Drugs and mitochondrial diseases: 40 queries and answers

Mancuso, Michelangelo; Orsucci, Daniele; Filosto, Massimiliano; Simoncini, Costanza; Siciliano, Gabriele

doi:10.1517/14656566.2012.657177

Cited by 30 publications

(53 citation statements)

References 132 publications

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“…As reported, VPA hepatotoxicity includes microvesicular steatosis, steatohepatitis, fibrosis, hepatocellular carcinomas, and even fulminant hepatitis, 46-48 mainly due to mitochondrial toxicity shown both in rodents and humans. 50,51 In this study, we have demonstrated that NaB protects HepG2 cells and primary rat hepatocytes from VPA-induced toxicity, by reducing cellular and mitochondrial oxidative damage. 50,51 In this study, we have demonstrated that NaB protects HepG2 cells and primary rat hepatocytes from VPA-induced toxicity, by reducing cellular and mitochondrial oxidative damage.…”

Section: Discussionmentioning

confidence: 74%

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

et al. 2019

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Sodium valproate (VPA), an antiepileptic drug, may cause dose-and time-dependent hepatotoxicity. However, its iatrogenic molecular mechanism and the rescue therapy are disregarded. Recently, it has been demonstrated that sodium butyrate (NaB) reduces hepatic steatosis, improving respiratory capacity and mitochondrial dysfunction in obese mice. Here, we investigated the protective effect of NaB in counteracting VPA-induced hepatotoxicity using in vitro and in vivo models. Human HepG2 cells and primary rat hepatocytes were exposed to high VPA concentration and treated with NaB. Mitochondrial function, lipid metabolism, and oxidative stress were evaluated, using Seahorse analyzer, spectrophotometric, and biochemical determinations.Liver protection by NaB was also evaluated in VPA-treated epileptic WAG/Rij rats, receiving NaB for 6 months. NaB prevented VPA toxicity, limiting cell oxidative and mitochondrial damage (ROS, malondialdehyde, SOD activity, mitochondrial bioenergetics), and restoring fatty acid oxidation (peroxisome proliferator-activated receptor α expression and carnitine palmitoyl-transferase activity) in HepG2 cells, primary hepatocytes, and isolated mitochondria. In vivo, NaB confirmed its activity normalizing hepatic biomarkers, fatty acid metabolism, and reducing inflammation and fibrosis induced by VPA. These data support the protective potential of NaB on VPA-induced liver injury, indicating it as valid therapeutic approach in counteracting this common side effect due to VPA chronic treatment. K E Y W O R D Santiepileptic drug, hepatotoxicity, lipid metabolism, mitochondrial dysfunction, oxidative stress, shortchain fatty acid | 677 PIROZZI et al. | 679 PIROZZI et al. incubated with tert-Butyl hydroperoxide (100 µM) plus H 2 O 2 for 3 hours. The fluorescence measurements were performed with aHTS-7000 Plus plate reader spectrofluorometer (Perkin Elmer, Wellesley, MA, USA) at 485 nm for excitation and 525 nm for emission wavelengths. ROS were quantified as percentage vs control unstimulated cells.

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Section: Discussionmentioning

confidence: 74%

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

et al. 2019

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“…However, idebenone may represent an inhibitor of both the redox and proton-pumping activity of complex I [5] and may cause mitochondrial depolarization and reduced nicotinamide adenine dinucleotide (NADH) depletion [4, 6]. Most recently, idebenone has been shown to be effective in improving recovery after the onset of vision loss in Leber’s hereditary optic neuropathy (LHON).…”

Section: Augmentation Of Respiratory Chain Componentsmentioning

confidence: 99%

Treatment of Mitochondrial Disorders

Avula

Parikh

Demarest

et al. 2014

Curr Treat Options Neurol

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Opinion statement While numerous treatments for mitochondrial disorders have been suggested, relatively few have undergone controlled clinical trials. Treatment of these disorders is challenging, as only symptomatic therapy is available. In this review we will focus on newer drugs and treatment trials in mitochondrial diseases, with a special focus on medications to avoid in treating epilepsy and ICU patient with mitochondrial disease, which has not been included in such a review. Readers are also referred to the opinion statement in A Modern Approach to the Treatment of Mitochondrial Disease published in Current Treatment Options in Neurology 2009. Many of the supplements used for treatment were reviewed in the previous abstract, and dosing guidelines were provided. The focus of this review is on items not previously covered in depth, and our discussion includes more recently studied compounds as well as any relevant updates on older compounds. We review a variety of vitamins and xenobiotics, including dichloroacetate (DCA), arginine, coenzyme Q10, idebenone, EPI-743, and exercise training. Treatment of epilepsy, which is a common feature in many mitochondrial phenotypes, warrants special consideration due to the added toxicity of certain medications, and we provide a discussion of these unique treatment challenges. Interesting, however, with only a few exceptions, the treatment strategies for epilepsy in mitochondrial cytopathies are the same as for epilepsy without mitochondrial dysfunction. We also discuss intensive care management, building upon similar reviews, adding new dimensions, and demonstrating the complexity of overall care of these patients.

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“…Most therapeutic strategies to treat this condition use supplements and enzyme cofactors to enhance mitochondrial metabolism and activity of the respiratory chain [34] . The treatment of choice may be represented by the combination of L-arginine (usually applied intravenously at a dosage of 0.4–0.5 g/kg in the acute phase and then switched to long-term oral supplementation) [33] , [35] , carnitine and coenzyme Q10, plus corticosteroids for the vasogenic oedema and anti-epileptic drugs or other supportive treatments when needed [36] . Other molecules such as creatine and idebenone have been suggested to decrease lactic acid levels and reduce stroke-like episodes [37] , [38] .…”

Section: Monogenic Diseasesmentioning

confidence: 99%

Genetics of ischaemic stroke in young adults

et al. 2015

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BackgroundStroke may be a clinical expression of several inherited disorders in humans. Recognition of the underlined genetic disorders causing stroke is important for a correct diagnosis, for genetic counselling and, even if rarely, for a correct therapeutic management. Moreover, the genetics of complex diseases such the stroke, in which multiple genes interact with environmental risk factors to increase risk, has been revolutionized by the Genome-Wide Association Study (GWAS) approach.Scope of reviewHere we review the single-gene causes of ischemic stroke, bringing the reader from the candidate gene method toward the exciting new horizons of genetic technology.Major conclusionsThe aetiological diagnosis of ischemic stroke in young adults is more complex than in the elderly. The identification of a genetic cause is important to provide appropriate counseling and to start a correct therapy, when available. The advent of GWAS technology, such as for other complex pathological conditions, has contributed enormously to the understanding of many of these genetic bases. For success large, well phenotyped case cohorts are required, and international collaborations are essential.General significanceThis review focuses on the main causes of genetically-based ischemic stroke in young adults, often classified as indeterminate, investigating also the recent findings of the GWAS, in order to improve diagnostic and therapeutic management.

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Drugs and mitochondrial diseases: 40 queries and answers

Abstract: Randomized clinical trials are necessary to establish efficacy and safety of drugs. Multicenter collaboration is essential for the advancement of therapy for mitochondrial disorders.

Cited by 30 publications

References 132 publications

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

Butyrate prevents valproate‐induced liver injury: In vitro and in vivo evidence

Treatment of Mitochondrial Disorders

Genetics of ischaemic stroke in young adults

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