Altered cholesterol and fatty acid metabolism in Huntington disease
ABSTRACT Huntington disease is an autosomal dominant neurodegenerative disorder characterized by behavioral abnormalities, cognitive decline, and involuntary movements that lead to a progressive decline in functional capacity, independence, and ultimately death. The pathophysiology of Huntington disease is linked to an expanded trinucleotide repeat of cytosine-adenine-guanine (CAG) in the IT-15 gene on chromosome 4. There is no disease-modifying treatment for Huntington disease, and novel pathophysiological insights and therapeutic strategies are needed. Lipids are vital to the health of the central nervous system, and research in animals and humans has revealed that cholesterol metabolism is disrupted in Huntington disease. This lipid dysregulation has been linked to specific actions of the mutant huntingtin on sterol regulatory element binding proteins. This results in lower cholesterol levels in affected areas of the brain with evidence that this depletion is pathologic. Huntington disease is also associated with a pattern of insulin resistance characterized by a catabolic state resulting in weight loss and a lower body mass index than individuals without Huntington disease. Insulin resistance appears to act as a metabolic stressor attending disease progression. The fish-derived omega-3 fatty acids, eicosapentaenoic acid and docosahexaenoic acid, have been examined in clinical trials of Huntington disease patients. Drugs that combat the dysregulated lipid milieu in Huntington disease may help treat this perplexing and catastrophic genetic disease.
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ABSTRACT: Cholesterol is an essential component for neuronal physiology not only during development stage but also in the adult life. Cholesterol metabolism in brain is independent from that in peripheral tissues due to blood-brain barrier. The content of cholesterol in brain must be accurately maintained in order to keep brain function well. Defects in brain cholesterol metabolism has been shown to be implicated in neurodegenerative diseases, such as Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), and some cognitive deficits typical of the old age. The brain contains large amount of cholesterol, but the cholesterol metabolism and its complex homeostasis regulation are currently poorly understood. This review will seek to integrate current knowledge about the brain cholesterol metabolism with molecular mechanisms.Protein & Cell 02/2015; 6(4). DOI:10.1007/s13238-014-0131-3 · 2.85 Impact Factor
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ABSTRACT: With our increasing appreciation of the true complexity of diseases and pathophysiologies, it is clear that this knowledge needs to inform the future development of pharmacotherapeutics. For many disorders, the disease mechanism itself is a complex process spanning multiple signaling networks, tissues, and organ systems. Identifying the precise nature and locations of the pathophysiology is crucial for the creation of systemically effective drugs. Diseases once considered constrained to a limited range of organ systems, e.g., central neurodegenerative disorders such as Alzheimer's disease (AD), Parkinson's disease (PD), and Huntington' disease (HD), the role of multiple central and peripheral organ systems in the etiology of such diseases is now widely accepted. With this knowledge, it is increasingly clear that these seemingly distinct neurodegenerative disorders (AD, PD, and HD) possess multiple pathophysiological similarities thereby demonstrating an inter-related continuum of disease-related molecular alterations. With this systems-level appreciation of neurodegenerative diseases, it is now imperative to consider that pharmacotherapeutics should be developed specifically to address the systemic imbalances that create the disorders. Identification of potential systems-level signaling axes may facilitate the generation of therapeutic agents with synergistic remedial activity across multiple tissues, organ systems, and even diseases. Here, we discuss the potentially therapeutic systems-level interaction of the glucagon-like peptide 1 (GLP-1) ligand-receptor axis with multiple aspects of the AD, PD, and HD neurodegenerative continuum.Frontiers in Endocrinology 09/2014; 5:142. DOI:10.3389/fendo.2014.00142
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ABSTRACT: Ethnopharmacological relevance: Cathinone hydrochloride is an active principle of the khat plant (Catha edulis) that produces pleasurable and stimulating effects in khat chewers. To the best of our knowledge no data of cathinone on oxidative stress in limbic areas of mice is available. This is the first study of cathinone on oxidative stress in limbic areas of the brain in Swiss albino male mice. Materials and methods: The animals were divided into four groups. Group-I was the control group and received vehicle, while groups-II to IV received (-)-cathinone hydrochloride (0.125, 0.25 and 0.5 mg/kg body wt., i.p.) once daily for 15 days. Results: The level of lipid peroxidation (LPO) was elevated dose-dependently and was significant (p < 0.05, p < 0.01) with doses of 0.25 and 0.5 mg/kg body wt. of cathinone as compared to control group. In contrast, the content of reduced glutathione (GSH) was decreased significantly (p < 0.01, p < 0.001) with doses of 0.25 and 0.5 mg/kg body wt. of cathinone as compared to control group. The activity of antioxidant enzymes (GPx, GR, GST, CAT, and SOD) was also decreased dose-dependently: the decreased activity of GPx, GR, catalase and SOD was significant with doses of 0.25 and 0.5 mg of cathinone as compared to control group, while the activity of GST was decreased dose-dependently and was significant with 0.5 mg of cathinone as compared to control group. Conclusions: The results indicate that the cathinone generated oxidative stress hampered antioxidant enzymes, glutathione and lipid peroxidation.Journal of Ethnopharmacology 08/2014; DOI:10.1016/j.jep.2014.08.004 · 2.94 Impact Factor