Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0040822 (tremor)
 18,428 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Parkinson's disease (PD) is a movement disorder characterized by rigidity, tremor, and bradykinesia, originating from degeneration of dopaminergic neurons in the substantia nigra (SN), retrorubral area, and locus ceoruleus (LC). Calpain has been implicated in the pathophysiology of neurodegenerative diseases. Since the spinal cord (SC) and brain are integrally connected and calpain is involved in cell death and mitochondrial dysfunction, we hypothesized that SC neurons are also affected in PD. In order to examine this hypothesis, we examined both brain and SC from mice treated with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To identify cells expressing calpain, double immunofluorescent labeling was performed with antibodies specific for calpain and a cell type (OX-42, GFAP, or NeuN). Combined terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL) and double immunofluorescent labeling were used to identify death of specific cells in the central nervous system (CNS). There was an increase in calpain expression in microglia, astrocytes, and neurons in the SC of MPTP-treated mice at 1 and 7 days, as compared to controls. TUNEL-positive neurons in the SC and SN showed apoptotic characteristics. These results demonstrated that neuronal death occurred not only in SN but also in the SC of MPTP-treated mice and has provided evidence for a possible calpain-mediated SC neuronal death in MPTP-induced parkinsonism in mice.
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PMID:Immunofluorescent labeling of increased calpain expression and neuronal death in the spinal cord of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. 1505 18

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic (DA) neurons in the substantia nigra and movement defects, including bradykinesia, tremor, and postural imbalance. Whereas the etiology and pathogenesis of PD is still poorly understood, studies in animal models are providing important insights. One valuable type of animal model for PD is established by treating animals with PD-inducing neurotoxins, including 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), rotenone, and paraquat. These neurotoxins are thought to inhibit mitochondrial complex I activity leading to oxidative stress, impaired energy metabolism, proteasomal dysfunction, and, eventually, dopamine neuronal loss. However, the genes and pathways that underlie the neurotoxicity of these agents are not known. In this study, we explored the effect of MPTP, rotenone, and paraquat in both adult and larval zebrafish, which are highly amenable to genetic analysis that can lead to the identification of the underlying genes and pathways. Here, we report that adult zebrafish display behavioral alterations, including decreased locomotor activity in response to MPTP, whereas larval zebrafish exhibited developmental, behavioral, and DA sensitivity to these agents. Taken together, these findings suggest that zebrafish could be a valuable model for genetically dissecting the molecular mechanisms underlying the neurotoxicity of PD-inducing agents.
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PMID:Sensitivity of zebrafish to environmental toxins implicated in Parkinson's disease. 1545 Oct 49

Neurological disorders in humans can be modeled in animals using standardized procedures that recreate specific pathogenic events and their behavioral outcomes. The development of animal models of Parkinson's disease (PD) is important to test new neuroprotective agents and strategies. Such animal models of PD have to mimic, at least partially, a Parkinson-like pathology and should reproduce specific features of the human disease. PD is characterized by massive degeneration of dopaminergic neurons in the substantia nigra, the loss of striatal dopaminergic fibers and a dramatic reduction of the striatal dopamine levels. The formation of cytoplasmic inclusion bodies (Lewy bodies) in surviving dopaminergic neurons represents the most important neuropathological feature of PD. Furthermore, the massive striatal dopamine deficiency causes easily detectable motor deficits in PD patients, including bradykinesia, rigidity, and resting tremor, which are the cardinal symptoms of PD. Over the years, a broad variety of experimental models of PD were developed and applied in diverse species. This review focuses on the two most common "classical" toxin-induced PD models, the 6-hydroxy-dopamine (6-OHDA model) and the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model. Both neurotoxins selectively and rapidly destroy catecholaminergic neurons, whereas in humans the PD pathogenesis follows a progressive course over decades. This discrepancy reflects one important and principal point of weakness related to most animal models. This review discusses the most important properties of 6-OHDA and MPTP, their modes of administration, and critically examines advantages and limitations of selected animal models. The new genetic and environmental toxin models of PD (e.show $132#g. rotenone, paraquat, maneb) are discussed elsewhere in this "special issue."
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PMID:Classic toxin-induced animal models of Parkinson's disease: 6-OHDA and MPTP. 1550 55

Animal models play a critical role in our understanding of the cause of human diseases and provide an opportunity to evaluate new therapeutic treatments. The usefulness of an animal model is dependent, in part, on how closely it resembles neurochemical, neuropathologic, and behavioral features of the human condition. Other considerations that may enhance the value of a model include expense, availability, reproducibility, animal morbidity and mortality, and investigator experience. Parkinson's disease (PD) is a progressive neurodegenerative disorder characterized by slow movements, tremor, and walking impairment due to loss of midbrain nigrostriatal neurons and depletion of striatal dopamine. In the PD research field, a number of neurotoxic, pharmacologic, and transgenic animal models are available for research studies. We will focus on the advantages and disadvantages of the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mouse and nonhuman primate models of PD. Our goal is to guide researchers in the appropriateness of the MPTP models in their studies by balancing understanding of the models, objectives of the study, and health and safety of the animals. In addition, the technical use and safe handling of MPTP are discussed.
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PMID:1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned model of parkinson's disease, with emphasis on mice and nonhuman primates. 1557 63

Parkinson's disease is one of the major neurodegenerative disorders. This disease is mainly characterized by tremor, bradykinesia, rigidity and postural instability that results primarily from a loss of dopaminergic neurons of nigrostriatal pathway. MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is well known to damage the nigrostriatal dopaminergic pathway as seen in Parkinson's disease. Recent evidence shows that glial-related response plays a key role in the MPTP neurotoxic process and the blockade of glial activation may be a new therapeutic approach, which has applicability for Parkinson's disease. On the other hand, dopamine transporters (DAT) are important to the appearance of MPTP neurotoxicity because to be neurotoxin, an MPTP metabolite must first gain access to the dopaminergic neurons via DAT. Several studies suggest that DAT is a mandatory factor for expression of MPTP neurotoxicity and may explain the selective neuronal damage in the substantia nigra in MPTP toxicity. Therefore, DAT is thought to play an important role in the MPTP neurotoxic process and specific blockade of DAT with high-affinity inhibitors in neurodegenerative diseases such as Parkinson's disease, where the effective levels of dopamine are markedly reduced, may have beneficial consequences. In view of these new insights, this article suggests that the overexpression of S100beta protein secreted by glial cells may be an exacerbating factor in the neurodegeneration of dopaminergic cells. In this review, we also demonstrate the possible role of DAT in the brain cells in MPTP neurotoxicity. Thus this review provides valuable information for progressive neurodegeneration of the nigrostriatal dopaminergic neuronal pathway.
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PMID:Mechanisms of MPTP toxicity and their implications for therapy of Parkinson's disease. 1561 2

The gradual loss of striatal dopamine and dopaminergic neurons residing in the substantia nigra (SN) causes parkinsonism characterized by slow, halting movements, rigidity, and resting tremor when neuronal loss exceeds a threshold of approximately 80%. It is estimated that there is extensive compensation for several years prior to symptom onset, during which vulnerable neurons asynchronously die. Recent evidence would argue that much of the compensatory response of the nigrostriatal system is multimodal including both pre-synaptic and striatal mechanisms. Although parkinsonism may have multiple causes, the classic syndrome, Parkinson's disease (PD), is frequently modeled in small animals by repeated administration of the selective neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Because the MPTP model of PD recapitulates many of the known behavioral and pathological features of human PD, we asked whether the striatal cells of mice treated with MPTP in a semi-chronic paradigm enact a transcriptional program that would help elucidate the response to dopamine denervation. Our findings reveal a time-dependent dysregulation in the striatum of a set of genes whose products may impact both the viability and ability to communicate of dopamine neurons in the SN.
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PMID:Temporal evolution of mouse striatal gene expression following MPTP injury. 1570 51

Parkinson's disease (PD) is a common neurodegenerative disease that exhibits motor dysfunctions, such as tremor, akinesia and rigidity. In the present study, we investigated whether swim-test could be used as one of the behavioural monitoring techniques to study motor disability in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonism in two mouse strains, Balb/c and C57BL/6. Mice were treated with different doses of MPTP (10, 20 and 30 mg/kg, twice, 16 h apart), and were subjected to swim-test on the third day of the first MPTP injection. MPTP-induced tremor was monitored at 30 min, and akinesia and rigidity developed were studied 3 h after the second MPTP treatment. While tremor and akinesia produced were dose-dependent and the intensity of tremor was comparable in the two strains of mice studied, the latter response in C57BL/6 was significantly lesser than that observed in Balb/c. Rigidity exhibited in Balb/c mice were dose-dependent, but not in C57BL/6. There was observed an inverse relationship between swim-score and the doses of MPTP in both the strains. MPTP caused a significant and dose-dependent reduction in striatal dopamine level in both the strains of mice, when assayed on the fourth day employing an HPLC with electrochemical detector. A significant positive correlation existed (r = 0.94 for Balb/c and r = 0.82 for C57BL/6) for the striatal dopamine-depletion and the swim-score in the MPTP-treated mice. While swim deficit and striatal dopamine loss were long lasting (till the third week) in C57BL/6, in Balb/c mice the motor deficit showed recovery by the second week. In these animals, a significant attenuation in striatal dopamine loss was observed by the third week. These results indicate that swim ability is directly proportional to striatal dopamine content, and suggest that swim-test could be used as a major technique to monitor motor dysfunction in experimental animals.
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PMID:Swim-test as a function of motor impairment in MPTP model of Parkinson's disease: a comparative study in two mouse strains. 1594 98

Fas (CD95), a member of the tumor necrosis factor-receptor superfamily, has been studied extensively as a death-inducing receptor in the immune system. However, Fas is also widely expressed in a number of other tissues, including in neurons. Here, we report that defects in the Fas/Fas ligand system unexpectedly render mice highly susceptible to neural degeneration in a model of Parkinson's disease. We found that Fas-deficient lymphoproliferative mice develop a dramatic phenotype resembling clinical Parkinson's disease, characterized by extensive nigrostriatal degeneration accompanied by tremor, hypokinesia, and loss of motor coordination, when treated with the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) at a dose that causes no neural degeneration or behavioral impairment in WT mice. Mice with generalized lymphoproliferative disease, which express a mutated Fas ligand, display an intermediate phenotype between that of lymphoproliferative and WT mice. Moreover, Fas engagement directly protects neuronal cells from MPTP/1-methyl-4-phenylpyridinium ion toxicity in vitro. Our data show that decreased Fas expression renders dopaminergic neurons highly susceptible to degeneration in response to a Parkinson-causing neurotoxin. These findings constitute the first evidence for a neuroprotective role for Fas in vivo.
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PMID:Defective Fas expression exacerbates neurotoxicity in a model of Parkinson's disease. 1612 3

Parkinson disease (PD) targets dopaminergic neurons in the substantia nigra, resulting in motor disturbances such as resting tremor, bradykinesia, and rigidity. Pathogenic processes likely occur over several decades, in that an overwhelming percentage of neurons are already dead at the time of clinical diagnosis. For this reason, the usage of animal model systems to discover the early steps in the pathologic cascade is required. These include exposure to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), which selectively kills dopamine neurons in the substantia nigra, and genetic models incorporating mutations in the alpha-synuclein gene that cause disease in human patients. Through the evaluation of these models at multiple time points, it is possible to discover novel gene expression changes that may underlie disease pathogenesis. Specifically, the authors hypothesize that animal models of PD and human PD brains share a gene expression profile that signifies certain aspects of pathogenesis and/or recovery-resistance. To test this and similar hypotheses, the authors and others have utilized new microarray technology that enables the sampling of thousands of genes' expression level in one assay. Because the technology is fairly new and results can vary depending on methods used, results must be evaluated with care. Multiple array and data-mining options can be used to make the most accurate inferences as to differentially expressed genes in each set of samples. The authors developed a fusion classifier approach whereby individual data-mining algorithms generate lists of significant genes. The lists are subsequently queried, and only genes unanimously called significant are retained for further validation. Although the authors' approach identified hundreds of differentially expressed genes in each of three PD systems, only a few were common between the human and animal substantia nigra. These were related to dopamine phenotype, synaptic function, and the mitochondrial metabolism, implicating the presynaptic terminal as a primary site of injury. The time course of the authors' experiments indicates that if the synaptic changes could be prevented, this may alleviate some cell death, in that these changes precede neuronal loss.
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PMID:Altered gene expression profiles reveal similarities and differences between Parkinson disease and model systems. 1628 95

Parkinson's disease (PD) is a debilitating neurodegenerative disease, with clinical features of tremor, muscular rigidity and akinesia, occurring as a result of midbrain dopamine loss. The search for treatments has relied heavily on animal models of the disorder. The use of monkey models of PD plays a distinct role in the development and assessment of novel treatments. The common marmoset (Callithrix jacchus) is a popular New World monkey used in the search for new treatments. These monkeys are easy to handle and survive well in captivity. This review examines the advantages of using marmoset monkeys in PD research and examines the different models available with reference to their use in pre-clinical assessment for novel therapeutic treatments. The most common models involve the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 6-hydroxydopamine (6-OHDA). Recently, selective cerebral transgenic over-expression of alpha-synuclein has also been attempted in marmosets as a potential model for PD. Each model has its advantages. The MPTP-based model in marmosets resembles the disease with regards to the neuroanatomy of neurotransmitter loss; the unilateral application of 6-OHDA allows for the assessment of more complex sensorimotor deficits due to the presence of an intact 'control' side; the over-expression of alpha-synuclein in the midbrain results in the slow onset of behavioural symptoms allowing for a pre-symptomatic time window. The appropriateness of each of these marmoset models for the assessment of treatments depends on several factors including the experimental aim of the study and whether emphasis is placed on the analysis of behavioural deficits.
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PMID:Marmoset monkey models of Parkinson's disease: which model, when and why? 1632 13


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