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)

We have now applied the enzyme immunoassay using anti-NGF monoclonal antibody (MAb) 27/21 and a blocking test validating the specificity of the immunoreactivity for NGF in serum samples to examine NGF levels in normal rat sera, hemiparkinsonian rat sera, normal monkey sera, and MPTP-treated monkey sera. The levels of NGF in treated animals showed reductions when compared with serum from normal animals. The NGF level alterations observed in lesioned animals and in human parkinsonian patients evidence a relationship between this neurotrophic factor and the neurodegenerative changes observed in Parkinson disease (PD).
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PMID:NGF in experimental models of Parkinson disease. 887 63

Treatment strategies based on transfer of genes, molecules, or cells to the central nervous system are summarized. When neurons are already degenerated, functional compensation can be effected by grafts of syngeneic or allogenic tissue to the target area. This technique is undergoing clinical trials in Parkinson's disease. Before degeneration has occurred, it may be possible to rescue "stressed" neurons, and stimulate terminal outgrowth using treatment with neurotrophic factors. Such approaches, with an emphasis on the NGF family of neurotrophins and their receptors, are reviewed. Finally, new molecular biology techniques may permit the transfer of genes directly into non-dividing cells of the central nervous system. These three approaches may have a more general applicability, and become important not only in neurodegenerative diseases, but also in other afflictions of the nervous system such as ischemia, stroke and injury.
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PMID:Treatment strategies for neurodegenerative diseases based on trophic factors and cell transplantation techniques. 926 9

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 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 TrkAII tyrosine kinase receptor differs from the TrkAI isoform by an insertion of six amino acids in the extracellular domain. We used RT-PCR to determine their respective distribution in rat and human brain. Only trkAII transcripts were detected in 12 rat brain regions, while both trkAI and trkAII transcripts were detected in the cerebellum and pituitary gland. In human, both trkAI and trkAII transcripts were detected in the frontal, temporal, and occipital cortex and thalamus, while only trkAI transcripts were detected in the hippocampus and cerebellum. In the caudate and putamen, trkAII transcripts were exclusively detected. Thereafter, we studied the expression of TrkA isoforms in the striatum of five patients with Alzheimer's disease (AD), four patients with non-AD dementia, seven patients with Parkinson's disease, and six paired nondemented elderly control individuals. In controls and non-AD patients, a constant expression of trkAII transcripts was detected within all striatum parts. In AD patients, a heterogeneous decrease in trkAII expression was observed in the caudate, putamen, and ventral striatum, resulting either in a drop of trkAII transcript levels or in a weak coamplification of trkAII and trkAI transcripts. The alteration of TrkAII gene expression paralleled those of choline acetyltransferase. Together with previous data, this suggests that the alteration of trk gene expression could contribute to a decrease in NGF binding sites and its protective effects on cholinergic neurons of AD patients.
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PMID:Expression of Trk isoforms in brain regions and in the striatum of patients with Alzheimer's disease. 1099 89

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

Adrenal chromaffin cells constitute one of the first cell types to have been defined as a neuroendocrine cell type. Since they produce dopamine, these cells have been proposed for the treatment of neuronal deficits in human Parkinson's disease. However, the factors involved in the development of chromaffin cells are still poorly understood. Based on recent insights from stem cell research, we decided to study the role of extracellular matrices, growth factors and neuropeptides on the neuroendocrine differentiation in a serum-free medium of PC12 cells. Employing immunohistochemistry, quantitative PCR and HPLC analysis, neuroendocrine differentiation was determined by evaluating neurite outgrowth, catecholamine biosynthesis and release as well as neuropeptide and vesicular protein mRNA expression. The combination of bFGF, NGF and PACAP could prevent the inhibition of neurite process development induced by dexamethasone in PC12 cells cultured on ECM. Whereas glucocorticoids were essential in the regulation of enzymes of catecholamine biosynthesis and metabolism, growth factors and PACAP were more efficient in inducing neuropeptide and chromogranin B expression as well as release of dopamine and 3-methoxytyramine. Therefore, in addition to glucocorticoids, chromaffin cells need a gradient of matrix, growth factors, and neuropeptides to develop the full functional phenotype of a neuroendocrine cell.
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PMID:Combinatorial code of growth factors and neuropeptides define neuroendocrine differentiation in PC12 cells. 1463 5

Parkinson's disease is characterized by the loss of dopaminergic neurons in the substantia nigra (SN). Studies show that anti-apoptotic and neurotrophic agents are suitable candidates to prevent delayed cell death and/or restore neural function. Here we present the nontoxic immunomodulating compound AS101, which has the ability to induce neurite outgrowth and neural differentiation in PC12 cells. The present study shows that components of the ras signaling pathway are crucial for AS101-induced PC12 differentiation. These include p21ras and its downstream effectors, c-raf-1 and MEK, as well as PI3K. Moreover, these components mediate AS101-induced upregulation of p21waf, which is obligatory for AS101-induced PC12 differentiation. Furthermore, nitric oxide plays a significant role in these AS101 activities. Finally, we show that AS101 prevents apoptosis of NGF-differentiated PC12 cells after NGF withdrawal. Taken together, these results suggest that AS101 induces PC12 cell differentiation and survival by activating the ras-ERK1/2 and ras-PI3K signal transduction pathways, as well as inducing NO production. Our findings may be important in understanding the regulation of survival/apoptosis of neurons deprived of neurotropic support. Futhermore the data propose that AS101 may have clinical potential in the treatment of neurodegenerative disorders like Parkinson's disease.
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PMID:Tellurium compound AS101 induces PC12 differentiation and rescues the neurons from apoptotic death. 1503 7

Different strategies have been worked out to promote survival of transplanted fetal ventral mesencephalic cells (VMCs) using trophic and nontrophic support. Olfactory ensheathing cells (OECs) express high level of growth factors including NGF, bFGF, GDNF, and NT3, which are known to play important role in functional restoration or neurodegeneration. In the present investigation, an attempt has been made to study functional restoration in 6-hydroxydopamine (6-OHDA)-lesioned rat model of Parkinson's disease (PD) following cotransplantation of VMC and OECs (cultured from olfactory bulb, OB) in striatal region. The functional restoration was assessed using neurobehavioral, neurochemical, and immunohistochemical approach. At 12 weeks, post-transplantation, a significant recovery (P < 0.001) in D-amphetamine induced circling behavior (73%), and spontaneous locomotor activity (SLA, 81%) was evident in cotransplanted animals when compared with 6-OHDA-lesioned animals. A significant restoration (P < 0.001) in [3H]-spiperone binding (77%), dopamine (DA) (82%) and 3,4-dihydroxy phenyl acetic acid (DOPAC) level (75%) was observed in animals cotransplanted with OECs and VMC in comparison to lesioned animals. A significantly high expression and quantification of tyrosine hydroxylase (TH)-positive cells in cotransplanted animals further confirmed the supportive role of OECs in viability of transplanted dopaminergic cells, which in turn may be helping in functional restoration. This was further substantiated by our observation of enhanced TH immunoreactivity and differentiation in VMC cocultured with OECs under in vitro conditions as compared to VMC alone cultures. The results suggest that cotransplantation of OECs and VMC may be a better approach for functional restoration in 6-OHDA-induced rat model of Parkinson's disease.
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PMID:Olfactory ensheathing cell transplantation restores functional deficits in rat model of Parkinson's disease: a cotransplantation approach with fetal ventral mesencephalic cells. 1526 63

We have used cDNA array analysis to examine the expression of genes in reactive astrocytes of dopamine-depleted striatum of rats in vivo, an animal model for Parkinson disease, compared to those from control striatum. The striatum of both normal adult rats and rats whose substantia nigra had been lesioned with 6-hydroxydopamine was removed one week following lesion. After fixing the tissue in RNAlater, individual astrocytes, isolated directly from dissociated striatum and confirmed to be astocytes by expression of glial fibrillary acidic protein (GFAP) mRNA using single cell RT-PCR, were used as the source of mRNA. Co-localization of GFAP with either of 2 antibodies known to label only reactive astrocytes in vivo confirmed that virtually all astrocytes in the lesioned striatum were reactive. The analysis has identified 29 genes whose expression is turned on or enhanced in dopamine-depleted striatal astrocytes and 2 whose expression is decreased. In situ hybridization was used to confirm the localization of 8 of these genes to astrocytes: these included GDNF, NGF, bFGF, TNF-alpha, MIP-1alpha, c-jun, Fra-1 and Fra-2. Understanding these gene differences that occur in astrocytes in response to dopamine depletion should enhance our ability to promote recovery from the injury.
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PMID:Gene expression profiles of reactive astrocytes in dopamine-depleted striatum. 1544 82


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