Article

Mitochondria: A Therapeutic Target in Neurodegeneration

Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
Biochimica et Biophysica Acta (Impact Factor: 4.66). 10/2009; 1802(1):212-20. DOI: 10.1016/j.bbadis.2009.10.007
Source: PubMed

ABSTRACT Mitochondrial dysfunction has long been associated with neurodegenerative disease. Therefore, mitochondrial protective agents represent a unique direction for the development of drug candidates that can modify the pathogenesis of neurodegeneration. This review discusses evidence showing that mitochondrial dysfunction has a central role in the pathogenesis of Alzheimer's, Parkinson's and Huntington's diseases and amyotrophic lateral sclerosis. We also debate the potential therapeutic efficacy of metabolic antioxidants, mitochondria-directed antioxidants and Szeto-Schiller (SS) peptides. Since these compounds preferentially target mitochondria, a major source of oxidative damage, they are promising therapeutic candidates for neurodegenerative diseases. Furthermore, we will briefly discuss the novel action of the antihistamine drug Dimebon on mitochondria.

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    • "Inflammation seems to play a key role in the early pathology of NDDs; but interestingly, the inflammatory response is also associated with the activation of free radical generating enzymes such as NADPH oxidase [7] and myeloperoxidase [8]. Mitochondrial dysfunctions in NDDs include deficiencies in several enzymes involved in tricarboxilic acid cycle like pyruvate dehydrogenase, aketoglutarate dehydrogenase and cytochrome c oxidase [9], reduced mitochondrial complexes activity [10] and accumulation of mutations in mitochondrial DNA [11]. Thus, during pathological conditions mitochondria become less efficient ATP producers and more deleterious ROS producers [3]. "
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    ABSTRACT: Subchronic oxidative stress and inflammation are being increasingly implicated in the pathogenesis of numerous diseases, such as Alzheimeŕs or Parkinsońs disease. This study was designed to evaluate the potential protective role of α7 nicotinic receptor activation in an in vitro model of neurodegeneration based on subchronic oxidative stress. Rat organotypic hippocampal cultures (OHCs) were exposed for 4 days to low concentration of lipopolysaccharide (LPS) and the complex III mitochondrial blocker, antimycin-A. Antimycin-A (0.1μM) and lipopolysaccharide (1 ng/ml) caused low neurotoxicity on their own, measured as propidium iodide fluorescence in CA1 and CA3 regions. However, their combination (LPS/AA) caused a greater detrimental effect, in addition to mitochondrial depolarization, overproduction of reactive oxygen species (ROS) and Nox4 overexpression. Antimycin-A per se increased ROS and mitochondrial depolarization, although these effects were significantly higher when combined with LPS. More interesting was the finding that exposure of OHCs to the combination of LPS/AA triggered aberrant protein aggregation, measured as thioflavin S immunofluorescence. The α7 nicotinic receptor agonist, PNU282987, prevented the neurotoxicity and the pathological hallmarks observed in the LPS/AA subchronic toxicity model (oxidative stress and protein aggregates); these effects were blocked by α-bungarotoxin and tin protoporphyrin, indicating the participation of α7 nAChRs and heme-oxygenase I induction. In conclusion, subchronic exposure of OHCs to low concentration of antimycin-A plus LPS reproduced pathological features of neurodegenerative disorders. α7 nAChR activation ameliorated these alterations by a mechanism involving heme-oxygenase I induction. Copyright © 2015. Published by Elsevier Inc.
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    • "Mitochondrial dysfunction has long been associated with several neurodegenerative diseases that include Alzheimer's disease (AD), Huntington's disease (HD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and Friedrich's Ataxia (FA; Schapira and Cooper, 1992; Moreira et al., 2010; Grubman et al., 2013). Mitochondrial dysfunction results in decreased ATP synthesis , as well as in decreased synthesis of iron–sulfur clusters (ISCs) and heme prosthetic groups. "
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    • "Mitochondria-targeted antioxidants are usually derivatives of antioxidants conjugated with compounds which provide an effective transport across the mitochondrial inner membrane; alternatively they might be amino acids/ peptides with antioxidant properties. Evidence has accumulated suggesting that strategies aimed at boosting mitochondrial antioxidant capacity through mitochondria-targeted antioxidants, like MitoQ, MitoVitE, or MitoGSH, may in the future become a therapeutic modality also for CNS disorders (reviewed in Moreira et al., 2010; Sheu et al., 2006; Smith and Murphy, 2011 "
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    ABSTRACT: Oxidative and nitrosative stress (ONS) contributes to the pathogenesis of most brain maladies, and the magnitude of ONS is related to the ability of cellular antioxidants to neutralize the accumulating reactive oxygen and nitrogen species (ROS/RNS). While the major ROS/RNS scavengers and regenerators of bio-oxidized molecules: superoxide dysmutases (SODs), glutathione (GSH), thioredoxin (Trx) and peroxiredoxin (Prx) are distributed in all cellular compartments. This review specifically focuses on the role of the systems operating in mitochondria. There is a growing consensus that the mitochondrial SOD isoform - SOD2 and GSH are critical for the cellular antioxidant defense. Variable changes of the expression or activities of one or more of the mitochondrial antioxidant systems have been documented in the brains derived from human patients and/or in animal models of neurodegenerative diseases (Alzheimer's disease, Parkinson's disease), cerebral ischemia, toxic brain cell damage associated with overexposure to mercury or excitotoxins, or hepatic encephalopathy. In many cases, ambiguity of the responses of the different antioxidant systems in one and the same disease need to be more conclusively evaluated before the balance of the changes in viewed as beneficial or detrimental. Modulation of the mitochondrial antioxidant systems may in the future become a target of antioxidant therapy. Copyright © 2014. Published by Elsevier Ltd.
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