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)

Cannabinoid CB1 receptors are the most abundant G-protein-coupled receptors in the brain. Its presynaptic location suggests a role for cannabinoids in modulating the release of neurotransmitters from axon terminals by retrograde signaling. The neuroprotective effects of cannabinoid agonists in animal models of ischemia, seizures, hypoxia, Multiple Sclerosis, Huntington and Parkinson disease have been demonstrated in several reports. The proposed mechanism for the neuroprotection ranges from antioxidant effects, reduction of microglial activation and anti-inflammatory reaction to receptor-mediated reduction of glutamate release. In the present work, we analyzed the morphological changes induced by a chronic treatment with the synthetic cannabinoid receptor agonist, WIN 55,212-2, in four brain regions where the CB1 cannabinoid receptor is present in high density: the CA1 hippocampal area, corpus striatum, cerebellum and frontal cortex. After a twice-daily treatment for 14 days with the cannabinoid receptor agonist (3 mg/kg sc, each dose) to male Wistar rats (150-170 g), the expression of neurofilaments (Nf-160 and Nf-200), microtubule-associated protein-2 (MAP-2), synaptophysin (Syn) and glial fibrillary acidic protein (GFAP) was studied by immunohistochemistry and digital image analysis. Ultrastructural study of the synapses was done using electron microscopy. After the treatment, a significant increase in the expression of neuronal cytoskeletal proteins (Nf-160, Nf-200, MAP-2) was observed, but we did not find changes in the expression of GFAP, the main astroglial cytoskeletal protein. In cerebellum, there was an increase in Syn expression and in the number of synaptic vesicles, while, in the hippocampus, an increase in the Syn expression and in the thickness of the postsynaptic densities was observed. The results obtained from these studies provide evidences on the absence of astroglial reaction and a sprouting phenomena induced by the WIN treatment that might be a key contributor to the long-term neuroprotective effects observed after cannabinoid treatments in different models of central nervous system (CNS) injury reported in the literature.
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PMID:Neuronal cytoskeleton and synaptic densities are altered after a chronic treatment with the cannabinoid receptor agonist WIN 55,212-2. 1656 7

Parkinson's disease is a neurodegenerative disorder which is in most cases of unknown etiology. Mutations of the Park-2 gene are the most frequent cause of familial parkinsonism and parkin knockout (PK-KO) mice have abnormalities that resemble the clinical syndrome. We investigated the interaction of genetic and environmental factors, treating midbrain neuronal cultures from PK-KO and wild-type (WT) mice with rotenone (ROT). ROT (0.025-0.1 microm) produced a dose-dependent selective reduction of tyrosine hydroxylase-immunoreactive cells and of other neurons, as shown by the immunoreactivity to microtubule-associated protein 2 in PK-KO cultures, suggesting that the toxic effect of ROT involved dopamine and other types of neurons. Neuronal death was mainly apoptotic and suppressible by the caspase inhibitor t-butoxycarbonyl-Asp(OMe)-fluoromethyl ketone (Boc-D-FMK). PK-KO cultures were more susceptible to apoptosis induced by low doses of ROT than those from WT. ROT increased the proportion of astroglia and microglia more in PK-KO than in WT cultures. Indomethacin, a cyclo-oxygenase inhibitor, worsened the effects of ROT on tyrosine hydroxylase cells, apoptosis and astroglial (glial fibrillary acidic protein) cells. N-nitro-L-arginine methyl ester, an inhibitor of nitric oxide synthase, increased ROT-induced apoptosis but did not change tyrosine hydroxylase-immunoreactive or glial fibrillary acidic protein area. Neither indomethacin nor N-nitro-L-arginine methyl ester had any effect on the reduction by ROT of the mitochondrial potential as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide. Microglial NADPH oxidase inhibition, however, protected against ROT. The roles of p38 MAPK and extracellular signal-regulated kinase signaling pathways were tested by treatment with SB20358 and PD98059, respectively. These compounds were inactive in ROT-naive cultures but PD98059 slightly increased cellular necrosis, as measured by lactate dehydrogenase levels, caused by ROT, without changing mitochondrial activity. SB20358 increased the mitochondrial failure and lactate dehydrogenase elevation induced by ROT. Minocycline, an inhibitor of microglia, prevented the dropout of tyrosine hydroxylase and apoptosis by ROT; the addition of microglia from PK-KO to WT neuronal cultures increased the sensitivity of dopaminergic neurons to ROT. PK-KO mice were more susceptible than WT to ROT and the combined effects of Park-2 suppression and ROT reproduced the cellular events observed in Parkinson's disease. These events were prevented by minocycline.
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PMID:Susceptibility to rotenone is increased in neurons from parkin null mice and is reduced by minocycline. 1657 51

S100beta is a calcium-binding peptide produced by astrocytes. This protein is expressed at high levels in brain and is known as a marker of brain damage. However, little is known about the role of S100beta protein during neuronal damage caused by MPTP. To determine exactly changes of expression of S100beta protein in relation to changes of glial cells, we investigated immunohistochemically the expression of S100beta protein using MPTP-treated mice. The present study showed that tyrosine hydroxylase (TH) immunoreactivity was decreased in the striatum and substantia nigra from 5 h and 1 day after MPTP treatment, respectively. Thereafter, a severe reduction in TH immunoreactivity was observed in the striatum and substantia nigra 1, 3 and 7 days after MPTP treatment. In our double-labeled immunostaining, the number of S100-positive/GFAP-negative cells decreased from 1 day up to 7 days after MPTP treatment. In contrast, the number of double-labeled S100/GFAP-immnoreactive cells increased from 1 day up to 7 days after MPTP treatment. The number of S100beta-positive/GFAP-negative cells also decreased 3 and 7 days after MPTP treatment. In contrast, the number of double-labeled S100beta/GFAP-immunoreactive cells increased from 1 day up to 7 days after MPTP treatment. The present study demonstrates that S100beta/GFAP-positive cells may play some role in the pathogenesis of MPTP-induced dopaminergic neurodegeneration in the striatum. The present results also suggest the presence of the S100beta protein in a subpopulation of GFAP-negative astrocytes in the striatum after MPTP treatment. These results suggest that the modulation of astrocytic activation may offer a novel therapeutic strategy of Parkinson's disease.
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PMID:Time dependent alterations of co-localization of S100beta and GFAP in the MPTP-treated mice. 1673 45

Exposure to pesticides has been suggested to increase the risk of Parkinson's disease (PD), but the mechanisms responsible for this association are not clear. Here, we report that perinatal exposure of mice during gestation and lactation to low levels of dieldrin (0.3, 1, or 3 mg/kg every 3 days) alters dopaminergic neurochemistry in their offspring and exacerbates MPTP toxicity. At 12 wk of age, protein and mRNA levels of the dopamine transporter (DAT) and vesicular monoamine transporter 2 (VMAT2) were increased by perinatal dieldrin exposure in a dose-related manner. We then administered MPTP (2 x 10 mg/kg s.c) at 12 wk of age and observed a greater reduction of striatal dopamine in dieldrin-exposed offspring, which was associated with a greater DAT:VMAT2 ratio. Additionally, dieldrin exposure during development potentiated the increase in GFAP and alpha-synuclein levels induced by MPTP, indicating increased neurotoxicity. In all cases there were greater effects observed in the male offspring than the female, similar to that observed in human cases of PD. These data suggest that developmental exposure to dieldrin leads to persistent alterations of the developing dopaminergic system and that these alterations induce a "silent" state of dopamine dysfunction, thereby rendering dopamine neurons more vulnerable later in life.
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PMID:Developmental exposure to the pesticide dieldrin alters the dopamine system and increases neurotoxicity in an animal model of Parkinson's disease. 1680 32

This study was to explore curative effect of bone marrow stromal cells (BMSCs) differentiated into nestin-positive cells transplantation on rat Parkinson's disease (PD) model. The PD rats were selected and allocated randomly into three groups. BMSCs with differentiation, BMSCs without differentiation and physiological saline were injected into right striatum of PD rat. The rotation test and immunofluorescence double staining were done. Frequency of rotation was significantly less in differentiated or non-differentiated BMSCs groups than that in normal saline group. Brdu/GFAP- and Brdu/NSE-positive cells appeared except BrdU/TH-positive cells. BMSCs differentiated had better effect than that of BMSCs without differentiated and physiological saline group.
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PMID:Therapeutic effects of differentiated bone marrow stromal cell transplantation on rat models of Parkinson's disease. 1700 32

This study describes the pathological findings in the brain of a patient with Parkinson's disease (PD) treated with bilateral subthalamic high-frequency deep brain stimulation (STN DBS) for 29 months prior to death. After routine neuropathological examination, tissue blocks containing the electrode tracts, the subthalamic nucleus (STN), the substantia nigra and the pre-frontal cortex were paraffin embedded and cut into 5-microm-thick serial sections and stained with several conventional staining methods and immunohistochemistry. Bilateral nigral depigmentation, cell loss and Lewy body formation confirmed the diagnosis of PD. Microscopic evaluation furthermore confirmed the location of the electrodes in the STN. The electrode tracts were surrounded by a 150-microm-wide glial fibrillary acidic protein (GFAP)-positive capsule consisting of a thin collagen layer lining the lumen of the tract, whilst an area with few cells and axons constituted the capsule wall towards the surrounding normal brain tissue. The brain tissue appeared normal outside the capsule boundaries with no difference in areas of stimulation compared with areas of no stimulation. Our results correspond with previous studies performed after fewer months of STN DBS and indicate mild histopathological changes in the vicinity of the electrode tract, appearing to result from the electrode placement and not from the electrical stimulation.
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PMID:Chronic subthalamic high-frequency deep brain stimulation in Parkinson's disease--a histopathological study. 1725 Jul 19

The experiment was to evaluate the therapeutic benefit of transplanted bone marrow stromal cells (BMSCs) transfected with a kind of neurotrophic factor gene, neurturin (NTN) gene, in treating the rat model of Parkinson's disease (PD). The 6-OHDA-lesioned rats were assigned to one of three groups, those receiving BMSCs transfected with NTN gene, those receiving untransfected BMSCs containing a void plasmid and those receiving phosphate buffer solution (PBS). Treatments were injected into the right striatum (6-OHDA-lesioned side). One to six months post-transplantation, apomorphine-induced rotational behavior was observed. One month after transplantation, green fluorescent protein (GFP)/NTN, GFP/glial fibrillary acidic protein (GFAP), GFP/neuron specific enolase (NSE) and GFP/tyrosine hydroxylase (TH) fluorescence determinations of brain sections were carried out. One to six months after transplantation, brain sections containing striatum and substantia nigra were stained for TH. In situ hybridization and Western blots were used to determine NTN mRNA and protein concentration, respectively, in affected brain regions. High performance liquid chromatography (HPLC) was used to measure the dopamine (DA) content in the lesioned striatum 1 and 3 month(s) post-transplantation. The results were shown that: in the first 3 months after transplantation, the number of rotations was lower in NTN-transplant group than the void vector group, and during 1-6 months post-transplantation, the number of rotations was lower in both transplant groups than that in the PBS group (P<0.05). One month after transplantation, we detected GFP/NTN-, GFP/GFAP- and GFP/NSE-labeled cells in the transplantation area of the NTN-transplanted group, but no obvious GFP/TH labeled cells were found. Quantitative analysis of TH-positive cells 1 to 6 months after transplantation indicated that there were no significant differences between groups in survival rates of TH-positive neurons in the lesioned substantia nigra (P>0.05). In situ hybridization and Western blot identified NTN mRNA and protein expression in the transplantation area of the NTN-transplanted group. After transplantation of NTN-expressing cells, DA content in the lesioned striatum was significantly higher in the transgenic group than that in the void vector group or the PBS group (P<0.05). The overall therapeutic effects of the NTN-transplanted group were superior to those of the void plasmid group and the PBS group. The mechanisms by which transgenic therapy treats PD might involve functional enhancement of residual dopaminergic neurons by NTN, which significantly reduces the number of rotations in animals, but not increase the numbers of existing dopaminergic neurons.
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PMID:Transplantation of bone marrow stromal cells containing the neurturin gene in rat model of Parkinson's disease. 1733 73

Exposure to environmental toxins increases the risk of neurodegenerative diseases including Parkinson's disease (PD). Rotenone is a neurotoxin that has been used to induce experimental Parkinsonism in rats. We used the rotenone model of experimental Parkinsonism to explore a novel aspect of extra-nigral degeneration, the neurodegeneration of spinal cord (SC), in PD. Rotenone administration to male Lewis rats caused significant neuronal cell death in cervical and lumbar SC as compared with control animals. Dying neurons were motoneurons as identified by double immunofluorescent labeling for terminal deoxynucleotidyl transferase, recombinant-mediated dUTP nick-end labeling-positive (TUNEL(+)) cells and choline acetyltransferase (ChAT)-immunoreactivity. Neuronal death was accompanied by abundant astrogliosis and microgliosis as evidenced from glial fibrillary acidic protein (GFAP)-immunoreactivity and OX-42-immunoreactivity, respectively, implicating an inflammatory component during neurodegeneration in SC. However, the integrity of the white matter in SC was not affected by rotenone administration as evidenced from the non co-localization of any TUNEL(+) cells with GFAP-immunoreactivity and myelin basic protein (MBP)-immunoreactivity, the selective markers for astrocytes and oligodendrocytes, respectively. Increased activities of 76 kD active m-calpain and 17/19 kD active caspase-3 further demonstrated involvement of these enzymes in cell death in SC. The finding of ChAT(+) cell death also suggested degeneration of SC motoneurons in rotenone-induced experimental Parkinsonism. Thus, this is the first report of its kind in which the selective vulnerability of a putative parkinsonian target outside of nigrostriatal system has been tested using an environmental toxin to understand the pathophysiology of PD. Moreover, rotenone-induced degeneration of SC motoneuron in this model of experimental Parkinsonism progressed with upregulation of calpain and caspase-3.
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PMID:The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats. 1736 52

It has recently been reported that Parkinson's disease (PD) is preceded and accompanied by daytime sleep attacks, nocturnal insomnia, REM sleep behaviour disorder, hallucinations and depression, symptoms which are frequently as troublesome as the motor symptoms of PD. All these symptoms are present in narcolepsy, which is linked to a selective loss of hypocretin (Hcrt) neurons. In this study, the Hcrt system was examined to determine if Hcrt cells are damaged in PD. The hypothalamus of 11 PD (mean age 79 +/- 4) and 5 normal (mean age 77 +/- 3) brains was examined. Sections were immunostained for Hcrt-1, melanin concentrating hormone (MCH) and alpha synuclein and glial fibrillary acidic protein (GFAP). The substantia nigra of 10 PD brains and 7 normal brains were used for a study of neuromelanin pigmented cell loss. The severity of PD was assessed using the Hoehn and Yahr scale and the level of neuropathology was assessed using the Braak staging criteria. Cell number, distribution and size were determined with stereologic techniques on a one in eight series. We found an increasing loss of hypocretin cells with disease progression. Similarly, there was an increased loss of MCH cells with disease severity. Hcrt and MCH cells were lost throughout the anterior to posterior extent of their hypothalamic distributions. The percentage loss of Hcrt cells was minimal in stage I (23%) and was maximal in stage V (62%). Similarly, the percentage loss of MCH cells was lowest in stage I (12%) and was highest in stage V (74%). There was a significant increase (P = 0.0006, t = 4.25, df = 15) in the size of neuromelanin containing cells in PD patients, but no difference in the size of surviving Hcrt (P = 0.18, t = 1.39, df = 14) and MCH (P = 0.28, t = 1.39, df = 14) cells relative to controls. In summary, we found that PD is characterized by a massive loss of Hcrt neurons. Thus, the loss of Hcrt cells may be a cause of the narcolepsy-like symptoms of PD and may be ameliorated by treatments aimed at reversing the Hcrt deficit. We also saw a substantial loss of hypothalamic MCH neurons. The losses of Hcrt and MCH neurons are significantly correlated with the clinical stage of PD, not disease duration, whereas the loss of neuromelanin cells is significantly correlated only with disease duration. The significant correlations that we found between the loss of Hcrt and MCH neurons and the clinical stage of PD, in contrast to the lack of a relationship of similar strength between loss of neuromelanin containing cells and the clinical symptoms of PD, suggests a previously unappreciated relationship between hypothalamic dysfunction and the time course of the overall clinical picture of PD.
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PMID:Hypocretin (orexin) cell loss in Parkinson's disease. 1789 5

In this study, we investigated the possible link between lipid peroxidation (LPO) and the formation of protein carbonyls (PCOs) during depletion of brain glutathione (GSH). To this end, rat brain slices were incubated with the GSH depletor diethyl maleate (DEM) in the absence or presence of classical LPO scavengers: trolox, caffeic acid phenethyl ester (CAPE), and butylated hydroxytoluene (BHT). All three scavengers reduced DEM-induced lipid oxidation and protein carbonylation, suggesting that intermediates/products of the LPO pathway such as lipid hydroperoxides, 4-hydroxynonenal and/or malondialdehyde are involved in the process. Additional in vitro experiments revealed that, among these products, lipid hydroperoxides are most likely responsible for protein oxidation. Interestingly, BHT prevented the carbonylation of cytoskeletal proteins but not that of soluble proteins, suggesting the existence of different mechanisms of PCO formation during GSH depletion. In pull-down experiments, beta-actin and alpha/beta-tubulin were identified as major carbonylation targets during GSH depletion, although other cytoskeletal proteins such as neurofilament proteins and glial fibrillary acidic protein were also carbonylated. These findings may be important in the context of neurological disorders that exhibit decreased GSH levels and increased protein carbonylation such as Parkinson's disease, Alzheimer's disease, and multiple sclerosis.
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PMID:Lipid peroxidation scavengers prevent the carbonylation of cytoskeletal brain proteins induced by glutathione depletion. 1755 32


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