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)

Epidemiological studies have strongly linked caffeine consumption with a reduced risk of developing Parkinson's disease (PD) in men. Interestingly, in women, this inverse association is present only in those who have not taken postmenopausal estrogens, suggesting an interaction between the influences of estrogen and caffeine use on the risk of PD. To explore a possible biological basis for this interaction, we systematically investigated how the neuroprotective effect of caffeine is influenced by gender, ovariectomy (OVX), and then exogenous estrogen in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD. (1) Caffeine treatment produced a dose-dependent attenuation of MPTP-induced striatal dopamine loss in both young and retired breeder (RB) male, but not female, mice. (2) In female mice (both young and RB), caffeine was less potent or altogether ineffective as a neuroprotectant after sham surgery compared to OVX or after OVX plus estrogen replacement compared to OVX plus placebo treatment. (3) Estrogen treatment also prevented the protection of caffeine against dopamine loss in young male mice. (4) Consistent with the putative protective effect of estrogen, female and OVX plus estrogen mice were relatively resistant to MPTP toxicity compared to male and OVX plus placebo mice, respectively. (5) There was no overall difference in brain levels of caffeine and its metabolites between OVX plus placebo and OVX plus estrogen mice. Together, these results suggest that estrogen can occlude and thereby prevent the neuroprotective effect of caffeine in a model of PD neurodegeneration, supporting a biological basis for the interaction between estrogen and caffeine in modifying the risk of PD.
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PMID:Estrogen prevents neuroprotection by caffeine in the mouse 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine model of Parkinson's disease. 1640 51

Estrogen increases methamphetamine (MA)-induced neurotoxicity within the impaired nigrostriatal dopaminergic (NSDA) system of ovariectomized female mice, as defined by enhanced striatal dopamine (DA) depletion. In this study we compared the effects of a lower dose of estradiol benzoate (EB, 1 microg) with related agents--tamoxifen (TMX, 12.5 microg), testosterone (5 microg) and dehydroepiandrosterone (DHEA, 3 mg) in this paradigm. In experiment 1, ovariectomized mice received an initial treatment with MA. At 1 week after MA, mice were treated with EB, TMX, testosterone, DHEA or oil vehicle and 24 h later a second MA treatment. Striatal DA and 3,4-dihydroxyphenylacetic acid (DOPAC) concentrations in the MA-treated groups were decreased compared to the non-MA-treated control. Neither EB nor any of the other agents tested showed enhanced neurodegenerative or neuroprotective effects against a second MA invasion. To verify that estrogen was capable of showing a neuroprotective effect under a condition of two administrations of MA, in experiment 2, EB was administered either once or twice prior to each of the two MA treatments. EB treatment prior to the first MA invasion or first and second MA protected the NSDA system against DA and DOPAC depletion. These results imply that a lower dose of EB, TMX, testosterone and DHEA cannot exert neurodegenerative or neuroprotective effects in the impaired NSDA model. However, EB administered prior to the introduction of neurotoxicity can protect the NSDA system. This study may provide an understanding of the variations in results on the effects of estrogen upon the NSDA neurodegenerative disorder, Parkinson's disease.
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PMID:Effects of estrogen and related agents upon methamphetamine-induced neurotoxicity within an impaired nigrostriatal dopaminergic system of ovariectomized mice. 1692 30

Since its' discovery over 20 years ago, BDNF has been shown to play a key role in neuronal survival, in promoting neuronal regeneration following injury, regulating transmitter systems and attenuating neural-immune responses. Estrogen's actions in the young and mature brain, and its role in neurodegenerative diseases in many cases overlaps with those observed for BDNF. Reduced estrogen and BDNF are observed in patients with Parkinson's disease and Alzheimer's disease, while high estrogen levels are a risk factor for development of multiple sclerosis. Estrogen receptors, which transduce the actions of estrogen, colocalize to cells that express BDNF and its receptor trkB, and estrogen further regulates the expression of this neurotrophin system. This review describes the distribution of BDNF and trkB expressing cells in the forebrain, and the roles of estrogen and the BDNF-trkB neurotrophin system in Parkinson's disease, Alzheimer's disease and multiple sclerosis.
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PMID:Estrogen-BDNF interactions: implications for neurodegenerative diseases. 1706 77

Estrogen plays key regulatory roles in a variety of biological actions besides its classic function as a sex hormone. Recently, estrogen has been linked to neurodegenerative diseases including Alzheimer's disease (AD) and Parkinson's disease (PD). Several lines of evidence support the notion that brain estrogen exerts neuroprotective effects against various types of neurotoxicity in different cellular and animal models. Despite some controversies, estrogen replacement therapy (ERT) at an early stage, especially when given prior to menopause, has been shown to reduce the risk of AD in postmenopausal women. In addition, multiple lines of evidence have proven the neuroprotective effects of estrogen, such as enhancing neurotrophin signaling and synaptic activities pertinent to memory functions and protecting neurons against oxidative injuries and beta-amyloid toxicity; the latter is widely accepted as the prime culprit known to trigger the pathogenesis of AD. Here we will summarize our findings that estrogen decreased generation and secretion of beta-amyloid peptides in cultured cells and primary neurons and that administration of estrogen in estrogen-deprived mice reversed the elevated levels of brain Abeta. We will also discuss the molecular and cellular mechanisms underlying estrogen's effects on Abeta metabolism, which is highlighted by our demonstration that estrogen increases intracellular trafficking of beta-amyloid precursor protein (betaAPP) and hence reduces maximal Abeta generation within the trans-Golgi network (TGN), a subcellular compartment in which APP is known to be cleaved by the secretase enzymes to generate Abeta.
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PMID:Estrogen, beta-amyloid metabolism/trafficking, and Alzheimer's disease. 1726 79

Estrogen is an important hormone signal that regulates multiple tissues and functions in the body. This review focuses on the neurotrophic and neuroprotective actions of estrogen in the brain, with particular emphasis on estrogen actions in the hippocampus, cerebral cortex and striatum. Sex differences in the risk, onset and severity of neurodegenerative disease such as Alzheimer's disease, Parkinson's disease and stroke are well known, and the potential role of estrogen as a neuroprotective factor is discussed in this context. The review assimilates a complex literature that spans research in humans, non-human primates and rodent animal models and attempts to contrast and compare the findings across species where possible. Current controversies regarding the Women's Health Initiative (WHI) study, its ramifications, concerns and the new studies needed to address these concerns are also addressed. Signaling mechanisms underlying estrogen-induced neuroprotection and synaptic plasticity are reviewed, including the important concepts of genomic versus nongenomic mechanisms, types of estrogen receptor involved and their subcellular targeting, and implicated downstream signaling pathways and mediators. Finally, a multicellular mode of estrogen action in the regulation of neuronal survival and neurotrophism is discussed, as are potential future directions for the field.
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PMID:Neurotrophic and neuroprotective actions of estrogen: basic mechanisms and clinical implications. 1737 65

Because estrogen has numerous effects on dopamine neurotransmission, many researchers are interested in its possible use to either slow the progression or reduce the risk of Parkinson's disease (PD). The incidence of PD is greater in men than in women. Gender differences in neurotoxicity have been observed, and basic research in experimental animals indicates that estrogen protects neurons from various forms of injury. However, the results of retrospective surveys of the neuroprotective effects of estrogen replacement in PD have been mixed, with some showing no effect on risk and others showing a reduction in risk. A mildly significant gender difference in disability and quality-of-life reporting has been noted, with women citing greater disability and reduced quality of life. Gender differences have been shown in response to treatment of PD, for example, in how levodopa is metabolized--women have greater levodopa bioavailability. In the Parkinson's Disease on Estrogen Therapy Replacement in the Menopause Years (POETRY) study, participants were found to have improved scores on the Unified Parkinson Disease Rating Scale. Based on the POETRY results, it is hypothesized that estrogen replacement therapy (ERT) may lead to improvement in PD symptoms and provide an opportunity to reduce the dosage of antiparkinsonian medication in women.
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PMID:Gender differences in Parkinson's disease. 1758 22

Eleven postmenopausal women with Parkinson disease and levodopa-induced peak-dose dyskinesias underwent a double-blind, placebo-controlled, crossover study. The active treatment consisted of estrogen replacement therapy for 12 weeks, followed by medroxyprogesterone acetate for 2 weeks. Estrogen replacement therapy-medroxyprogesterone acetate administration significantly improved peak-dose dyskinesia without worsening motor disability, thus suggesting a possible benefit on dyskinesias in postmenopausal women with Parkinson disease.
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PMID:Hormonal replacement therapy in women with Parkinson disease and levodopa-induced dyskinesia: a crossover trial. 1790 5

Estrogen and phytoestrogens such as the isoflavones have received considerable attention in Parkinson's disease (PD) research. Because they have been reported to possess neuroprotective effects on dopaminergic neurons in the substantia nigra (SN), isoflavones appear particularly promising for post-menopausal women at risk for PD. However, most previous studies were limited to morphological investigation, and the preventive effects of isoflavones on motor function have not been evaluated. The aim of the present study was to elucidate the prevention by an isoflavone against motor dysfunction after injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle of ovariectomized rats, which mimics post-menopausal status in women. Pretreatment with genistein, an isoflavone, significantly preserved motor function in rats injected with low-dose 6-OHDA, as evaluated by the stepping and cylinder tests. An estrogen receptor antagonist, ICI182780, reversed the effects of genistein, indicating that this effect of genistein is mediated through estrogen receptors. The functional effects of genistein were accompanied by preservation of tyrosine hydroxylase-immunoreactive neurons in the SN after injection of low-dose 6-OHDA. These findings suggest that genistein may be useful for the prevention of PD in post-menopausal women.
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PMID:Preventive effects of genistein on motor dysfunction following 6-hydroxydopamine injection in ovariectomized rats. 1895 48

This review considers evidence which reveals considerable complexity and sex differences in the response of the nigrostriatal dopaminergic (NSDA) system to hormonal influences. This pathway degenerates in Parkinson's disease (PD) and sex hormones contribute to sex differences in PD, where men fare worse than women. Here we discuss evidence from animal studies which allows us to hypothesize that, contrary to expectations, the acclaimed neuroprotective property of physiological concentrations of estradiol arises not by promoting NSDA neuron survival, but by targeting powerful adaptive responses in the surviving neurons, which restore striatal DA functionality until over 60% of neurons are lost. Estrogen generated locally in the NSDA region appears to promote these adaptive mechanisms in females and males to preserve striatal DA levels in the partially injured NSDA pathway. However, responses to systemic steroids differ between the sexes. In females there is general agreement that gonadal steroids and exogenous estradiol promote striatal adaptation in the partially injured NSDA pathway to protect against striatal DA loss. In contrast, the balance of evidence suggests that in males gonadal factors and exogenous estradiol have negligible or even harmful effects. Sex differences in the organization of NSDA-related circuitry may well account for these differences. Compensatory mechanisms and sexually dimorphic hard-wiring are therefore likely to represent important biological substrates for sex dimorphisms. As these processes may be targeted differentially by systemic steroids in males and females, further understanding of the underlying processes would provide valuable insights into the potential for hormone-based therapies in PD, which would need to be sex-specific. Alternatively, evidence that estrogen generated locally is protective in the injured male NSDA pathway indicates the great therapeutic potential of harnessing central steroid synthesis to ameliorate neurodegenerative disorders. A clearer understanding of the relative contributions and inter-relationships of central and systemic steroids within the NSDA system is an important goal for future studies.
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PMID:Independent influences of sex steroids of systemic and central origin in a rat model of Parkinson's disease: A contribution to sex-specific neuroprotection by estrogens. 1953 62

In addition to regulating reproductive functions in the brain and periphery, estrogen has tropic and neuroprotective functions in the central nervous system (CNS). Estrogen administration has been demonstrated to provide protection in several animal models of CNS disorders, including stroke, brain injury, epilepsy, Parkinson's disease, Alzheimer's disease, age-related cognitive decline and multiple sclerosis. Here, we use a model of toxin-induced oligodendrocyte death which results in demyelination, reactive gliosis, recruitment of oligodendrocyte precursor cells and subsequent remyelination to study the potential benefit of 17beta-estradiol (E2) administration in male mice. The results indicate that E2 partially ameliorates loss of oligodendrocytes and demyelination in the corpus callosum. This protection is accompanied by a delay in microglia accumulation as well as reduced mRNA expression of the pro-inflammatory cytokine, tumor necrosis factor alpha (TNFalpha), and insulin-like growth factor-1 (IGF-1). E2 did not significantly alter the accumulation of astrocytes or oligodendrocyte precursor cells, or remyelination. These data obtained from a toxin-induced, T cell-independent model using male mice provide an expanded view of the beneficial effects of estrogen on oligodendrocyte and myelin preservation.
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PMID:17beta-estradiol protects male mice from cuprizone-induced demyelination and oligodendrocyte loss. 2034 81


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