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 markedly decreased number of nigrostriatal dopaminergic neurons. The pathogenesis of PD is still unknown; among other etiological factors, immunological abnormalities have been suggested. Recently, interleukin-2 (IL-2) has been hypothesized to be an endogenous cytokine that regulates striatal dopaminergic function. We examined the plasma concentrations of IL-1, IL-2, IL-6 and blood levels of ACTH, cortisol and prolactin of 21 patients with PD without any previous treatment. Age- and sex-matched subjects without any neurological or immune disorders were used as controls. Significantly higher serum concentrations of IL-2 in patients with PD were found. Treatment with antiparkinsonian drugs reduced IL-2 levels in these patients. Our results suggested a functional relationship between central dopaminergic and immune systems and a possible involvement of the latter in the pathogenesis of PD.
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PMID:Evaluation of interleukins, ACTH, cortisol and prolactin concentrations in the blood of patients with parkinson's disease. 894 28

We have come to understand apoptosis as not merely a single form of cell death, but as a fundamental theme in cell biology that has far-reaching implications in the fields of physiology and pathology. At the present time, however, the mechanism of apoptosis is not clearly understood, as research into apoptosis is still at the initial stages. Nevertheless, the links between apoptosis and a variety of pathological conditions are gradually becoming clearer. In this article, we will provide a simple explanation of apoptosis and its mechanism as a novel concept of cell death and discuss the way in which apoptosis has been linked to a variety of pathological conditions. WHAT IS APOPTOSIS?: In normal tissue, cells that are no longer needed are rapidly eliminated without affecting the overall function of the tissue. In this process cells undergo an active and spontaneous suicide called programmed cell death. In fact, the majority of physiological cell deaths take the form of apoptosis. The word apoptosis is used, in contrast to necrosis, to describe the situation in which a cell actively pursues a course toward death upon receiving certain stimuli [1]. The morphological changes of apoptosis found in most cell types first involve contraction in cell volume and condensation of the nucleus. When this happens the intracellular organelles such as the mitochondria retain their normal morphology. As apoptosis proceeds, blebbing of the plasma membrane occurs, and the nucleus becomes fragmented. Finally, the cell itself fragments to form apoptotic bodies that are engulfed by nearby phagocytes. With respect to biochemical changes, it is known that the chromosomes become fragmented into nucleosome units, and DNA forms characteristic ladder patterns when subjected to agarose gel electrophoresis. MECHANISM OF APOPTOSIS: It has been reported that apoptosis is induced in various cells by many kinds of irritations, but the precise mechanism is still unclear. Cell injuries that induce apoptosis include those that cause DNA damage such as radiation and anticancer drugs, those that are mediated by the TNF receptor and Fas receptor (the so-called "death signal receptors"), and the deprivation of cytokines that supply survival signals such as IL-3 and erythropoietin. The tumor suppressor gene p53 plays a very important role in apoptosis induced by damage to DNA. This has been demonstrated by studying resistance to apoptosis of cells derived from p53 knockout mice [2]. Other than the irritations that induce apoptosis, molecules that have been strongly implicated as major players in the drama of apoptosis include the Bcl-2 family proteins and the IL-1 converting enzyme (ICE) and its homolog proteases (caspase family). Both groups of proteins show homology with proteins that affect cell death in nematodes. It is believed that molecules that contribute to cell death have been well conserved in multicellular organisms all the way from the relatively primitive nematodes to mammals including humans. It was discovered that Bcl-2 suppressed apoptosis induced in IL-3 dependent cells by deprivation of IL-3 [3]. It has since become the gene around which apoptosis research revolves. Recently, it has become clear that cell death involving the Bcl-2 protein is under the control of similar proteins from the same family [4]. It is interesting that the phenomenon of cell death may be regulated by the balance of the molecules involved in it. APOPTOSIS ABNORMALITIES AND DISEASE: Physiological cell death plays a major role in the growth and permanent maintenance of the human body [5]. In the process of forming the nervous system, neurons that do not form proper connections die. Physiological cell death also accompanies the removal of virus-infected cells by cytotoxic T cells, the elimination of autoreactive immune cells, the formation of the gut, the reconstitution of cartilage and bone, etc. When physiological cell death that normally should occur is inhibited, inappropriate physiological cell death may occur that is harmful to the body and forms the basis of disease. For example, in patients with neural degenerative disorders such as Alzheimer's disease and Parkinson's disease, we can find premature cell death in a particular subset of neurons. The death of T cells in AIDS patients is also a form of physiological cell death. Inhibition of cell death in the immune system enables the survival of autoreactive B cells and T cells, and is therefore a cause of autoimmune disorders. Apoptosis has been particularly linked to cancer. Normal cells are programmed for death if they are subjected to many types of non-physiological stress such as anticancer drugs or radiation, if they become isolated from surrounding cells and are unable to receive their tissue-specific survival signals [6], or if oncogenes are expressed haphazardly [7]. On the other hand, it is believed that the ability to survive is enhanced in transformed cancer cells because they are more resistant to apoptosis, they exhibit resistance to anticancer drugs, they are no longer dependent on survival signals, and they can metastasize. Therefore, the cancer progresses as the cancer cells maintain the proliferative superiority they acquire from their oncogenes. In other words, when cancer cells become resistant to apoptosis, they become resistant to treatment, metastasize, and proliferate destructively. The concept that the malignancy of cancer is due to its resistance to apoptosis is a relatively new one and is worthy of further study.
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PMID:Physician Education: Apoptosis. 1038 21

We studied genetic polymorphisms in the promoter region (position -511) and exon 5 (position +3953) of the interleukin (IL)-1beta gene in 122 Japanese patients with Parkinson's disease (PD) and 112 controls. We also examined polymorphisms in the IL-1alpha and the IL-1 receptor antagonist genes. No significant difference was found in these genetic markers between PD patients and controls. However, PD patients with homozygotes for allele 1 at position -511 of the IL-1beta gene (IL-1B-511*1), a low producer of IL-1beta, were significantly earlier in the disease onset than those with the IL-1B-511*2 homozygotes, a high producer of IL-1beta. This suggests that IL-1beta might play a role, possibly a protective effect for dopaminergic neurons, in PD. Further population and functional studies are necessary to clarify the role of IL-1beta in PD patients.
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PMID:Influence of interleukin-1beta gene polymorphisms on age-at-onset of sporadic Parkinson's disease. 1077 Nov 65

Poor survival of transplanted dopaminergic (DA) neurons remains a serious obstacle to the success of cell replacement therapy as an alternative to the current treatments for Parkinson's disease. We have examined the temporal release profile of an inflammatory cytokine, interleukin-1 beta (IL-1 beta) following transplantation of fetal mesencephalic tissue into the rat striatum. The amounts of IL-1 beta released in vivo when added to cultures of embryonic DA neurons, did not significantly reduce the survival of DA neurons in vitro, and inclusion of the naturally-occurring IL-1 receptor antagonist, IL-1ra, did not appear to affect the numbers of surviving DA neurons present after 5 days in vitro. Neither did inclusion of IL-1ra in cell suspensions during transplantation increase the survival of transplanted fetal DA neurons. Thus, although IL-1 beta is released following implantation of a neural transplant, we suggest that this pro-inflammatory cytokine does not play an active role in reducing survival of transplanted DA neurons, unlike other cytokines such as tumor necrosis factor alpha. Modulation of IL-1 beta activity, therefore, will not offer significant improvements to neural transplantation as a treatment for PD.
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PMID:IL-1 beta is released from the host brain following transplantation but does not compromise embryonic dopaminergic neuron survival. 1236 7

Inflammatory events may contribute to the pathogenesis of Parkinson's disease (PD) and interleukin 1 (IL-1) may exert both neurotoxic and neuroprotective effects. We conducted a case-control study in a cohort of 493 PD cases and 388 ethnically matched controls to investigate the association of IL-1alpha C-889T and IL-1beta C-511T polymorphisms with the risk of PD. No significant difference in the genotype distribution of the analyzed polymorphisms was found between PD and controls. However, after stratification by age, individuals over 70 years of age carrying IL-1alpha-889 C/T genotype demonstrated a significant decrease in risk of developing PD (OR = 0.44; 95% CI = 0.22-0.88, p = 0.021) and the decrease is strengthened by IL-1beta-511 T-carrying genotype (OR = 0.28; 95% CI = 0.11-0.71, p = 0.008). Our data suggest that IL-1alpha, acting synergistically with IL-1beta, plays role in PD susceptibility among Taiwanese people older than 70 years of age.
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PMID:Interleukin-1 alpha polymorphism has influence on late-onset sporadic Parkinson's disease in Taiwan. 1745 95

The cytokines interleukin-1 (IL-1alpha and IL-1beta) and the tumor necrosis factor-alpha (TNF-alpha) both play a major role in the initiation and regulation of inflammation and immunity responses. Polymorphisms within the gene sequences of these cytokines IL-1 and TNF-alpha have been proposed to play an important role in the pathogenesis of certain diseases. Affecting nearly every organ, various diseases, including some cancers, are described to be associated with an increased level of IL-1 and TNF-alpha proteins, for example, solid tumors, hematologic malignancies, malignant histiocytosis, autoimmune disorders, Alzheimer's disease, Parkinson's disease, sepsis, and rheumatoid arthritis. Regarding genetic backgrounds and pathways, numerous canine diseases show close similarities to their human counterparts. As a genetic model, the dog could be used to unravel the genetic mechanisms, for example, in particular the predispositions, the development, and progression of cancer and metabolic diseases. The identity comparison of gene and protein sequences of different species could be used to elucidate the structure and function of the genes and proteins by identifying the evolutionary conserved regions and domains. Herein we analyzed in detail the mRNA and protein structures and identities of the present known mammalian (human, canine, murine, rat, ovine, equine, feline, porcine, and bovine) TNF-alpha, IL-1alpha, and IL-1beta mRNAs and proteins. Additionally, based on the canine genome sequence, we derived in silico the complete mRNA structures of the IL-1alpha and IL-1beta mRNAs.
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PMID:Comparison of the human and canine cytokines IL-1(alpha/beta) and TNF-alpha to orthologous other mammalians. 1757 84

Neuroinflammation may play a role in the pathogenesis of Parkinson's disease (PD). The present study questioned whether this neuroinflammatory response differs between the olfactory bulb, as an early affected region and the nigrostriatal system. Indeed, increased microgliosis was shown in post-mortem olfactory bulb of PD patients. Also in olfactory bulb of MPTP-treated mice, microgliosis and increased expression of IL-1alpha, IL-1beta and IL-1ra mRNA was observed early after treatment. These observations implicate that neuroinflammation is not restricted to the nigrostriatal system. MPTP-induced microgliosis in striatum and olfactory bulb was reduced in IL-1alpha/beta knockout mice, indicating that IL-1 affects microglia activation. Importantly, MPTP induced differential regulation of IL-1 receptors. mRNA levels of IL-1RI and, to a lesser extent, IL-1RII were increased in striatum. Interestingly, in the olfactory bulb only IL-1RII mRNA was enhanced. We suggest that differential regulation of IL-1 signaling can serve as an important mechanism to modulate neuroinflammatory activity after MPTP treatment and possibly during PD.
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PMID:Neuroinflammation in Parkinson's patients and MPTP-treated mice is not restricted to the nigrostriatal system: microgliosis and differential expression of interleukin-1 receptors in the olfactory bulb. 1759 50

The importance of glial cell-propagated inflammation (i.e., neuroinflammation) disorders such as Alzheimer's disease (AD) was viewed previously as a bystander effect, or epiphenomenon, with inflammation occurring when damaged neurons elicit an activation response by glia. However, an accumulating body of evidence has challenged this earlier perspective and indicates a more active role of neuroinflammation in the pathophysiology of progressive neurodegenerative disorders such as AD, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis. This insight into pathophysiology evolved in concert with the appreciation that the brain is not as immunologically privileged as once thought. The central nervous system (CNS) has its own resident immune system, in which glial cells (microglia, astrocytes, and oligodendrocytes) not only serve supportive and nutritive roles for neurons but also engage from time to time in several "inflammatory" processes that defend the CNS from pathogens and help it to recover from stress and injury. These otherwise "normal" glial functions can sometimes result in a more severe and chronic neuroinflammatory cycle that actually promotes or propagates neurodegenerative disease. Excessive glial cell activation may thus constitute a viable target for the discovery of and development of neurodegenerative disease therapeutics. Suggestive clinical evidence in support of neuroinflammation as a drug discovery target for chronic neurodegenerative diseases, such as AD, comes from epidemiological and genetic linkage data. For example, long-term use of nonsteroidal anti-inflammatory drugs is correlated with a protective effect against AD, and certain polymorphisms in the genes for interleukin 1 and other proinflammatory mediator genes are associated with increased risk. In AD and Parkinson's disease, activated microglia and complement proteins have been identified in the brain regions most affected in these disorders. This report will briefly review selected clinical and preclinical data that reflect the prevailing approaches targeting neuroinflammation as a pathophysiological process contributing to the onset or progression of neurodegenerative diseases, as well as their neuroprotective potential.
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PMID:The brain as a target for inflammatory processes and neuroprotective strategies. 1807 62

Parkinson's disease is a neurodegenerative disorder with uncertain aetiology and ill-defined pathophysiology. Activated microglial cells in the substantia nigra (SN) are found in all animal models of Parkinson's disease and patients with the illness. Microglia may, however, have detrimental and protective functions in this disease. In this study, we tested the hypothesis that a sub-toxic dose of an inflammogen (lipopolysaccharide) can shift microglia to a pro-inflammatory state and exacerbate disease progression in an animal model of Parkinson's disease. Central lipopolysaccharide injection in a degenerating SN exacerbated neurodegeneration, accelerated and increased motor signs and shifted microglial activation towards a pro-inflammatory phenotype with increased interleukin-1beta (IL-1beta) secretion. Glucocorticoid treatment and specific IL-1 inhibition reversed these effects. Importantly, chronic systemic expression of IL-1 also exacerbated neurodegeneration and microglial activation in the SN. In vitro, IL-1 directly exacerbated 6-OHDA-triggered dopaminergic toxicity. In vivo, we found that nitric oxide was a downstream molecule of IL-1 action and partially responsible for the exacerbation of neurodegeneration observed. Thus, IL-1 exerts its exacerbating effect on degenerating dopaminergic neurons by direct and indirect mechanisms. This work demonstrates an unequivocal association between IL-1 overproduction and increased disease progression, pointing to inflammation as a risk factor for Parkinson's disease and suggesting that inflammation should be efficiently handled in patients to slow disease progression.
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PMID:Central and systemic IL-1 exacerbates neurodegeneration and motor symptoms in a model of Parkinson's disease. 1850 91

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.
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PMID:Altered lipid metabolism in brain injury and disorders. 1875 14


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