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)

Parkinson's disease (PD) is characterized by a heterogeneous loss of dopaminergic neurons in the human mesencephalon affecting mainly the substantia nigra pars compacta (SNpc) and to a lesser extent the other dopaminergic cell groups. A rise in intracellular calcium concentrations represents one of the final events leading to nerve cell death. Calbindin D28k, a protein capable of buffering intracellular calcium concentrations is present in the dopaminergic neurons that are selectively preserved in PD but not in those that degenerate. To determine whether other calcium-binding proteins also represent putative protective factors of dopaminergic neurons in PD, we analyzed immunohistochemically the distribution of calretinin-containing (CR+) neurons, in the human mesencephalon of three control subjects and four patients with PD. No significant differences were observed between the number of CR+ neurons in the two subject groups. Sequential double immunostaining for calretinin and tyrosine hydroxylase showed a variable proportion of CR+ neurons among dopaminergic neurons: moderate co-localization was found in catecholaminergic cell group A8 and in the dorsal part of the ventral tegmental area (VTA) and low co-localization in the SNpc, the ventral part of the VTA and the central gray substance. This indicates that calretinin may only protect some dopaminergic neurons against degeneration in PD. Yet, in the SNpc a selective preservation of CR+ dopaminergic neurons was observed, suggesting a neuroprotective role in some dopaminergic cell groups only.
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PMID:Does the calcium binding protein calretinin protect dopaminergic neurons against degeneration in Parkinson's disease? 770 19

A substantial number of adults and half of the children with acquired immunodeficiency syndrome (AIDS) suffer from neurological manifestations. Among the various pathologies reported in brains of patients with AIDS is neuronal injury and loss, although neurons themselves do not appear to be infected by HIV-1. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or demise of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. HIV-infected monocytoid cells, especially after interacting with astrocytes, secrete neurotoxic substances. Not all of these substances are yet known, but they may include eicosanoids, platelet-activating factor, quinolinate, cysteine, cytokines, and free radicals. Macrophages activated by HIV-1 envelope protein gp120 also appear to release similar toxins. Some of these factors can lead to increased glutamate release or decreased glutamate reuptake. A final common pathway for neuronal suceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-asparate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:Neuronal injury associated with HIV-1 and potential treatment with calcium-channel and NMDA antagonists. 770 21

Flunarizine and cinnarizine have been well documented to cause EPS. Other CCBs, on rare occasions, also have been reported to cause EPS. Theoretical explanations for these events include the inhibition of calcium influx into striatal cells and direct dopaminergic antagonistic properties. In addition, the chemical structures of flunarizine and cinnarizine, which are related to neuroleptics, may explain the relatively greater incidence of EPS with these agents. Suggested risk factors for acquiring EPS with flunarizine or cinnarizine use appear to be age, although experience with using these agents in younger patients is limited, and a family history of tremors and/or Parkinson's disease. The onset and type of presentation is unpredictable and, in most instances, discontinuation of the medication relieves the symptoms within a few days to months. Pharmacologic management of EPS with continued use of the offending agent generally has not been of clinical benefit. In conclusion, patients receiving CCBs, particularly flunarizine and cinnarizine, should be monitored for EPS.
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PMID:Extrapyramidal symptoms associated with calcium-channel blockers. 771 50

Muscarinic receptors regulate a number of important basic physiologic functions including heart rate and motor and sensory control as well as more complex behaviors including arousal, memory, and learning. Loss of muscarinic receptor number or function has been implicated in the etiology of several neurological disorders including Alzheimer's dementia, Down's syndrome, and Parkinson's disease. Muscarinic receptors transduce their signals by coupling with G-proteins, which then modulate the activity of a number of effector enzymes and ion channels. Five subtypes of muscarinic receptors (m1-m5) have been identified by molecular cloning and much has been learned about their distribution, pharmacology, and structure. Less is known about the molecular mechanisms of receptor-effector coupling and the biological role of each receptor subtype. The ectopic expression of genes encoding a single muscarinic receptor subtype in mammalian cell lines has provided an important model system in which to investigate receptor subtype-specific pharmacology and signal transduction. Expression models have revealed that single muscarinic receptor m1, m3, or m5 subtypes can activate multiple signaling effectors simultaneously including phospholipases A2, C, and D, as well as tyrosine kinase and a novel class of voltage-insensitive calcium channels. The m2 or m4 receptors have been shown to augment phospholipase A2 in addition to their established role as inhibitory receptors acting through the attenuation of adenylate cyclase. In addition to allowing investigations of the regulatory mechanisms of muscarinic receptors, expression models provide an excellent tool to investigate receptor-subtype specific physiology and pharmacology.
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PMID:Muscarinic acetylcholine receptors: signal transduction through multiple effectors. 776 53

The aim of this study was to achieve a better understanding of the integration in striatal medium-sized spiny neurons (MSNs) of converging signals from glutamatergic and dopaminergic afferents. The review of the literature in the first section shows that these two types of afferents not only contact the same striatal cell type, but that individual MSNs receive both a corticostriatal and a dopaminergic terminal. The most common sites of convergence are dendritic shafts and spines of MSNs with a distance between the terminals of less than 1-2 microns. The second section focuses on synaptic transmission and second messenger activation. Glutamate, the candidate transmitter of corticostriatal terminals, via different types of glutamate receptors can evoke an increase in intracellular free calcium concentrations. The net effect of dopamine in the striatum is a stimulation of adenylate cyclase activity leading to an increase in cAMP. The subsequent sections present information on calcium- and cAMP-sensitive biochemical pathways and review the regional and subcellular distribution of the components in the striatum. The specific biochemical reaction steps were formalized as simplified equilibrium equations. Parameter values of the model were chosen from published experimental data. Major results of this analysis are: at intracellular free calcium concentrations below 1 microM the stimulation of adenylate cyclase by calcium and dopamine is at least additive in the steady state. Free calcium concentrations exceeding 1 microM inhibit adenylate cyclase, which is not overcome by dopaminergic stimulation. The kinases and phosphatases studied can be divided in those that are almost exclusively calcium-sensitive (PP2B and CaMPK), and others that are modulated by both calcium and dopamine (PKA and PP1). Maximal threonine-phosphorylation of the phosphoprotein DARPP requires optimal concentrations of calcium (about 0.3 microM) and dopamine (above 5 microM). It seems favourable if the glutamate signal precedes phasic dopamine release by approximately 100 msec. The phosphorylation of MAP2 is under essentially calcium-dependent control of at least five kinases and phosphatases, which differentially affect its heterogeneous phosphorylation sites. Therefore, MAP2 could respond specifically to the spatio-temporal characteristics of different intracellular calcium fluxes. The quantitative description of the calcium- and dopamine-dependent regulation of DARPP and MAP2 provides insights into the crosstalk between glutamatergic and dopaminergic signals in striatal MSNs. Such insights constitute an important step towards a better understanding of the links between biochemical pathways, physiological processes, and behavioural consequences connected with striatal function. The relevance to long-term potentiation, reinforcement learning, and Parkinson's disease is discussed.
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PMID:Postsynaptic integration of glutamatergic and dopaminergic signals in the striatum. 783 76

The in vivo generation of .OH free radicals in specific brain regions can be measured by intracerebral microdialysis perfusion of salicylate, avoiding many of the pitfalls inherent in systemic administration of salicylate. Direct infusion of salicylate into the brain can minimize the hepatic hydroxylation of salicylate and its contribution to brain levels of 2,5-DHBA. Levels of 2,5-DHBA detected in the brain dialysate may reflect the .OH adduct plus some enzymatic hydroxylation of salicylate in the brain. After minimizing the contribution of enzyme and/or blood-borne 2,5-DHBA, the present data demonstrate the validity of the use of 2,3-DHBA and apparently 2,5-DHBA as indices of .OH formation in the brain. Therefore, intracranial microdialysis of salicylic acid and measurement of 2,3-DHBA appears to be a useful .OH trapping procedure for monitoring the time course of .OH generation in the extracellular fluid of the brain. These results indicate that nonenzymatic and/or enzymatic oxidation of the dopamine released by MPTP analogues in the extracellular fluid may play a key role in the generation of .OH free radicals in the iron-rich basal ganglia. Moreover, a site-specific generation of cytotoxic .OH free radicals and quinone/semiquinone radicals in the striatum may cause the observed lipid peroxidation, calcium overload, and retrograde degeneration of nigrostriatal neurons. This free-radical-induced nigral injury can be suppressed by antioxidants (i.e., U-78517F, DMSO, and deprenyl) and possibly hypothermia as well. In the future, this in vivo detection of .OH generation may be useful in answering some of the fundamental questions concerning the relevance of oxidants and antioxidants in neurodegenerative disorders during aging. It could also pave the way for the research and development of novel neuroprotective antioxidants and strategies for the early or preventive treatment of neurodegenerative disorders, such as Parkinson's disease (Wu et al., this issue), amyotrophic lateral sclerosis, head trauma, and possibly Alzheimer's cognitive dysfunction as well. In conclusion, this in vivo free-radical trapping procedure provides evidence to support a current working hypothesis that a site-specific formation of cytotoxic .OH free radicals in the basal ganglia may be one of the neurotoxic mechanisms underlying nigrostriatal degeneration and Parkinsonism caused by the dopaminergic neurotoxin MPTP. Addendum added in proof: The controversy concerning possible neurotoxic and/or neuroprotective roles of NO. in cell cultures was discussed and debated at the symposium (Wink et al., this issue; Dawson et al., this issue; Lipton et al., this issue).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vivo generation of hydroxyl radicals and MPTP-induced dopaminergic toxicity in the basal ganglia. 783 34

Problems associated with aging will become one of the leading health dilemmas of the next century. Age-associated diseases, including those affecting the neuronal system, are increasing in frequency. Age-related deficiencies in the brain result in impaired motor functions, sleep, behaviour and cognitive functions. Good functioning of the brain is based on the communication between neurons, by means of signal sending and processing. Neuronal transmission is a very complex phenomenon which involves neuromediator receptors, ion channels and various signal transduction systems. Aging is associated with modification of many brain neurotransmitter and second messenger systems directly involved in signal transduction. Thus, signal transduction events that are deficient in the aged include calcium mobilisation, phosphatidylinositol breakdown, cyclic nucleotides formation, accumulation of proto-oncogene transcripts and synthesis of new proteins, such as certain neurotransmitters. Other events in signal transduction, such as protein tyrosine kinase activity, G-protein structure and function and receptor-G-protein coupling, have not been studied in great detail as yet. Alterations in these various intracellular signalling events may fundamentally influence the functional activity of neurons, and, in consequence, play an important role in the age-dependent alterations of brain functions. Future studies are needed to better understand the molecular basis and the importance of signal transduction changes with aging. Such knowledge will certainly lead to design of better drugs for the prevention or treatment of age-related deficiencies or diseases, such as Parkinson's disease or Alzheimer's disease.
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PMID:Age-related changes in signal transduction. Implications for neuronal transmission and potential for drug intervention. 783 90

Approximately a third of adults and half of children with acquired immunodeficiency syndrome (AIDS) eventually suffer from neurological manifestations, including dysfunction of cognition, movement, and sensation. Among the various pathologies reported in the brain of patients with AIDS is neuronal injury and loss. A paradox arises, however, because neurons themselves are for all intents and purposes not infected by human immunodeficiency virus type 1 (HIV-1). This paper reviews evidence suggesting that at least part of the neuronal injury observed in the brain of AIDS patients is related to excessive influx of Ca2+. There is growing support for the existence of HIV- or immune-related toxins that lead indirectly to the injury or death of neurons via a potentially complex web of interactions between macrophages (or microglia), astrocytes, and neurons. Human immunodeficiency virus-infected monocytoid cells (macrophages, microglia, or monocytes), especially after interacting with astrocytes, secrete substances that potentially contribute to neurotoxicity. Not all of these substances are yet known, but they may include eicosanoids, that is, arachidonic acid and its metabolites, as well as platelet-activating factor. Macrophages activated by HIV-1 envelope protein gp120 also appear to release arachidonic acid and its metabolites. These factors can lead to increased glutamate release or decreased glutamate reuptake. In addition, gamma interferon (IFN-gamma) stimulation of macrophages induce release of the glutamate-like agonist quinolinate. Human immunodeficiency virus-infected or gp120-stimulated macrophages also produce cytokines, including tumor necrosis factor-alpha and interleukin-1 beta, which contribute to astrogliosis. A final common pathway for neuronal susceptibility appears to be operative, similar to that observed in stroke, trauma, epilepsy, neuropathic pain, and several neurodegenerative diseases, possibly including Huntington's disease, Parkinson's disease, and amyotrophic lateral sclerosis. This mechanism involves the activation of voltage-dependent Ca2+ channels and N-methyl-D-aspartate (NMDA) receptor-operated channels, and therefore offers hope for future pharmacological intervention. This review focuses on clinically tolerated calcium channel antagonists and NMDA antagonists with the potential for trials in humans with AIDS dementia in the near future.
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PMID:AIDS-related dementia and calcium homeostasis. 784 72

Calpains (CANPs) are a family of calcium-dependent cysteine proteases under complex cellular regulation. By making selective limited proteolytic cleavages, they activate or alter the regulation of certain enzymes, including key protein kinases and phosphatases, and induce specific cytoskeletal rearrangements, accounting for their suspected involvement in intracellular signaling, vesicular trafficking, and structural stabilization. Calpain activity has been implicated in various aging phenomena, including cataract formation and erythrocyte senescence. Abnormal activation of the large stores of latent calpain in neurons induces cell injury and is believed to underlie neurodegeneration in excitotoxicity, Wallerian degeneration, and certain other neuropathologic states involving abnormal calcium influx. In Alzheimer's disease, we found the ratio of activated calpain I to its latent precursor isoform in neocortex to be threefold higher than that in normal individuals and those with Huntington's or Parkinson's disease. Immunoreactivity toward calpastatin, the endogenous inhibitor of calpain, was also markedly reduced in layers II-V of the neocortex in Alzheimer's disease. The excessive calpain system activation suggested by these findings represents a potential molecular basis for synaptic loss and neuronal cell death in the brain in Alzheimer's disease given the known destructive actions of calpain I and its preferential neuronal and synaptic localization. In surviving cells, persistent calpain activation may also contribute to neurofibrillary pathology and abnormal amyloid precursor protein trafficking/processing through its known actions on protein kinases and the membrane skeleton. The degree of abnormal calpain activation in the brain in Alzheimer's disease strongly correlated with the extent of decline in levels of secreted amyloid precursor protein in brain. Cytoskeletal proteins that are normally good calpain substrates become relatively calpain resistant when they are hyperphosphorylated, which may contribute to their accumulation in neurofibrillary tangles. As a major effector of calcium signals, calpain activity may mirror disturbances in calcium homeostasis and mediate important pathologic consequences of such disturbances.
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PMID:Calcium-activated neutral proteinase (calpain) system in aging and Alzheimer's disease. 784 93

Substantial evidence has accumulated implicating metals and free radicals in the pathogenesis of the major neurodegenerative disorders (Parkinson's disease, Alzheimer's disease, and amyotrophic lateral sclerosis). Metal-induced oxidant stress can damage critical biological molecules and initiate a cascade of events including mitochondrial dysfunction, excitotoxicity, and a rise in cytosolic free calcium, leading to cell death. In Parkinson's disease and Alzheimer's disease there is evidence of oxidative stress in affected brain regions, as indicated by increased metal accumulation (which promotes free radical formation), decreased antioxidant levels (which protect against free radical formation), and oxidative damage. Recently, studies of the familial form of amyotrophic lateral sclerosis have detected mutations in the gene that encodes superoxide dismutase, which is one of the body's primary oxidant defense mechanisms. Mice that are transfected with the human mutant superoxide dismutase gene develop an amyotrophic lateral sclerosis syndrome. These studies demonstrate that oxidant stress can initiate the development of a chronic progressive neurodegenerative disorder.
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PMID:Metals and free radicals in neurodegeneration. 786 88


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