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)

Lower rates of cancer mortality/incidence in patients with Parkinson's disease (PD) have given rise to speculations about risk or preventative factors common to both diseases, including life-style factors (such as smoking) and genetic susceptibility. Melatonin, a hormone known for its sleep regulatory effects, may play an important role in carcinogenesis as suggested by substantial laboratory and less direct epidemiologic evidence. Particularly, a reduction in melatonin, such as experienced by persons who are exposed to light at night, appears to increase cancer risk. Variations in melatonin levels have been linked to PD in several different ways. Some studies show higher morning melatonin levels in PD patients than in healthy controls. One could speculate that the sleep disorders that affect almost two thirds of those suffering from PD and can precede PD motor symptoms by several years may be associated with variations in melatonin levels. Moreover, in animal models, interventions that increase the bioavailability of melatonin appears to increase the severity of parkinsonian symptoms, whereas reduction in melatonin by pinealectomy or exposure to bright light can enhance recovery from parkinsonisms symptoms. Finally, preliminary epidemiological evidence suggests that longer years of working night shifts is associated with a reduced risk of PD among participants of the Nurses' Health Study (NHS), whereas longer hours of sleep appear to increase their risk. In sum, while lower melatonin concentrations may predict a higher cancer risk, there is also some evidence that they may be associated with a lower risk of PD. We therefore hypothesize that elevated circulating melatonin levels in PD patients may contribute to their lower cancer rates.
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PMID:Circulating melatonin levels: possible link between Parkinson's disease and cancer risk? 1659 13

Increased oxidative stress and mitochondrial dysfunction have been identified as common pathophysiological phenomena associated with neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). As the age-related decline in the production of melatonin may contribute to increased levels of oxidative stress in the elderly, the role of this neuroprotective agent is attracting increasing attention. Melatonin has multiple actions as a regulator of antioxidant and prooxidant enzymes, radical scavenger and antagonist of mitochondrial radical formation. The ability of melatonin and its kynuramine metabolites to interact directly with the electron transport chain by increasing the electron flow and reducing electron leakage are unique features by which melatonin is able to increase the survival of neurons under enhanced oxidative stress. Moreover, antifibrillogenic actions have been demonstrated in vitro, also in the presence of profibrillogenic apoE4 or apoE3, and in vivo, in a transgenic mouse model. Amyloid-beta toxicity is antagonized by melatonin and one of its kynuramine metabolites. Cytoskeletal disorganization and protein hyperphosphorylation, as induced in several cell-line models, have been attenuated by melatonin, effects comprising stress kinase downregulation and extending to neurotrophin expression. Various experimental models of AD, PD and HD indicate the usefulness of melatonin in antagonizing disease progression and/or mitigating some of the symptoms. Melatonin secretion has been found to be altered in AD and PD. Attempts to compensate for age- and disease-dependent melatonin deficiency have shown that administration of this compound can improve sleep efficiency in AD and PD and, to some extent, cognitive function in AD patients. Exogenous melatonin has also been reported to alleviate behavioral symptoms such as sundowning. Taken together, these findings suggest that melatonin, its analogues and kynuric metabolites may have potential value in prevention and treatment of AD and other neurodegenerative disorders.
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PMID:Melatonin in Alzheimer's disease and other neurodegenerative disorders. 1667 4

Melatonin, a secretory product of the pineal gland, is involved in the regulation of circadian and seasonal rhythms, in oncostasis, and in inducing osteoblast differentiation. Furthermore, melatonin is a scavenger of a number of reactive oxygen and reactive nitrogen species both in vitro and in vivo. In this study, the antioxidant nature of melatonin was shown to prevent cultured neural cells from apoptosis induced by endocrine-disrupting chemical, maneb. The neurotoxicity of the fungicide, maneb (1 microg/mL), on the PC12 cells was elicited through apoptotic cell death, concomitant with aggregation of alpha-synuclein, a feature of Parkinson's disease. Activation of caspase-3/7 was associated with this process. A fluorescence rationing technique using a mitochondrial dye revealed that maneb altered the mitochondrial membrane potential of the neural cells. However, melatonin (1 nm) largely prevented the neural cells from the neural toxicant by inhibition of both caspase-3/7 activation and disruption of the mitochondrial transmembrane potential. Furthermore, aggregation of alpha-synuclein by maneb was also inhibited by melatonin. Thus, melatonin prevents maneb-induced neurodegeneration at a nighttime physiological blood concentration, most likely by inhibiting the aggregation of alpha-synuclein as well as preventing mitochondrial dysfunction in PC 12 cells.
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PMID:Melatonin inhibits maneb-induced aggregation of alpha-synuclein in rat pheochromocytoma cells. 1728 43

In the present study, we evaluated the effect of melatonin, a well-known free radical scavenger and neuroprotector, against rotenone-induced oxidative stress in a hemiparkinsonian rat model. The effect of melatonin on glutathione (GSH) depletion caused by unilateral, intranigral infusion of rotenone was investigated employing a spectrofluorimetric procedure. We also studied the effect of melatonin on rotenone-induced changes in the antioxidant enzymes superoxide dismutase (SOD) and catalase in the cytosolic fractions of substantia nigra (SN), employing spectrophotometric procedures. Rotenone-induced hydroxyl radicals (*OH) in the isolated mitochondria, as measured employing a sensitive HPLC-electrochemical method, were significantly scavenged by melatonin. Melatonin treatment restored the rotenone-induced decrease in GSH level and changes in antioxidant enzyme (SOD and catalase) activities in the SN. Our results strongly indicate melatonin's beneficial use in Parkinson's disease therapy as an antioxidant.
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PMID:Melatonin protects against rotenone-induced oxidative stress in a hemiparkinsonian rat model. 1734 22

Insomnia, sleep fragmentation and excessive daytime sleepiness are common in Parkinson's disease (PD) and may contribute to the reduction of cognition and alertness in those patients. Melatonin has been shown to improve sleep in several conditions. In experimental models of PD, melatonin can ameliorate motor symptoms. To evaluate the effect of melatonin on sleep and motor dysfuntion in PD, we studied 18 patients (Hoehn & Yahr I to III) from a PD clinic. Prior to treatment, motor dysfunction was assessed by UPDRS II, III and IV. Subjective sleep quality was assessed by the Pittsburgh Sleep Quality Index (PSQI) and daytime somnolence by the Epworth Sleepiness Scale (ESS). Full polysomnography (PSG) was performed in all subjects. Patients were then randomized to receive melatonin (3mg) or placebo one hour before bedtime for four weeks. All measures were repeated at the end of treatment. On initial assessment, 14 patients (70%) showed poor quality sleep (PSQI > 6) and eight (40%) excessive daytime sleepiness (ESS > 10). Increased sleep latency (50%), REM sleep without atonia (66%), and reduced sleep efficiency (72%) were found on PSG. Eight patients had an apnea/ hipopnea index greater than 15 but no severe oxygen desaturation was observed. Sleep fragmentation tended to be more severe in patients on lower doses of levodopa (p = 0.07). Although melatonin significantly improved subjective quality of sleep (p = 0.03) as evaluated by the PSQI index, PSG abnormalities were not changed. Motor dysfunction was not improved by the use of melatonin. Undetected differences in motor scores and PSG findings may have been due to a small sample size and a type II error.
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PMID:Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson's disease. A randomized, double blind, placebo-controlled study. 1828 17

Melatonin has multiple roles including neuroprotection. Melatonin signaling involves diverse targets including two G-protein-coupled receptors, MT(1) and MT(2), which have both been localized to the nigrostriatal pathway. Previous studies in our laboratory demonstrated preservation of tyrosine hydroxylase immunoreactivity, following chronic treatment with a physiological dose of melatonin, in the 6-hydroxydopamine rat model of Parkinson's disease. Additionally, we reported the presence of the melatonin MT(1) receptor subtype in cultured C17.2 neural stem cells (NSCs). In the present study, we examined the effects of C17.2 NSC transplantation on dopaminergic denervation following 6-hydroxydopamine lesioning in the rat striatum. Moreover, based on our detection of the MT(1) in these cells, we examined the effects of combined C17.2 NSC transplantation and melatonin treatment, following striatal lesioning. Behavioral studies indicated a marked inhibition of apomorphine-induced rotations in lesioned animals that received C17.2 NSC transplantation, melatonin, or the combined regimen. In addition, these treatments resulted in a significant protection of tyrosine hydroxylase immunoreactivity in the striatum and substantia nigra of lesioned animals, when compared with untreated controls. Lesioned animals treated with C17.2 NSCs, melatonin or a combination of both agents exhibited no significant differences in the number of tyrosine hydroxylase-positive cells in the substantia nigra or ventral tegmental area ipsilateral or contralateral to the lesioned striatum. These findings suggest that stem cell therapy and concomitant use of neuroprotective agents such as melatonin could be a viable approach in Parkinson's disease.
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PMID:Neural stem cell transplantation and melatonin treatment in a 6-hydroxydopamine model of Parkinson's disease. 1780 21

Parkinson's disease (PD) is a movement disorder resulting from nigrostriatal dopaminergic neurodegeneration. The impairment of mitochondrial function and dopamine synaptic transmission are involved in the pathogenesis of PD. Two mitochondrial inhibitors, 1-methyl-4-phenylpyridine (MPP(+)) and rotenone, have been used to induce dopaminergic neuronal death both in in vitro and in vivo models of PD. Because the uptake of MPP(+) is mediated by the dopamine transporter (DAT), we used a cell-permeable rotenone-induced PD model to investigate the role of DAT and dopamine D2 receptor (D2R) on dopaminergic neuronal loss. Rotenone subcutaneously infused for 14 days induced PD symptoms in rats, as indicated by reduced spontaneous locomotor activity (hypokinesis), loss of tyrosine hydroxylase (TH, a marker enzyme for dopamine neurons) immunoreactivity in the substantia nigra and striatum, obvious alpha-synuclein accumulation, downregulated DAT protein expression, and upregulated D2R expression. Interestingly, rotenone also caused significant noradrenergic neuronal loss in the locus coeruleus. Melatonin, an antioxidant, prevented nigrostriatal neurodegeneration and alpha-synuclein aggregation without affecting the rotenone-induced weight loss and hypokinesis. However, rotenone-induced hypokinesis was markedly reversed by the DAT antagonist nomifensine and body weight loss was attenuated by the D2R antagonist sulpiride. In addition, both antagonists significantly prevented the reduction of striatal TH or DAT immunoreactivity but not the loss of nigral TH- and DAT-immunopositive neurons. These results suggested that oxidative stress and DAT downregulation are involved in the rotenone-induced pathogenesis of nigrostriatal dopaminergic neurodegeneration, whereas D2R upregulation may simply represent a compensatory response.
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PMID:Melatonin reduces the neuronal loss, downregulation of dopamine transporter, and upregulation of D2 receptor in rotenone-induced parkinsonian rats. 1828 73

Parkinson's disease is a chronic neurological disease characterized by dopaminergic neuron degeneration in the substantia nigra pars compacta. Melatonin is a powerful antioxidant agent secreted by the pineal gland which has numerous physiological functions and seems to exert an important neuroprotective effect. The 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model has been used to understand the pathophysiology of the disease because of its capacity to mimic biochemical and histological features observed in Parkinson's disease. This study investigated the effect of pretreatment with melatonin (50 mg/kg) on MPTP-lesioned animals 24 h and 7 days after neurotoxin infusion using the open-field test, two-way avoidance task and immunohistochemistry. Twenty-four hours after lesioning, the MPTP+vehicle group exhibited hypolocomotion and significant loss of tyrosine hydroxylase-immunoreactive cells, whereas no differences in these parameters were observed in lesioned animals receiving melatonin. Seven days after surgery, the MPTP-lesioned rats did not show hypolocomotion compared to control animals, while there was a significant dopaminergic neuronal loss. In the two-way avoidance task, MPTP-treated animals presented a cognitive deficit compared to the control groups and melatonin administration did not repair this defect. The present results suggest that melatonin reduces neuronal loss in the MPTP animal model of Parkinson's disease.
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PMID:Melatonin attenuates tyrosine hydroxylase loss and hypolocomotion in MPTP-lesioned rats. 1867 31

N-acetyl-5-methoxytryptamine (melatonin) is an endogenous indoleamine produced by all vertebrate organisms. Its production in the pineal gland has been extensively investigated but other organs also synthesize this important amine. Melatonin's functions in organisms are diverse. The actions considered in the current review relate to its ability to function in the reduction of oxidative stress, i.e., molecular damage produced by reactive oxygen and reactive nitrogen species. Numerous publications have now shown that not only is melatonin itself an efficient scavenger of free radicals and related reactants, but so are its by-products cyclic 3-hydroxymelatonin, N1-acetyl-N2-formyl-5-methoxykynuramine, and others. These derivatives are produced sequentially when each functions in the capacity of a free radical scavenger. These successive reactions are referred to as the antioxidant cascade of melatonin. That melatonin has this function within cells has been observed in studies employing time lapse conventional, confocal and multiphoton fluorescent microscopy coupled with the use of appropriate mitochondrial-targeted fluorescent probes. The benefits of melatonin and its metabolites have been described in the brain where they are found to be protective in models of Parkinson's disease, Alzheimer's disease and spinal cord injury. The reader is reminded, however, that data not covered in this review has documented beneficial actions of these amines in every organ where they have been tested. The outlook for the use of melatonin in clinical trials looks encouraging given its low toxicity and high efficacy.
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PMID:Biogenic amines in the reduction of oxidative stress: melatonin and its metabolites. 1876 65

Oxidative stress is implicated in the pathogenesis of a number of neurological disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis and stroke in the adult as well as in conditions such as periventricular white matter damage in the neonatal brain. It has also been linked to the disruption of blood brain barrier (BBB) in hypoxic-ischemic injury. Both experimental and clinical results have shown that antioxidants such as melatonin, a neurohormone synthesized and secreted by the pineal gland and edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a newly developed drug, are effective in reducing oxidative stress and are promising neuroprotectants in reducing brain damage. Indeed, the neuroprotective effects of melatonin in many central nervous system (CNS) disease conditions such as amyotrophic lateral sclerosis, PD, AD, ischemic injury, neuropsychiatric disorders and head injury are well documented. Melatonin affords protection to the BBB in hypoxic conditions by suppressing the production of vascular endothelial growth factor and nitric oxide which are known to increase vascular permeability. The protective effects of melatonin against hypoxic damage have also been demonstrated in newborn animals whereby it attenuated damage in different areas of the brain. Furthermore, exogenous administration of melatonin in newborn animals effectively enhanced the surface receptors and antigens on the macrophages/microglia in the CNS indicating its immunoregulatory actions. Edaravone has been shown to reduce oxidative stress, edema, infarct volume, inflammation and apoptosis following ischemic injury of the brain in the adult as well as decrease free radical production in the neonatal brain following hypoxic-ischemic insult. It can counteract toxicity from activated microglia. This review summarizes the clinical and experimental data highlighting the therapeutic potential of melatonin and edaravone in neuroprotection in various disorders of the CNS.
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PMID:Antioxidants and neuroprotection in the adult and developing central nervous system. 1907 54


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