Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0030567 (Parkinson's disease)
 63,064 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxygen free radicals and other oxygen derived species (Superoxide, O2-; Hydroperoxide, HOO; Singlet oxygen, 1O2-; Hydroxyl radical, OH; and Hydrogen peroxide, H2O2) including lipid peroxides have been suggested as important causative agents of aging and several human diseases, including cancer, multiple sclerosis, Parkinson's disease, autoimmune disease, ischemia, anemia, senile dementia, asbestosis and in thalassemia. This paper aims to communicate some of the theories and rationales in aging process and thalassemia.
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PMID:Role of lipid peroxidation and antioxidants in aging process and thalassemia. 134 11

The newly identified association of human nonnarcoleptic rapid eye movement (REM) sleep behavior disorder (RBD) with human leukocyte antigen (HLA) DQw1 class II genes raises the possibility that RBD may arise from autoimmune mechanisms. Two recent case reports involving postmortem brain stem histochemical analyses in elderly males with RBD identified severe monoaminergic cell loss in the locus ceruleus (LC). Thus, we designed a study to detect anti-LC antibodies in RBD. Ten Caucasian males (mean age, 66 years) with polygraphically confirmed RBD (n = 5, idiopathic RBD: n = 5, RBD with Parkinson's disease), but without narcolepsy, idiopathic hypersomnia, or autoimmune disease, were recruited for this study, along with 10 Caucasian male controls (mean age, 63 years) without a history of sleep disorder or autoimmune disease. In a blinded design, sera from the RBD patients and their controls were tested against human LC and other brainstem neurons. Brainstem tissue was obtained from autopsies of neurologically normal individuals. The presence of anti-LC antibodies was examined using immunohistochemistry on brainstem sections. Sections incubated with sera from normal individuals and sera from patients with paraneoplastic antineuronal antibodies (anti-Hu and anti-Ri) were used as controls. No reactivity with LC or any other brainstem area was identified with sera from either RBD patients or their controls, or from the other group of normal individuals. In contrast, sera from patients with paraneoplastic anti-Hu and anti-Ri antibodies reacted strongly with nuclei of LC and other brainstem neurons, sparing the nucleoli, and reacted to a lesser extent with the cytoplasm of these neurons. Therefore, it is unlikely that human RBD is associated with anti-LC antibodies. However, an autoimmune process in RBD has not been excluded by this study.
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PMID:A controlled study of serum anti-locus ceruleus antibodies in REM sleep behavior disorder. 938 Oct 56

Nerve injury causes degeneration of directly injured neurons and the damage spreads to neighboring neurons. Research on containing the damage has been mainly pharmacological, and has not recruited the immune system. We recently discovered that after traumatic injury to the central nervous system (spinal cord or optic nerve), the immune system apparently recognizes certain injury-associated self-compounds as potentially destructive and comes to the rescue with a protective antiself response mediated by a T-cell subpopulation that can recognize self-antigens. We further showed that individuals differ in their ability to manifest this protective autoimmunity, which is correlated with their ability to resist the development of autoimmune diseases. This finding led us to suggest that the antiself response must be tightly regulated to be expressed in a beneficial rather than a destructive way. In seeking to develop a neuroprotective therapy by boosting the beneficial autoimmune response to injury-associated self-antigens, we looked for an antigen that would not induce an autoimmune disease. Candidate vaccines were the safe synthetic copolymer Cop-1, known to cross-react with self-antigens, or altered myelin-derived peptides. Using these compounds as vaccines, we could safely boost the protective autoimmune response in animal models of acute and chronic insults of mechanical or biochemical origin. Since this vaccination is effective even when given after the insult, and because it protects against the toxicity of glutamate (the most common mediator of secondary degeneration), it can be used to treat chronic neurodegenerative disorders such as glaucoma, Alzheimer's disease, Parkinson's disease, and amyotrophic lateral sclerosis.
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PMID:Harnessing the immune system for neuroprotection: therapeutic vaccines for acute and chronic neurodegenerative disorders. 1204 37

Inflammatory and regulatory or anti-inflammatory cytokines (TNFalpha, IL-1beta, -6, -8, -10 and -12) regulate both the humoral and cellular immune responses. Cytokines have diverse peripheral and central functions. They are critical mediators of protective host responses, including defense against microbial invasion and tumorigenesis. However, the production of specific proinflammatory cytokines must be tightly regulated and compartmentalized to prevent the overexpression of these molecules that can end in chronic inflammation and tissue injury. Many diseases like autoimmune disease (rheumatoid arthritis, multiple sclerosis, arteriosclerosis, Crohn's disease), neurodegenerative disease (Alzheimer's and Parkinson's disease), tumor invasion and metastasis correlate with a deregulation in cytokine action. Thus, cytokines network provides an attractive and intensely competitive area of potential targets for therapeutic intervention. To monitor such secretion patterns in presence of putative drugs obtained by high throughput screening (HTS) some new techniques recently appeared on the market. We here compared results obtained by CBA (BD Cytometric Bead Array) to IC50 values obtained by classical sandwich Elisa. The complexity and cost of this new method is largely compensated by simultaneous testing of 6 cytokines in only 25 micro L of cell supernatant.
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PMID:[How to test at once six cytokines in samples as small as 25 microl?]. 1504 92

Parkinson's disease (PD) is a motor disease including disorders of mobility, fine tremor, rigidity and posture caused by a relentless deterioration of dopaminergic cells in the substantia nigra (SN). Disorders of affect and a range of other symptoms including fatigue, cognitive dysfunction and mental confusion, sleep disorder and addictions are also seen as other CNS sites are also affected. Idiopathic and genetic causes together with inflammatory and degenerative disorders of ageing have been postulated as contributing to PD. Autoimmunity affecting certain vasoactive neuropeptides (VNs) has been postulated as contributing to certain fatigue-related conditions in humans and may be consistent with compromise of receptors associated with VNs and including receptors for vasoactive intestinal polypeptide (VIP) and pituitary adenylate cyclase-activating polypeptide (PACAP). Pro-inflammatory responses are seen in PD patients consistent with apoptotic neurodegeneration. Involvement of the Th1 directed cytokine interferon-gamma has been demonstrated and Th2 directed cytokines such as IL-10 protect against inflammation-mediated degeneration of dopaminergic neurons in the SN. Nitric-oxide dysregulation is also postulated in PD by fostering dopamine depletion via nitric-oxide synthase (iNOS). Both PACAP and VIP have neuroprotective effects in PD models by inhibiting the production of inflammatory mediators. PACAP specifically protects against the neurotoxicity induced by rotenone as well as protecting against oxidative stress-induced apoptosis. These findings suggest that a defect in VN function may act adversely on SN cells and hence contribute to a clinical presentation consistent with PD. The conclusion drawn from these findings is that PD may be an autoimmune disorder of VNs, specifically PACAP and VIP. Possibly unusual or anatomically specific receptors for these VNs may be involved. If proven, this hypothesis would have significant implications for immunological and pharmacological treatment and prevention of PD.
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PMID:Is Parkinson's disease an autoimmune disorder of endogenous vasoactive neuropeptides? 1756 59

The finding that activation of peroxisome proliferator-activated receptor-gamma (PPARgamma) suppresses inflammation in peripheral macrophages and in models of human autoimmune disease instigated the evaluation of this salutary action for the treatment of CNS disorders with an inflammatory component. The fact that NSAIDs delay the onset of and reduce the risk of developing Alzheimer's disease (AD), while also binding to and activating PPARgamma, led to the hypothesis that one dimension of NSAID protection in AD is mediated by PPARgamma. Several lines of evidence from experiments using AD-related transgenic cellular and animal models have supported this hypothesis. The capacity of PPARgamma agonists to elicit anti-inflammatory, anti-amyloidogenic and insulin-sensitizing effects might account for their observed protective effects. Several clinical trials employing PPARgamma agonists have yielded promising results, and further trials are in preparation. Positive outcomes following PPARgamma administration have been obtained in animal models of other neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis, both of which are associated with a considerable degree of neuroinflammation. Finally, activation of PPARgamma has been found to be protective in several models of multiple sclerosis. The verification of these findings in human cells prompted the initiation of clinical studies evaluating PPARgamma activation in patients with multiple sclerosis.
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PMID:Drug insight: effects mediated by peroxisome proliferator-activated receptor-gamma in CNS disorders. 1780 44

Despite decades of research and the development of a large group of animal models, our understanding of the mechanisms responsible for the progressive loss of dopamine neurons in Parkinson's disease (PD) is unknown. So-called neuroprotective studies demonstrate that a vast group of molecules readily attenuate the dopamine (DA) neuron loss produced by DA neurotoxin insult. Despite these successes, these neuroprotective strategies have been surprisingly ineffective in patients. This may reflect the fact that the initial pathogenic event and the subsequent disease progression is a consequence of different mechanisms. As we began to think about this disconnect, we discovered that animals exposed to DA neurotoxins exhibited blood-brain barrier (BBB) dysfunction. If the BBB in PD patients is disrupted, then the barrier that normally segregates peripheral vascular factors from brain parenchyma is no longer present. Immune cells could then enter brain and produce a self-perpetuating (progressive) degenerative process. In this review, we propose that peripheral immunity contributes to the degenerative process of PD and may be responsible for the progressive nature of the disease. This hypothesis is supported by a broad and diverse literature that is just beginning to come together to suggest that PD is, in part, an autoimmune disease. In order to understand this hypothesis, the reader must question the conventional wisdom that the BBB is intact in PD, the brain is an immune privileged area, and that pathogenic insult and disease progression may reflect different mechanisms.
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PMID:Neuroinflammation and peripheral immune infiltration in Parkinson's disease: an autoimmune hypothesis. 1852 39

Stem cells, as subjects of study for use in treating neurological diseases, are envisioned as a replacement for lost neurons and glia, a means of trophic support, a therapeutic vehicle, and, more recently, a tool for in vitro modeling to understand disease and to screen and personalize treatments. In this review we analyze the requirements of stem cell-based therapy for clinical translation, advances in stem cell research toward clinical application for neurological disorders, and different animal models used for analysis of these potential therapies. We focus on Parkinson's disease (typically defined by the progressive loss of dopaminergic nigral neurons), stroke (neurodegeneration associated with decreased blood perfusion in the brain), and multiple sclerosis (an autoimmune disorder that generates demyelination, axonal damage, astrocytic scarring, and neurodegeneration in the brain and spinal cord). We chose these disorders for their diversity and the number of people affected by them. An additional important consideration was the availability of multiple animal models in which to test stem cell applications for these diseases. We also discuss the relationship between the limited number of systematic stem cell studies performed in animals, in particular nonhuman primates and the delayed progress in advancing stem cell therapies to clinical success.
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PMID:Preclinical assessment of stem cell therapies for neurological diseases. 2007 96

Hormesis is defined as a dose-response phenomenon characterized by low-dose stimulation and high-dose inhibition, and has been recognized as representing an overcompensation for mild environmental stress. The beneficial effects of mild stress on aging and longevity have been studied for many years. In experimental animals, mild dietary stress (dietary restriction, DR) without malnutrition delays most age-related physiological changes, and extends maximum and average lifespan. Animal studies have also demonstrated that DR can prevent or lessen the severity of cancer, stroke, coronary heart disease, autoimmune disease, allergy, Parkinson's disease and Alzheimer's disease. The effects of DR are considered to result from hormetic mechanisms. These effects were reported by means of various DR regimens, such as caloric restriction, total-nutrient restriction, alternate-day fasting, and short-term fasting. Mild dietary stress, including restriction of amount or frequency of intake, is the essence of DR. For more than 99% of their history, humans lived as hunter-gatherers and adapted to restrictions in their food supply. On the other hand, an oversufficiency of food for many today has resulted in the current global epidemic of obesity and obesity-related diseases. DR may be used, therefore, as a novel approach for therapeutic intervention in several diseases, when detailed information about effects of mild dietary stress on human health is obtained from clinical trials.
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PMID:Beneficial effects of mild stress (hormetic effects): dietary restriction and health. 2068 25

In nonneuronopathic type 1 Gaucher disease (GD1), mutations in the glucocerebrosidase gene (GBA1) gene result in glucocerebrosidase deficiency and the accumulation of its substrate, glucocerebroside (GL-1), in the lysosomes of mononuclear phagocytes. This prevailing macrophage-centric view, however, does not explain emerging aspects of the disease, including malignancy, autoimmune disease, Parkinson disease, and osteoporosis. We conditionally deleted the GBA1 gene in hematopoietic and mesenchymal cell lineages using an Mx1 promoter. Although this mouse fully recapitulated human GD1, cytokine measurements, microarray analysis, and cellular immunophenotyping together revealed widespread dysfunction not only of macrophages, but also of thymic T cells, dendritic cells, and osteoblasts. The severe osteoporosis was caused by a defect in osteoblastic bone formation arising from an inhibitory effect of the accumulated lipids LysoGL-1 and GL-1 on protein kinase C. This study provides direct evidence for the involvement in GD1 of multiple cell lineages, suggesting that cells other than macrophages may be worthwhile therapeutic targets.
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PMID:Glucocerebrosidase gene-deficient mouse recapitulates Gaucher disease displaying cellular and molecular dysregulation beyond the macrophage. 2096 79


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