8 results on '"Klivenyi, P."'
Search Results
2. Mice deficient in dihydrolipoamide dehydrogenase show increased vulnerability to MPTP, malonate and 3-nitropropionic acid neurotoxicity.
- Author
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Klivenyi P, Starkov AA, Calingasan NY, Gardian G, Browne SE, Yang L, Bubber P, Gibson GE, Patel MS, and Beal MF
- Subjects
- Animals, Caudate Nucleus drug effects, Caudate Nucleus enzymology, Caudate Nucleus pathology, Cell Count, Cerebral Cortex drug effects, Cerebral Cortex enzymology, Cerebral Cortex pathology, Corpus Striatum drug effects, Corpus Striatum enzymology, Corpus Striatum pathology, Dihydrolipoamide Dehydrogenase genetics, Disease Models, Animal, Heterozygote, Huntington Disease chemically induced, Huntington Disease enzymology, Huntington Disease pathology, Ketoglutarate Dehydrogenase Complex drug effects, Ketoglutarate Dehydrogenase Complex metabolism, Mice, Mice, Inbred C57BL, Mice, Knockout, Mitochondria drug effects, Mitochondria metabolism, Neurodegenerative Diseases chemically induced, Neurodegenerative Diseases pathology, Neurons drug effects, Neurons pathology, Nitro Compounds, Parkinsonian Disorders chemically induced, Parkinsonian Disorders enzymology, Parkinsonian Disorders pathology, Putamen drug effects, Putamen enzymology, Putamen pathology, Pyruvate Dehydrogenase Complex drug effects, Pyruvate Dehydrogenase Complex metabolism, Substantia Nigra drug effects, Substantia Nigra enzymology, Substantia Nigra pathology, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine, Dihydrolipoamide Dehydrogenase deficiency, Genetic Predisposition to Disease, Malonates, Neurodegenerative Diseases enzymology, Propionates
- Abstract
Altered energy metabolism, including reductions in activities of the key mitochondrial enzymes alpha-ketoglutarate dehydrogenase complex (KGDHC) and pyruvate dehydrogenase complex (PDHC), are characteristic of many neurodegenerative disorders including Alzheimer's Disease (AD), Parkinson's disease (PD) and Huntington's disease (HD). Dihydrolipoamide dehydrogenase is a critical subunit of KGDHC and PDHC. We tested whether mice that are deficient in dihydrolipoamide dehydrogenase (Dld+/-) show increased vulnerability to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), malonate and 3-nitropropionic acid (3-NP), which have been proposed for use in models of PD and HD. Administration of MPTP resulted in significantly greater depletion of tyrosine hydroxylase-positive neurons in the substantia nigra of Dld+/- mice than that seen in wild-type littermate controls. Striatal lesion volumes produced by malonate and 3-NP were significantly increased in Dld+/- mice. Studies of isolated brain mitochondria treated with 3-NP showed that both succinate-supported respiration and membrane potential were suppressed to a greater extent in Dld+/- mice. KGDHC activity was also found to be reduced in putamen from patients with HD. These findings provide further evidence that mitochondrial defects may contribute to the pathogenesis of neurodegenerative diseases.
- Published
- 2004
- Full Text
- View/download PDF
3. Additive neuroprotective effects of creatine and cyclooxygenase 2 inhibitors in a transgenic mouse model of amyotrophic lateral sclerosis.
- Author
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Klivenyi P, Kiaei M, Gardian G, Calingasan NY, and Beal MF
- Subjects
- Amyotrophic Lateral Sclerosis genetics, Amyotrophic Lateral Sclerosis metabolism, Animals, Creatine pharmacology, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Cyclooxygenase Inhibitors pharmacology, Drug Synergism, Drug Therapy, Combination, Female, Isoenzymes antagonists & inhibitors, Isoenzymes metabolism, Male, Mice, Mice, Transgenic, Neuroprotective Agents pharmacology, Prostaglandin-Endoperoxide Synthases metabolism, Superoxide Dismutase biosynthesis, Superoxide Dismutase genetics, Amyotrophic Lateral Sclerosis drug therapy, Creatine therapeutic use, Cyclooxygenase Inhibitors therapeutic use, Disease Models, Animal, Neuroprotective Agents therapeutic use
- Abstract
There is substantial evidence implicating both inflammation and mitochondrial dysfunction in amyotrophic lateral sclerosis (ALS) pathogenesis. We investigated the therapeutic effects of cyclooxygenase 2 (COX-2) inhibitors both alone and in combination with creatine in the G93A transgenic mouse model of ALS. Oral administration of either celecoxib or rofecoxib significantly improved motor performance, attenuated weight loss and extended survival. The administration of COX-2 inhibitors significantly reduced prostaglandin E2 levels at 110 days of age. The combination of creatine with COX-2 inhibitors produced additive neuroprotective effects and extended survival by approximately 30%. The COX-2 inhibitors significantly protected against depletion of anterior horn motor neurons and creatine with COX-2 inhibitors showed greater protection than COX-2 inhibitors alone. These results suggest that combinations of therapies targeting different disease mechanisms may be a useful strategy in the treatment of ALS.
- Published
- 2004
- Full Text
- View/download PDF
4. Increased survival and neuroprotective effects of BN82451 in a transgenic mouse model of Huntington's disease.
- Author
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Klivenyi P, Ferrante RJ, Gardian G, Browne S, Chabrier PE, and Beal MF
- Subjects
- Administration, Oral, Animals, Behavior, Animal drug effects, Brain drug effects, Brain pathology, Disease Models, Animal, Huntington Disease genetics, Huntington Disease pathology, Inclusion Bodies drug effects, Inclusion Bodies metabolism, Inclusion Bodies pathology, Mice, Mice, Transgenic, Motor Activity drug effects, Neurons drug effects, Neurons metabolism, Neurons pathology, Survival Rate, Treatment Outcome, Ubiquitin biosynthesis, Antioxidants therapeutic use, Huntington Disease drug therapy, Neuroprotective Agents therapeutic use
- Abstract
There is substantial evidence that excitotoxicity and oxidative damage may contribute to Huntington's disease (HD) pathogenesis. We examined whether the novel anti-oxidant compound BN82451 exerts neuroprotective effects in the R6/2 transgenic mouse model of HD. Oral administration of BN82451 significantly improved motor performance and improved survival by 15%. Oral administration of BN82451 significantly reduced gross brain atrophy, neuronal atrophy and the number of neuronal intranuclear inclusions at 90 days of age. These findings provide evidence that novel anti-oxidants such as BN82451 may be useful for treating HD.
- Published
- 2003
- Full Text
- View/download PDF
5. Malonate and 3-nitropropionic acid neurotoxicity are reduced in transgenic mice expressing a caspase-1 dominant-negative mutant.
- Author
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Andreassen OA, Ferrante RJ, Hughes DB, Klivenyi P, Dedeoglu A, Ona VO, Friedlander RM, and Beal MF
- Subjects
- Animals, Brain drug effects, Brain enzymology, Crosses, Genetic, Disease Models, Animal, Female, Huntington Disease metabolism, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Neostriatum drug effects, Neostriatum pathology, Nitro Compounds, Point Mutation, Brain pathology, Caspase 1 genetics, Caspase 1 metabolism, Malonates toxicity, Neurotoxins toxicity, Propionates toxicity
- Abstract
Increasing evidence implicates caspase-1-mediated cell death as a major mechanism of neuronal death in neurodegenerative diseases. In the present study we investigated the role of caspase-1 in neurotoxic experimental animal models of Huntington's disease (HD) by examining whether transgenic mice expressing a caspase-1 dominant-negative mutant are resistant to malonate and 3-nitropropionic acid (3-NP) neurotoxicity. Intrastriatal injection of malonate resulted in significantly smaller striatal lesions in mutant caspase-1 mice than those observed in littermate control mice. Caspase-1 was significantly activated following malonate intrastriatal administration in control mice but significantly attenuated in mutant caspase-1 mice. Systemic 3-NP treatment induced selective striatal lesions that were significantly smaller within mutant caspase-1 mice than in littermate control mice. These results provide further evidence of a functional role for caspase-1 in both malonate- and 3-NP-mediated neurotoxin models of HD.
- Published
- 2000
- Full Text
- View/download PDF
6. Nonlinear decrease over time in N-acetyl aspartate levels in the absence of neuronal loss and increases in glutamine and glucose in transgenic Huntington's disease mice.
- Author
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Jenkins BG, Klivenyi P, Kustermann E, Andreassen OA, Ferrante RJ, Rosen BR, and Beal MF
- Subjects
- Animals, Aspartic Acid metabolism, Blood Glucose analysis, Brain metabolism, Humans, Huntington Disease diagnosis, Huntington Disease genetics, Magnetic Resonance Spectroscopy, Mice, Mice, Transgenic genetics, Mice, Transgenic metabolism, Nonlinear Dynamics, Time Factors, Aspartic Acid analogs & derivatives, Glucose metabolism, Glutamine metabolism, Huntington Disease metabolism, Huntington Disease pathology, Neurons pathology
- Abstract
Mice transgenic for exon I of mutant huntingtin, with 141 CAG repeats, exhibit a profound symptomatology characterized by weight loss, motor disorders, and early death. We performed longitudinal analysis of metabolite levels in these mice using NMR spectroscopy in vivo and in vitro. These mice exhibited a large (53%), nonlinear drop in in vivo N-acetyl aspartate (NAA) levels over time, commencing at approximately 6 weeks of age, coincident with onset of symptoms. These drops in NAA levels occurred in the absence of neuronal death as measured by postmortem Nissl staining and neuronal counting but in the presence of nuclear inclusion bodies. In addition to decreased NAA, these mice showed a large elevation of glucose in the brain (600%) consistent with a diabetic profile and elevations in blood glucose levels both before and after glucose loading. In vitro NMR analysis revealed significant increases in glutamine (100%), taurine (95%) cholines (200%), and scyllo-inositol (333%) and decreases in glutamate (24%) and succinate (47%). These results lead to two conclusions. NAA is reflective of the health of neurons and thus is a noninvasive marker, with a temporal progression similar to nuclear inclusion bodies and symptoms, of neuronal dysfunction in transgenic mice. Second, the presence of elevated glutamine is evidence of a profound metabolic defect. We present arguments that the elevated glutamine results from a decrease in neuronal-glial glutamate-glutamine cycling and a decrease in glutaminase activity.
- Published
- 2000
- Full Text
- View/download PDF
7. Increased vulnerability to 3-nitropropionic acid in an animal model of Huntington's disease.
- Author
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Bogdanov MB, Ferrante RJ, Kuemmerle S, Klivenyi P, and Beal MF
- Subjects
- Animals, Corpus Striatum metabolism, Corpus Striatum pathology, Drug Resistance physiology, Huntington Disease pathology, Hydroxybenzoates metabolism, Hydroxyl Radical metabolism, Mice, Mice, Transgenic genetics, Microdialysis, Nitro Compounds, Parabens metabolism, Reference Values, Huntington Disease physiopathology, Propionates pharmacology
- Abstract
There is substantial evidence for both metabolic dysfunction and oxidative damage in Huntington's disease (HD). In the present study, we used in vivo microdialysis to measure the conversion of 4-hydroxybenzoic acid to 3,4-dihydroxybenzoic acid (3,4-DHBA) as a measure of hydroxyl radical production in a transgenic mouse model of HD, as well as in littermate controls. The conversion of 4-hydroxybenzoic acid to 3,4-DHBA was unchanged in the striatum of transgenic HD mice at baseline. Following administration of the mitochondrial toxin 3-nitropropionic acid (3-NP), there were significant increases in 3,4-DHBA generation in both control and transgenic HD mice, and the increases in the transgenic HD mice were significantly greater than those in controls. Furthermore, administration of 3-NP produced significantly larger striatal lesions in transgenic HD mice than in littermate controls. The present results show increased sensitivity to the mitochondrial toxin 3-NP in transgenic HD mice, which suggests metabolic dysfunction in this mouse model of HD.
- Published
- 1998
- Full Text
- View/download PDF
8. Mice deficient in group IV cytosolic phospholipase A2 are resistant to MPTP neurotoxicity.
- Author
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Klivenyi P, Beal MF, Ferrante RJ, Andreassen OA, Wermer M, Chin MR, and Bonventre JV
- Subjects
- 1-Methyl-4-phenylpyridinium metabolism, 3,4-Dihydroxyphenylacetic Acid metabolism, Animals, Cell Count drug effects, Corpus Striatum metabolism, Dopamine Agents pharmacology, Drug Resistance genetics, Homovanillic Acid metabolism, Mice, Mice, Knockout genetics, Phospholipases A genetics, Phospholipases A2, Substantia Nigra drug effects, Substantia Nigra enzymology, Substantia Nigra pathology, Tyrosine 3-Monooxygenase metabolism, 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine pharmacology, Cytosol enzymology, Neurotoxins pharmacology, Phospholipases A deficiency
- Abstract
Phospholipase A2 (PLA2) enzymes are critical regulators of prostaglandin and leukotriene synthesis, and they may also play an important role in the generation of intracellular free radicals. The group IV cytosolic form of phospholipase A2 (cPLA2) is regulated by changes in intracellular calcium concentration, and the enzyme preferentially acts to release arachidonic acid esterified at the sn-2 position of phospholipids. We examined the susceptibility of mice carrying a targeted mutation of the cPLA2 gene to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced neurotoxicity. Mutant mice have no functional cPLA2 activity. Mice that were homozygous for the mutation (cPLA2-/-) were significantly resistant to MPTP-induced dopamine depletion as compared with littermate control (cPLA2+/+) and heterozygous mice (cPLA2+/-). These findings provide evidence that cPLA2 plays a role in MPTP neurotoxicity and suggest that cPLA2 may play a role in the development of Parkinson's disease in humans.
- Published
- 1998
- Full Text
- View/download PDF
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