Mitochondrial modulators in experimental Huntington’s disease: reversal of mitochondrial dysfunctions and cognitive deficits

Mehrotra, Arpit; Kanwal, Abhinav; Banerjee, Sanjay K.; Sandhir, Rajat

doi:10.1016/j.neurobiolaging.2015.02.004

Cited by 30 publications

(20 citation statements)

References 81 publications

(77 reference statements)

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“…Similarly, impaired Rhes/mTORC1 activity underlies numerous metabolic phenotypes including; mitochondrial dysfunction, striatal atrophy, aberrant cholesterol homeostasis and impaired dopamine signaling have also been reported in HD [61]. Furthermore, increased levels of protein carbonyls, malondialdehyde (C 3 H 4 O 2 ) and nitrite (NO 2 − ) along with reduced Mn-superoxide dismutase (Mn-SOD) and catalase activity is involved in impaired mitochondrial dynamics associated with altered cytochrome C levels and reduced mRNA expression of respiratory chain complexes in HD brain [62]. In addition, caspase-3 and − 9 activity coupled with altered expression of apoptotic proteins such as Bim, AIF, Bad and Bax has also been reported to be involved in cognitive impairment leading to HD [63].…”

Section: Huntington's Diseasementioning

confidence: 99%

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Jha

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Mounting evidence suggests a link between metabolic syndrome (MetS) such as diabetes, obesity, non-alcoholic fatty liver disease in the progression of Alzheimer's disease (AD), Parkinson's disease (PD) and other neurodegenerative diseases (NDDs). For instance, accumulated Aβ oligomer is enhancing neuronal Ca release and neural NO where increased NO level in the brain through post translational modification is modulating the level of insulin production. It has been further confirmed that irrespective of origin; brain insulin resistance triggers a cascade of the neurodegeneration phenomenon which can be aggravated by free reactive oxygen species burden, ER stress, metabolic dysfunction, neuorinflammation, reduced cell survival and altered lipid metabolism. Moreover, several studies confirmed that MetS and diabetic sharing common mechanisms in the progression of AD and NDDs where mitochondrial dynamics playing a critical role. Any mutation in mitochondrial DNA, exposure of environmental toxin, high-calorie intake, homeostasis imbalance, glucolipotoxicity is causative factors for mitochondrial dysfunction. These cumulative pleiotropic burdens in mitochondria leads to insulin resistance, increased ROS production; enhanced stress-related enzymes that is directly linked MetS and diabetes in neurodegeneration. Since, the linkup mechanism between mitochondrial dysfunction and disease phenomenon of both MetS and NDDs is quite intriguing, therefore, it is pertinent for the researchers to identify and implement the therapeutic interventions for targeting MetS and NDDs. Herein, we elucidated the pertinent role of MetS induced mitochondrial dysfunction in neurons and their consequences in NDDs. Further, therapeutic potential of well-known biomolecules and chaperones to target altered mitochondria has been comprehensively documented. This article is part of a Special Issue entitled: Oxidative Stress and Mitochondrial Quality in Diabetes/Obesity and Critical Illness Spectrum of Diseases - edited by P. Hemachandra Reddy.

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Section: Huntington's Diseasementioning

confidence: 99%

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Jha

Kumar

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Huntington's disease (HD) is a chronic neurodegenerative disease and a hereditary autosomal-dominant disorder of the central nervous system caused by a single genetic mutation (Ross et al, 2014 ), characterized by neuronal death in caudate and putamen and in the cerebral cortex, and to a lesser extent in hippocampus and subthalamic nucleus (Mehrotra et al, 2015 ). This disorder is classically characterized by motor symptoms and cognitive and behavioral features (Ross et al, 2014 ).…”

Section: Effects Of La In Experimental Models Of Memory Deficits Assomentioning

confidence: 99%

“…A HD model that has been easily replicated in animals is based on the treatment with 3-nitropropionic acid (3-NP), which promotes development of mitochondrial dysfunctions leading to bioenergetic failure (energy impairment, oxidative stress, and excitotoxicity). A study by Mehrotra et al ( 2015 ) investigated the effects of LA in 3-NP-induced HD in rats. Administration of LA improved spatial memory acquisition and retrieval assessed using the Morris water maze.…”

Section: Effects Of La In Experimental Models Of Memory Deficits Assomentioning

confidence: 99%

“…In this context, nutrition can be considered a critical life-style factor that impacts the development and progression of neurodegenerative diseases (Virmani et al, 2013 ). Dietary supplementation with mitochondrial nutrients could promote natural neuroprotective effects, delaying the onset or progression of cognitive dysfunction and neurodegenerative diseases (Miquel, 2002 ; Abadi et al, 2013 ; Di Domenico et al, 2015 ; Mehrotra et al, 2015 ).…”

Section: Introductionmentioning

confidence: 99%

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Potential Therapeutic Effects of Lipoic Acid on Memory Deficits Related to Aging and Neurodegeneration

Molz

Schröder

2017

Front. Pharmacol.

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The aging process comprises a series of organic alterations, affecting multiple systems, including the nervous system. Aging has been considered the main risk factor for the advance of neurodegenerative diseases, many of which are accompanied by cognitive impairment. Aged individuals show cognitive decline, which has been associated with oxidative stress, as well as mitochondrial, and consequently energetic failure. Lipoic acid (LA), a natural compound present in food and used as a dietary supplement, has been considered a promising agent for the treatment and/or prevention of neurodegenerative disorders. In spite of a number of preclinical studies showing beneficial effects of LA in memory functioning, and pointing to its neuroprotective potential effect, to date only a few studies have examined its effects in humans. Investigations performed in animal models of memory loss associated to aging and neurodegenerative disorders have shown that LA improves memory in a variety of behavioral paradigms. Moreover, cell and molecular mechanisms underlying LA effects have also been investigated. Accordingly, LA displays antioxidant, antiapoptotic, and anti-inflammatory properties in both in vivo and in vitro studies. In addition, it has been shown that LA reverses age-associated loss of neurotransmitters and their receptors, which can underlie its effects on cognitive functions. The present review article aimed at summarizing and discussing the main studies investigating the effects of LA on cognition as well as its cell and molecular effects, in order to improve the understanding of the therapeutic potential of LA on memory loss during aging and in patients suffering from neurodegenerative disorders, supporting the development of clinical trials with LA.

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“…One reason is that ALA and ALCAR act on different sites to improve mitochondrial functions, where ALCAR stimulates mitochondrial function, while ALA is an effective mitochondrial antioxidant. ALA and ALCAR supplementations have shown to be effective in reducing mitochondrial dysfunctions in aged animals, and their combination is suggested to reduce oxidative damage to neurons [18,19]. Therefore, the present study was designed to examine the efficacy of combined supplementation with mitochondrial modulators (ALA ?…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington’s disease

2015

Self Cite

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3-Nitropropionic acid (3-NP) is an irreversible inhibitor of succinate dehydrogenase and induces neuropathological changes similar to those observed in Huntington's disease (HD). The objective of the present study was to investigate neuroprotective effect of mitochondrial modulators; alpha-lipoic acid (ALA) and acetyl-L-carnitine (ALCAR) on 3-NP-induced alterations in mitochondrial lipid composition, mitochondrial structure and memory functions. Experimental model of HD was developed by administering 3-NP at sub-chronic doses, twice daily for 17 days. The levels of conjugated dienes, cholesterol and glycolipids were significantly increased, whereas the levels of phospholipids (phosphatidylethanolamine, phosphatidylcholine, phosphatidylserine) including cardiolipin were significantly decreased in the mitochondria isolated from the striatum of 3-NP-treated animals. In addition, the difference in molecular composition of each phospholipid class was also evaluated using mass spectrometry. Mitochondria lipid from 3-NP-treated animals showed increased cholesterol to phospholipid ratio, suggesting decreased mitochondrial membrane fluidity. 3-NP administration also resulted in ultra-structural changes in mitochondria, accompanied by swelling as assessed by transmission electron microscopy. The 3-NP administered animals had impaired spatial memory evaluated using elevated plus maze test. However, combined supplementation with ALA + ALCAR for 21 days normalized mitochondrial lipid composition, improved mitochondrial structure and ameliorated memory impairments in 3-NP-treated animals, suggesting an imperative role of these two modulators in combination in the management of HD.

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Mitochondrial modulators in experimental Huntington’s disease: reversal of mitochondrial dysfunctions and cognitive deficits

Cited by 30 publications

References 81 publications

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration

Potential Therapeutic Effects of Lipoic Acid on Memory Deficits Related to Aging and Neurodegeneration

Mitochondrial modulators improve lipid composition and attenuate memory deficits in experimental model of Huntington’s disease

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