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 studied how stimulation of protein kinase C and cAMP-dependent protein kinases affect the development of mesencephalic dopaminergic neurons in primary cell cultures derived from fetal rats at embryonic day E14. The effects of compounds which activate these second messenger systems were compared to those of basic fibroblast growth factor (bFGF) and insulin-like growth factor I (IGF-I). In mesencephalic cultures, there was a continuous loss of dopaminergic neurons. Despite this decline in cell number, neurotransmitter uptake per neuron increased with time, indicating that the surviving dopaminergic neurons continued their biochemical differentiation while others degenerated. IGF-I and bFGF did not affect the number of dopaminergic neurons. However, dopamine uptake per neuron was significantly higher in bFGF and IGF-I treated cultures, suggesting that these factors stimulated differentiation. Protein kinase C and cAMP-dependent protein kinases were not involved in mediating the effects of bFGF and IGF-I. Treatment of cultures with phorbol esters did not affect dopamine uptake, whereas elevated levels of intracellular cAMP resulted in an increase in dopamine uptake which was additive to that elicited by bFGF or IGF-I. Further analysis revealed that exposure of mesencephalic cultures to dibutyryl cAMP (dbcAMP) during the first 3 days after plating increased the survival of dopaminergic neurons, whereas prolonged treatment attenuated the development of the dopamine uptake system. Moreover, cyclic AMP, but not bFGF, was able to prevent the degeneration of dopaminergic neurons induced by 1-methyl-4-phenyl-pyridinium ion (MPP+), the active metabolite of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). The results suggest that increased intracellular levels of cAMP protect dopaminergic neurons in situations of stress like the process of dissociation and plating or the exposure to neurotoxic compounds. Our results reveal novel possibilities for the treatment of Parkinson's disease.
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PMID:Cyclic AMP, but not basic FGF, increases the in vitro survival of mesencephalic dopaminergic neurons and protects them from MPP(+)-induced degeneration. 135 86

We have characterized and localized phorbol ester binding sites in human autopsied brains, using [3H]phorbol 12,13-dibutyrate ([3H]PDBu). When the tissue was homogenized in the absence of Ca2+ chelator (10 mM EGTA/2 mM EDTA), Scatchard analysis of the specific [3H]PDBu bindings to both particulate and soluble fractions yielded a single class of high-affinity binding site (Kd = 7.1 and 7.4 nM: Bmax = 45.4 and 3.1 pmol/mg protein, respectively). The particulate fraction retained the majority of [3H]PDBu binding (98% of total binding activity), while the soluble fraction was almost devoid of binding activity (2%). In the presence of Ca2+ chelator, more of the activity was found in the soluble fraction (30%). The binding of [3H]PDBu was potently inhibited by active phorbol esters and related diterpenes with Ki of nanomolar concentration but not by inactive ones. Diolein (OAG), a synthetic diacylglycerol, and polymixin B, an inhibitor of protein kinase C (PKC), inhibited the binding moderately (Ki = 5.8 and 1.3 microM, respectively). H-7, an inhibitor of PKC and cyclic nucleotides-dependent kinase, did not compete with [3H]PDBu for the binding sites (Ki greater than 100,000 nM). The regional distribution of specific [3H]PDBu binding in the human brain was rather uneven and resembled that of [3H]PDBu autoradiograms and PKC-like immunoreactivities in the rat brain. The binding capacities were generally in the order: rhinencephalon greater than basal ganglia greater than cerebral cortex greater than diencephalon greater than cerebellum greater than mesencephalon. Age-related loss of binding sites was observed in the prefrontal cortex of the subjects 33-81 years of age. In Parkinson's disease, the phorbol ester binding showed a significant reduction in the substantia nigra, caudate putamen, and pallidum, whereas it was unchanged in the prefrontal cortex and caudate nucleus of schizophrenics, when compared with the relevant controls.
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PMID:Phorbol ester binding sites in human brain: characterization, regional distribution, age-correlation, and alterations in Parkinson's disease. 264 64

The clinical efficacy of dopamine (DA) replacement therapy for patients with Parkinson's disease (PD) depends on the preservation of postsynaptic DA receptors and their intracellular signalling mechanisms in the striatum long after degeneration of the nigrostriatal DA pathway. DA activates adenylyl cyclase (AC) and phospholipase C (PLC) via the D1 receptor, and inhibits through the D2 receptor, thereby regulating the production of intracellular second messengers, cyclic adenosine 3',5'-monophosphate (cAMP), 1,2-diacylglycerol (DAG) and Ca2+. Recent advances in molecular biology have made it possible to monitor the intracellular signal transduction cascade following receptor activation by various transmitters. The authors review the literature addressing this issue, summarized as follows: (1) striatal D1 and D2 receptor densities remain constant, at least in treated and non-demented patients; (2) DA-sensitive AC activity appears to be increased in the putamen of treated patients, although this remains to be confirmed; (3) levels of cAMP-dependent protein kinase (PKA) are normal in non-demented patients, consistent with unchanged levels of DARPP-32 (dopamine- and cAMP-regulated phosphoprotein of M(r) 32,000); (4) levels of Ca2+/phospholipid-dependent protein kinase (PKC) and of inositol 1,4,5-trisphosphate (InsP3) receptor also remain unchanged in non-demented patients; (5) the above three second messenger sites as well as densities of D1 and D2 receptors are decreased in the striatum of demented PD patients (PDD). We tentatively conclude that postreceptor signalling function is intact in the striatum of non-demented PD patients and that there is a clear difference between non-demented patients and PDD, i.e. striatal dopaminoceptive neurons are affected in PDD.
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PMID:Transmembrane signalling systems in the brain of patients with Parkinson's disease. 795 88

Alterations in protein kinase C (PKC) and myo-inositol 1,4,5-trisphosphate (IP3) receptors were studied in the autopsied human striata from 21 patients with Parkinson's disease (PD) (Yahr III, IV, and V), 8 patients with Huntington's disease (HD), and 23 age-matched and postmortem time-matched nonneurological controls. The concentrations of PKC and IP3 receptors were determined using [3H]4 beta-phorbol 12,13-dibutyrate (PDBu) and [3H]IP3 as respective ligands. Both the specific [3H]-PDBu and [3H]IP3 bindings were significantly reduced in the striata of Yahr V patients with dementia (PDD) and in that of HD patients, as compared to findings in the controls. These bindings were unchanged when all the PD patients without dementia, Yahr (III plus IV) patients, or Yahr V patients without dementia were compared with evidence from the controls. Immunoquantification of four PKC subspecies (alpha, beta I, beta II, and gamma) in the HD putamen revealed a selective reduction in the beta II-PKC immunoreactions. These results are supported by immunohistochemical findings in the rat brain that beta II-PKC is expressed in the striatal gabaergic efferent pathway, while the alpha-PKC is present in the nigrostriatal dopaminergic neurons. The neurochemical pathophysiology of PD differs between patients with and without dementia.
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PMID:Second messenger systems in brains of patients with Parkinson's or Huntington's disease. 809 76

Oxidative stress and antioxidants have been related in a wide variety of ways with nervous tissue. This review attempts to gather the most relevant information related to a) the antioxidant status in non pathologic nervous tissue; b) the hypothesis and evidence for oxidative stress (considered as the disequilibrium between prooxidants and antioxidants in the cell) as the responsible mechanism of diverse neurological diseases; and c) the correlation between antioxidant alterations and neural function, in different experimental neuropathies. Decreased antioxidant availability has been observed in different neurological disorders in the central nervous system, for example, Parkinson's disease, Alzheimer's disease, epilepsy, amyotrophic lateral sclerosis, cerebral ischaemia, etc. Moreover, the experimental manipulation of the antioxidant defense has led in some cases to interesting experimental models in which electrophysiological alterations are associated with the metabolic modifications induced. In view of the electrophysiological and biochemical effects of some protein kinase C inhibitors on different neural experimental models, special attention is dedicated to the role of this kinase in peripheral nervous tissue. The nervous tissue, central as well as peripheral, has two main special features that are certainly related to its antioxidant metabolism: the lipid-enriched membrane and myelin sheaths, and cellular excitability. The former explains the importance of the glutathione (GSH)-conjugating activity towards 4-hydroxy-nonenal, a biologically active product of lipid peroxidation, present in nervous tissue and in charge of its inactivation. The impairment of the latter by oxidative damage or experimental manipulation of antioxidant metabolism is discussed. Work on different experimental neuropathies from author's laboratory has been primarily used to provide information about the involvement of free radical damage and antioxidants in peripheral nerve metabolic and functional impairment.
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PMID:Antioxidants in peripheral nerve. 874 79

We have studied how stimulation of protein kinase C and cAMP-dependent protein kinases affect the development of mesencephalic dopaminergic neurons in vitro. IGF-I and bFGF did not activate either second messenger system nor affect the survival of dopaminergic neurons but stimulated dopamine uptake per neuron. Phorbol esters, which stimulate protein kinase C, had no effect on dopamine uptake. Dibutyryl-cAMP caused an increase in dopamine uptake, which was blocked with (Rp)-cAMPS, a specific inhibitor of cAMP-dependent protein kinases. Treating cells with specific phosphodiesterase type IV inhibitors elevated the forskolin-induced increase in dopamine uptake. Furthermore, cAMP, but neither bFGF nor activation dependent astrocyte factor (ADAF), was able to prevent the degeneration of dopaminergic neurons induced by MPP+. These results suggest that increased intracellular cAMP protects dopaminergic neurons in situations of stress and therefore reveal novel possibilities for the treatment of Parkinson's disease.
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PMID:Cyclic AMP promotes the survival of dopaminergic neurons in vitro and protects them from the toxic effects of MPP+. 882 Oct 58

Tachykinins belong to an evolutionarily conserved family of peptide neurotransmitters. The mammalian tachykinins include substance P, neurokinin A and neurokinin B, which exert their effects by binding to specific receptors. These tachykinin receptors are divided into three types, designated NK1, NK2 and NK3, respectively. Tachykinin receptors have been cloned and contain seven segments spanning the cell membrane, indicating their inclusion in the G-protein-linked receptor family. The continued development of selective agonists and antagonists for each receptor has helped elucidate roles for these mediators, ranging from effects in the central nervous system to the perpetuation of the inflammatory response in the periphery. Various selective ligands have shown both inter- and intraspecies differences in binding potencies, indicating distinct binding sites in the tachykinin receptor. The interaction of tachykinin with its receptor activates Gq, which in turn activates phospholipase C to break down phosphatidyl inositol bisphosphate into inositol trisphosphate (IP3) and diacylglycerol (DAG). IP3 acts on specific receptors in the sarcoplasmic reticulum to release intracellular stores of Ca2+, while DAG acts via protein kinase C to open L-type calcium channels in the plasma membrane. The rise in intracellular [Ca2+] induces the tissue response. With an array of actions as diverse as that seen with tachykinins, there is scope for numerous therapeutic possibilities. With the development of potent, selective non-peptide antagonists, there could be potential benefits in the treatment of a variety of clinical conditions, including chronic pain, Parkinson's disease, Alzheimer's disease, depression, rheumatoid arthritis, irritable bowel syndrome and asthma.
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PMID:Tachykinins: receptor to effector. 892 4

Microglial activation selectively kills certain neuron populations in mixed neuronal/glial cultures, which may prove useful for modeling neurodegenerative diseases such as Parkinson's disease. In mesencephalic mixed neuronal/glial cultures, microglial activation by zymosan A killed more dopaminergic neurons, assessed by [3H]dopamine uptake and by counting tyrosine hydroxylase-immunoreactive neuron number, than did microglial activation by lipopolysaccharide (LPS). The additional toxicity of zymosan resulted from microglial protein kinase C (PKC) activation. Both zymosan and PMA, but not LPS, activated PKC in enriched microglial preparations. In the mixed neuronal/glial cultures, activation of PKC by phorbol myristate acetate (PMA) increased LPS-induced nitric oxide (NO; by nitrite measurements), but not zymosan-induced NO production, and increased LPS-induced dopaminergic neurotoxicity, but not zymosan-induced dopaminergic neurotoxicity. Additive effects of PMA and LPS, similar to zymosan effects alone, reflected activation of distinct neurotoxic pathways in the microglia. The NO synthase inhibitor N-nitro-L-arginine methyl ester (NAME) totally blocked the neurotoxicity of LPS, and partially blocked zymosan-induced neurotoxicity; NAME did not block the PKC component of neurotoxicity. In addition to stimulating NO production as effectively as LPS, zymosan also activates microglial PKC and associated non-NO-mediated neurotoxic pathways that may be important in human neurodegenerative diseases. Since the role of NO in human microglia-induced neurotoxicity is controversial, zymosan may prove more useful than LPS as a microglial activator in the rodent mixed neuronal/glial culture model.
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PMID:Role of protein kinase C in microglia-induced neurotoxicity in mesencephalic cultures. 905 44

The dopamine transporter, a member of the family of Na+,Cl(-)-dependent transporters, mediates uptake of dopamine into dopaminergic neurons by an electrogenic, Na(+)- and Cl(-)-transport-coupled mechanism. Dopamine and blockers of uptake such as cocaine probably bind to both shared and separate domains on the transporter, which can be influenced dramatically by the presence of cations. Regulation of the dopamine transporter occurs both by chronic occupancy with blocker and by acute effects of D2 dopamine receptors or second messengers such as diacylglycerol (protein kinase C) and arachidonic acid. The dopamine transporter is involved in the uptake of toxins generating Parkinson's disease; it is also an important target for psychostimulant drugs, ligands for in vivo imaging and medications used for neurologic diseases involving changes in the dopamine system.
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PMID:Pharmacology and regulation of the neuronal dopamine transporter. 913 7

Oxidative stress is implicated in a number of neurological disorders including stroke, Parkinson's disease, and Alzheimer's disease. To study the effects of oxidative stress on neuronal cells, we have used an immortalized mouse hippocampal cell line (HT-22) that is particularly sensitive to glutamate. In these cells, glutamate competes for cystine uptake, leading to a reduction in glutathione and, ultimately, cell death. As it has been reported that protein kinase C activation inhibits glutamate toxicity in these cells and is also associated with the inhibition of apoptosis in other cell types, we asked if glutamate toxicity was via apoptosis. Morphologically, glutamate-treated cells underwent plasma membrane blebbing and cell shrinkage, but no DNA fragmentation was observed. At the ultrastructural level, there was damage to mitochondria and other organelles although the nuclei remained intact. Protein and RNA synthesis inhibitors as well as certain protease inhibitors protected the cells from glutamate toxicity. Both the macromolecular synthesis inhibitors and the protease inhibitors had to be added relatively soon after the addition of glutamate, suggesting that protein synthesis and protease activation are early and distinct steps in the cell death pathway. Thus, the oxidative stress brought about by treatment with glutamate initiates a series of events that lead to a form of cell death distinct from either necrosis or apoptosis.
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PMID:Oxidative stress induces a form of programmed cell death with characteristics of both apoptosis and necrosis in neuronal cells. 964 55


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