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)

The adenosine A2A receptor subtype is one of the four adenosine receptors that have been identified in the mammalian organism. In addition to being found in blood vessels, platelets and polymorphonuclear leukocytes, the A2A receptors are abundant in the central nervous system, especially in the striatum. The recent development of selective A2A receptor ligands, in particular of receptor antagonists, makes it possible to elucidate the function of A2A receptors in normal and altered conditions. Pharmacological studies have shown that A2A receptor antagonists are potentially effective for treatment of neurodegenerative processes such as Parkinson's disease. Their activity is attributed to the close anatomical and functional links between A2A receptors and dopaminergic pathways in the basal ganglia. More recently, A2A receptor antagonists have proved to be active in models of cerebral ischemia. While the mechanisms underlying the role of A2A receptors in the hypoxia/ ischemia processes remains to be clarified, it is recognized that A2A receptor antagonists counteract the effects of excitatory aminoacids, which are massively released after cerebral ischemia. Another function of A2A receptors is related to protection from seizures, but further studies are needed to elucidate their specific interaction, if any, with neuronal excitability. Altogether, the great advance recently made with the discovery of selective A2A receptor ligands provides increasing information on the function of A2A receptors and opens new perspectives for treatment of neurological disorders.
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PMID:Adenosine A2A receptors and neuroprotection. 936 73

Enormous interest in cell death in the past several years has moved apoptosis to the forefront of scientific research. Apoptosis has been found to mediate cell deletion in tissue homeostasis, embryological development, and immunological functioning. It also occurs in pathological conditions, including cancer and acquired immunodeficiency syndrome, and is implicated in neurodegenerative diseases. Claims of neuronal apoptosis induced by various agents and conditions are published regularly, but in many instances the data are questionable because they are incomplete. This review presents a brief history of apoptosis and describes the evidence required before claims of apoptosis are made. Summaries and critiques of important investigations concerning the genetic and biochemical regulation of neuronal apoptosis are presented, as are other studies describing connections between apoptosis and neuronal cell death in physiological and pathological situations. There is a realization that apoptosis can be programmed and is distinguishable from necrotic cell death. Combining apoptosis with programmed cell death produces misleading terminology and confusion over these two forms of cell degeneration. Further investigations into neuronal apoptosis should focus on all of the criteria that the original investigators outlined 25 years ago, to clarify whether apoptosis and/or another form of cell death mediates neuronal degeneration in physiological settings and in neurological diseases such as Alzheimer's disease, Parkinson's disease, epilepsy, and ischemia/stroke.
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PMID:Apoptosis in neurological disease. 952 91

The Transforming Growth Factor-betas (TGF-beta) are a group of multifunctional proteins whose cellular sites of production and action are widely distributed throughout the body, including the central nervous system (CNS). Within the CNS, various isoforms of TGF-beta are produced by both glial and neural cells. When evaluated in either cell culture or in vivo models, the various isoforms of TGF-beta have been shown to have potent effects on the proliferation, function, or survival of both neurons and all three glial cell types, astrocytes, microglia and oligodendrocytes. TGF-beta has also been shown to play a role in several forms of acute CNS pathology including ischemia, excitotoxicity and several forms of neurodegenerative diseases including multiple sclerosis, Parkinson's disease, AIDS dementia and Alzheimer's disease.
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PMID:TGF-beta in the central nervous system: potential roles in ischemic injury and neurodegenerative diseases. 962 Jun 42

The potential of most N-methyl-D-aspartate antagonists as neuroprotectants is limited by side effects. We previously reported that memantine is an open-channel N-methyl-D-aspartate blocker with a faster off-rate than many uncompetitive N-methyl-D-aspartate antagonists such as dizocilpine maleate. This parameter correlated with memantine's known clinical tolerability in humans with Parkinson's disease. Memantine is the only N-methyl-D-aspartate antagonist that has been used clinically for excitotoxic disorders at neuroprotective doses. Therefore, we wanted to investigate further the basis of its clinical efficacy, safety, and tolerability. Here we show for the first time for any clinically-tolerated N-methyl-D-aspartate antagonist that memantine significantly reduces infarct size when administered up to 2 h after induction of hypoxia/ischemia in immature and adult rats. We found that at neuroprotective concentrations memantine results in few adverse side effects. Compared to dizocilpine maleate, memantine displayed virtually no effects on Morris water maze performance or on neuronal vacuolation. At concentrations similar to those in brain following clinical administration, memantine (6-10 microM) did not attenuate long-term potentiation in hippocampal slices and substantially spared the N-methyl-D-aspartate component of excitatory postsynaptic currents, while dizocilpine maleate (6-10 microM) or D-2-amino-5-phosphovalerate (50 microM) completely blocked these phenomena. We suggest that the favorable kinetics of memantine interaction with N-methyl-D-aspartate channels may be partly responsible for its high index of therapeutic safety, and make memantine a candidate drug for use in many N-methyl-D-aspartate receptor-mediated human CNS disorders.
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PMID:Neuroprotective concentrations of the N-methyl-D-aspartate open-channel blocker memantine are effective without cytoplasmic vacuolation following post-ischemic administration and do not block maze learning or long-term potentiation. 969 19

Free radicals are known to occur as natural by-products under physiological conditions and have been implicated in the neuronal loss observed in a variety of neuropathological conditions including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), and ischemia. Oxyradical-induced cytotoxicity arises from both chronic and acute increases in reactive oxygen species which give rise to subsequent lipid peroxidation (LP). By reacting with polyunsaturated fatty acids in the the various cellular membranes, oxyradicals such as hydroxyl (OH.) and peroxynitrite (ONOO) give rise to a variety of lipid peroxidation products (LPP), including 4-hydroxynonenal (HNE) and malondialdehyde (MD). Once formed, these peroxidation metabolites have been demonstrated to have relatively long half-lives within cells (minutes to hours), allowing for multiple interactions with cellular components. Emerging data suggest that LP and LPP may underlie the neuronal alterations and neurotoxicity observed in numerous neurodegenerative conditions. Data supporting this involvement include the detection of LP and formation of LPP in a variety of neuropathological conditions including AD, ALS, PD, and ischemia. Secondly, direct application of LPP, either in vivo or in vitro, has been shown to be cytotoxic and mimic neuronal alterations observed in neuropathological conditions. Furthermore, prevention of LP and subsequent LPP formation have been demonstrated to be neuroprotective in a variety of neurodegenerative paradigms. Additionally, LP and LPP have been implicated in the modulation of a wide array of activities within the central nervous system including long term potentiation, neurite outgrowth, and proliferation. Understanding the mechanism(s) and involvement of LP in these processes will greatly enhance the understanding of oxyradical and ion homeostasis in neurophysiological and neuropathological conditions. The focus of this review is to describe the process by which lipid peroxidation occurs and establish a framework for its involvement in the central nervous system.
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PMID:Roles of lipid peroxidation in modulation of cellular signaling pathways, cell dysfunction, and death in the nervous system. 971 2

Melatonin was recently reported to be an effective free radical scavenger and antioxidant. Melatonin is believed to scavenge the highly toxic hydroxyl radical, the peroxynitrite anion, and possibly the peroxyl radical. Also, secondarily, it reportedly scavenges the superoxide anion radical and it quenches singlet oxygen. Additionally, it stimulates mRNA levels for superoxide dismutase and the activities of glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase (all of which are antioxidative enzymes), thereby increasing its antioxidative capacity. Also, melatonin, at least at some sites, inhibits nitric oxide synthase, a pro-oxidative enzyme. In both in vivo and in vitro experiments melatonin has been shown to reduce lipid peroxidation and oxidative damage to nuclear DNA. While these effects have been observed primarily using pharmacological doses of melatonin, in a small number of experiments melatonin has been found to be physiologically relevant as an antioxidant as well. The efficacy of melatonin in inhibiting oxidative damage has been tested in a variety of neurological disease models where free radicals have been implicated as being in part causative of the condition. Thus, melatonin has been shown prophylactically to reduce amyloid beta protein toxicity of Alzheimer's disease, to reduce oxidative damage in several models of Parkinson's disease (dopamine auto-oxidation, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and 6-hydroxydopamine), to protect against glutamate excitotoxicity, to reduce ischemia-reperfusion injury, to lower neural damage due to gamma-aminolevulinic acid (phorphyria), hyperbaric hyperoxia and a variety of neural toxins. Since endogenous melatonin levels fal 1 markedly in advanced age, the implication of these findings is that the loss of this antioxidant may contribute to the incidence or severity of some age-associated neurodegenerative diseases.
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PMID:Oxidative damage in the central nervous system: protection by melatonin. 977 Feb 44

The pathophysiology of organ system failure in sepsis, in particular the effects of septic shock on the central nervous system, are still incompletely understood. Lipopolysaccharide (LPS) from Gram-negative bacteria affects the permeability of the blood-brain barrier and causes the activation of brain microglia. A growing body of research supports involvement of activated brain microglia in brain pathologies caused by infectious diseases, trauma, tumors, ischemia, Alzheimer's disease, Parkinson's disease, Down's syndrome, multiple sclerosis and AIDS. Those seminal studies that have contributed to the characterization of the in vivo and in vitro effects of LPS on microglia function, mediator generation and receptor expression are presented within a historical perspective. In particular, all those in vitro studies on O2-, H2O2 and NO. generation by either unprimed or primed microglia have been extensively reviewed. The apparent controversial effect of LPS on microglia O2- is discussed. Because treatment modalities for septic shock have not significantly affected the current high mortality, alternative strategies with antioxidants are currently being investigated. Reduction of microglia O2- generation is proposed as a possible complementary strategy to antioxidative therapy for septic shock and CNS pathologies that involve activated microglia.
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PMID:Therapeutic implications of microglia activation by lipopolysaccharide and reactive oxygen species generation in septic shock and central nervous system pathologies: a review. 981

DNA fragmentation was examined in situ in flash-frozen human postmortem midbrain as a marker for programmed cell death. A large series of cases comprising 16 pathologically confirmed idiopathic Parkinson's disease (IPD) cases, 14 control cases without brain pathology, and a group of 6 patients with other parkinsonian movement disorders were examined using TdT-mediated dUTP-biotin 3' end-labeling histology. Labeling of neurons and glia was seen in the substantia nigra of control and IPD cases and in other movement disorder cases. Labeled nuclei were seen in melanized nigral neurons; apoptotic bodies were also found but were more commonly associated with nigral glia. In the control group, labeling of neurons and glia was strongly associated with poor agonal status, assessed by tissue pH, a marker for antemortem hypoxia. The mean tissue pH of the control group with neuronal labeling was 6.28 (SEM .057), which was significantly different from that of the unlabeled group 6.55 (SEM .055). Mean tissue pH for all cases was 6.38. There was no association of nigral neuronal labeling with poor agonal status in the IPD cases, which showed labeling throughout the range of pH values. However, extranigral labeling, seen in the mesencephalon, red nucleus, superior colliculus, rostral pons, and periaqueductal gray matter, in all three subject groups was associated with tissue pH values of less than 6.3. These findings suggest that DNA fragmentation is influenced by antemortem hypoxia and that apoptosis-like changes seen in the postmortem nigra may parallel those seen in experimental ischemia in the animal brain. The likely influence of perimortem factors on these changes indicates that results from postmortem studies of apoptotic cell death in neurodegenerative disease should be treated with caution and underlines the importance of determining postmortem markers for agonal status in human brain.
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PMID:DNA fragmentation in human substantia nigra: apoptosis or perimortem effect? 982 10

1. Free radicals may play an important role in several pathological conditions of the central nervous system (CNS) where they directly injure tissue and where their formation may also be a consequence of tissue injury. 2. Free radicals produce tissue damage through multiple mechanisms, including excito-toxicity, metabolic dysfunction, and disturbance of intracellular homeostasis of calcium. 3. Oxidative stress can significantly worsen acute insults, such as ischemia, as well as chronic neurodegenerative disorders including amyotrophic lateral sclerosis (ALS) and Parkinson's disease. 4. For instance, recent findings suggest a causal role for chronic oxidative stress in familial ALS, as this disease is linked to missence mutations of the copper/zinc superoxide dismutase (SOD). 5. Thus, therapeutic approaches which limit oxidative stress may be potentially beneficial in several neurological diseases.
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PMID:Free radicals as mediators of neuronal injury. 987 73

In the CNS, reactive oxygen species (ROS) have been implicated in a wide range of degenerative processes including amyotrophic lateral sclerosis, ischemia-reperfusion injury, Alzheimer disease, Parkinson disease and aging. However, the exact mechanism is unknown, and there is little information on possible roles of ROS in cell injury and the process on recovery of astrocytes, the most abundant glial cells in the brain. We examined hydrogen peroxide (H2O2)-induced DNA fragmentation and thymidine incorporation into cultured astrocytes as an indicator of the process of recovery from astrocytic DNA injury. Astrocytes were isolated from cerebral cortices of 0-day-old rats and treated with 1 mM dibutyryl cyclic AMP for 4 days. H2O2 of 100 microM stimulated thymidine incorporation into astrocytes. Caffeine, ryanodine, cyclic ADP-ribose (endogenous ryanodine receptor agonist) and beta-NAD+ (precursor of cyclic ADP-ribose) suppressed partially the stimulatory effect of H2O2. Ruthenium red (ryanodine receptor antagonist) facilitated further the stimulatory effect of H2O2. The facilitated effect of ruthenium red on H2O2-induced thymidine incorporation was suppressed by caffeine, ryanodine, cyclic ADP-ribose and beta-NAD+. H2O2-induced DNA fragmentation and astrocytic death were suppressed by ruthenium red. These findings suggest that the process of recovery from astrocytic DNA injury by H2O2 may be regulated by Ca2+ efflux from ryanodine-sensitive intracellular Ca2+ stores.
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PMID:[Role of ryanodine receptors in hydrogen peroxide-induced DNA fragmentation and thymidine incorporation in cultured rat astrocytes]. 1019 Jan 45


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