrophin to be used to prevent degeneration of surviving neurons at early stages of the disease.
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PMID:trkB messenger RNA expression in normal human brain and in the substantia nigra of parkinsonian patients: an in situ hybridization study. 969 19

To assess the action of neurotrophin in human dopaminergic neurons, we studied the immunolocalization of neurotrophins or trks in human substantia nigra pars compacta (SNc). The neuromelanin-containing neurons in the SNc showed immunoreactivities for neurotrophins or trks, suggesting an autocrine/paracrine regulation. Quantitative analysis revealed that the percentage of those expressing NGF-like immunoreactivity (NGF-LI), BDNF-LI, NT3-LI, trkA-LI, trkB-LI, or trkC-LI was 66%, 74%, 85%, 66%, 71% or 86%, respectively. The percentage of cells expressing neurotrophins or trks was higher in the medial part than in the lateral part of the SNc. The preferential expression of neurotrophin-trk systems in the medial neurons may, at least partially, explain the differential susceptibility in Parkinson's disease.
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PMID:Medial nigral dopamine neurons have rich neurotrophin support in humans. 976 Jan 32

The repeated finding of an apparent protective effect of cigarette smoking on the risk of Parkinson's disease is one of the few consistent results in the epidemiology of this disorder. Among the numerous substances that originate from tobacco smoke, nicotine is by far the most widely studied. Nicotine is a natural alkaloid that has considerable stimulatory effects on the CNS. Its effects on the CNS are mediated by the activation of neuronal heteromeric acetylcholine-gated ion channel receptors (nAChRs, also termed nicotinic acetylcholine receptors). In the present study, we describe the neuroprotective effects of (-)-nicotine in two animal models of parkinsonism: diethyldithiocarbamate-induced enhancement of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in mice and methamphetamine-induced neurotoxicity in rats and mice. The neuroprotective effect of (-)-nicotine was very similar to that of the noncompetitive NMDA receptor antagonist (+)-MK-801. In parallel experiments, we found that (-)-nicotine induces the basic fibroblast growth factor-2 (FGF-2) and the brain-derived neurotrophic factor in rat striatum. The effect of (-)-nicotine on the induction of FGF-2 was prevented by the nAChR antagonist mecamylamine. We also found that (+)-MK-801 was able to induce FGF-2 in the striatum. As trophic factors have been reported to be neuroprotective for dopaminergic cells, our data suggest that the increase in neurotrophic factors is a possible mechanism by which (-)-nicotine protects from experimental parkinsonisms.
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PMID:Nicotine prevents experimental parkinsonism in rodents and induces striatal increase of neurotrophic factors. 983 42

Free-floating roller tube (FFRT) cultures of fetal rat and human nigral tissue are a means for tissue storage prior to grafting in experimental Parkinson's disease. In the present study, FFRT cultures prepared from embryonic-day-14 rat ventral mesencephalon were maintained for 4, 8, 12, or 16 days in vitro (DIV) in the presence or absence (controls) of BDNF [100 ng/ml]. The dopamine content in the culture medium, analyzed by HPLC, was significantly higher (4-5 fold) in the BDNF group at DIV 8 and DIV 12 compared to the corresponding control levels (40 pg/ml). The number of tyrosine hydroxylase immunoreactive neurons was significantly higher for BDNF treated cultures (2729+/-300) at DIV 8, as compared to controls (1679+/-217). At DIV 12, the culture volume was significantly increased by BDNF (1.05+/-0.12 vs. 0.71+/-0.04 mm3). Similar results were obtained for total protein. Western blot analysis demonstrated increasing signals for GFAP with increasing time in culture, but levels for control and BDNF treated cultures did not differ at any time-point investigated. In conclusion, it is suggested that the time window for effective storage of dopaminergic tissue prior to grafting can be extended by using the FFRT culture technique and that the in vitro storage may be further prolonged by treatment with BDNF.
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PMID:Rat fetal ventral mesencephalon grown as solid tissue cultures: influence of culture time and BDNF treatment on dopamine neuron survival and function. 983 77

The major pathological lesion of Parkinson's disease (PD) is the selective cell death of dopaminergic (DA) neurons in substantia nigra (SN). Although the initial cause and subsequent molecular signaling mechanisms leading to DA cell death underlying the PD process remain elusive, brain-derived neurotrophic factor (BDNF) is thought to exert neuroprotective as well as neurotrophic roles for the survival and differentiation of DA neurons in SN. Addressing molecular mechanisms of BDNF action in both primary embryonic mesencephalic cultures and in vivo animal models has been technically difficult because DA neurons in SN are relatively rare and present with many heterogeneous cell populations in midbrain. We have developed and characterized a DA neuronal cell line of embryonic SN origin that is more accessible to molecular analysis and can be used as an in vitro model system for studying SN DA neurons. A clonal SN DA neuronal progenitor cell line SN4741, arrested at an early DA developmental stage, was established from transgenic mouse embryos containing the targeted expression of the thermolabile SV40Tag in SN DA neurons. The phenotypic and morphological differentiation of the SN4741 cells could be manipulated by environmental cues in vitro. Exogenous BDNF treatment produced significant neuroprotection against 1-methyl-4-phenylpyridinium, glutamate, and nitric oxide-induced neurotoxicity in the SN4741 cells. Simultaneous phosphorylation of receptor tyrosine kinase B accompanied the neuroprotection. This SN DA neuronal cell line provides a unique model system to circumvent the limitations associated with primary mesencephalic cultures for the elucidation of molecular mechanisms of BDNF action on DA neurons of the SN.
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PMID:Neuroprotection and neuronal differentiation studies using substantia nigra dopaminergic cells derived from transgenic mouse embryos. 987 Sep 33

Several in vitro and in vivo studies have shown that brain-derived neurotrophic factor (BDNF) promotes survival of damaged mesencephalic dopaminergic neurons. Using a specific antibody directed against human recombinant BDNF, we studied the expression of the protein at the cellular level in the post-mortem mesencephalon of control subjects and patients with Parkinson's disease (PD). In control subjects, BDNF was expressed in all mesencephalic regions containing dopaminergic neurons, and in the substantia nigra pars compacta (SNpc) 65% of the melanized neurons expressed BDNF. In the PD SNpc, the total number of pigmented neurons containing BDNF was reduced to 9.6% of the corresponding control value. In contrast, the number of pigmented neurons non-immunoreactive for BDNF was reduced to 23.9% of the corresponding control value. This result appears to indicate that SNpc melanized neurons not expressing BDNF have a 2.5-fold greater probability of surviving than BDNF-positive melanized neurons. Furthermore, we found that in parkinsonian mesencephalon almost all dopaminergic neurons containing Lewy bodies were immunoreactive for BDNF. These findings demonstrate a reduced expression of BDNF in PD and suggest that BDNF protein expression does not protect melanized SNpc neurons from the degenerative process in this disease.
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PMID:Reduced expression of brain-derived neurotrophic factor protein in Parkinson's disease substantia nigra. 1020 89

The ability of trophic factors to regulate developmental neuronal survival and adult nervous system plasticity suggests the use of these molecules to treat neurodegeneration associated with human diseases, such as Alzheimer's, Huntington's and Parkinson's disease, of amyotrophic lateral sclerosis and peripheral sensory neuropathies. Recent biological data on the neutrotrophins NGF and BDNF, on GDNF, CNTF and IGF-I are discussed together with first results from clinical trials. Literature is presented on the three-dimensional structures of these trophic factors and on models proposed for ligand-receptor interactions. Substantial progress has been made in the understanding of the mechanisms of apoptosis. The cascade consisting of interaction of apoptosis-inducing ligands with death receptors, the coupling of this complex to adaptor proteins via death domains, the further recruitment of procaspases via death effector or caspase recruitment domains and the execution of cell death via the effector caspases is briefly outlined.
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PMID:Receptors in neurodegenerative diseases. 1081 65

The biomedical literature on the subject of neurotrophic growth factors has expanded prodigiously. This essay reviews neurotrophic factors (NTF) and their receptors in Alzheimer's disease (AD) and Parkinson's disease (PD) brain and recent updates on receptor signaling. The hypotheses for specific NTF involvement in neurodegenerative diseases in human and as potential therapy are based mainly on experimental animal and in vitro models. There are wide gaps in information on regional synthesis and cell contents of NTFs and their receptors in human brain. Observations on AD brain indicate increases in NGF and decreases in BDNF in surviving neurons of hippocampus and certain neocortical regions and decreases in TrkA in cortex and nucleus basalis. In PD brain, the few data available indicate decreases in neuronal content of GDNF and bFGF in surviving substantia nigra dopaminergic neurons. There are very few data regarding age-dependent effects on NTFs and on their receptors in human brain. Since NTFs in neurons are subject to retrograde and, in at least some cases, to anterograde transport from and to target neurons, their effects may be related to synthesis in local or remote sites or to changes in axoplasmic transport. Also, certain NTFs and their receptors are found to be expressed in activated glia. Thus, comparative in situ data for transcription levels and protein contents for NTFs and their receptors in both sites of neuronal origin and termination in human brain are needed to understand their potential roles in treating human diseases.
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PMID:Neurotrophic factors in Alzheimer's and Parkinson's disease brain. 1101 Oct 66

Embryonic midbrain can be maintained as free-floating roller tube cultures prior to grafting in experimental Parkinson's disease. We examined the influence of pregrafting culture time and pretreatment with brain-derived neurotrophic factor on graft survival and function. Cultures were prepared from solid pieces of embryonic (E14) rat ventral mesencephalon and maintained 4, 8, or 12 days in vitro with or without brain-derived neurotrophic factor (100 ng/ml) and grafted into the striatum of 6-hydroxydopamine-lesioned rats. Graft survival and function were evaluated by amphetamine-induced rotation behavior, number of tyrosine hydroxylase-immunoreactive neurons, striatal reinnervation, and graft volume. Rats receiving untreated tissue cultured for 4 or 8 days displayed no differences in graft quality, while grafts from 12-day-old cultures contained significantly fewer (P < 0.05) tyrosine hydroxylase-immunoreactive neurons (340 +/- 97, 267 +/- 92, and 62 +/- 19) and displayed a lower survival rate (9.6 +/- 2.7, 7.9 +/- 2.7, and 2.6 +/- 0.8% for 4, 8, and 12 days in vitro, respectively). Only rats grafted with 4- and 8-day-old cultures recovered significantly (P < 0.05) from lesion-induced rotations (69.4 +/- 18.6, 70.3 +/- 13.9, and 23.2 +/- 12.1% for 4, 8, and 12 days in vitro, respectively). Striatal reinnervation decreased with increasing culture time (P < 0.05). Pretreatment of the cultures with brain-derived neurotrophic factor affected only graft-induced fiber reinnervation, which was reduced even after short culture times. We therefore suggest that a storage period of 8 days is well suited to maintain embryonic rat ventral mesencephalon with the free-floating roller tube culture technique prior to transplantation. BDNF pretreatment as a new strategy to improve graft survival and function, however, was not effective.
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PMID:Influence of time in culture and BDNF pretreatment on survival and function of grafted embryonic rat ventral mesencephalon in the 6-OHDA rat model of Parkinson's disease. 1116 2


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