Perspectives of drug-based neuroprotection targeting mitochondria
(Impact Factor: 0.66).
05/2014; 170(5). DOI: 10.1016/j.neurol.2014.03.005
Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet.
Available from: Shyam Gajavelli
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ABSTRACT: Traumatic brain injury (TBI) is still the leading cause of disability in young adults worldwide. The major mechanisms - diffuse axonal injury, cerebral contusion, ischemic neurological damage, and intracranial hematomas have all been shown to be associated with mitochondrial dysfunction in some form. Mitochondrial dysfunction in TBI patients is an active area of research, and attempts to manipulate neuronal/astrocytic metabolism to improve outcomes have been met with limited translational success. Previously, several preclinical and clinical studies on TBI induced mitochondrial dysfunction have focused on opening of the mitochondrial permeability transition pore (PTP), consequent neurodegeneration and attempts to mitigate this degeneration with cyclosporine A (CsA) or analogous drugs, and have been unsuccessful. Recent insights into normal mitochondrial dynamics and into diseases such as inherited mitochondrial neuropathies, sepsis and organ failure could provide novel opportunities to develop mitochondria-based neuroprotective treatments that could improve severe TBI outcomes. This review summarizes those aspects of mitochondrial dysfunction underlying TBI pathology with special attention to models of penetrating traumatic brain injury, an epidemic in modern American society.
Journal of Bioenergetics 10/2014; 47(1-2). DOI:10.1007/s10863-014-9589-1 · 3.21 Impact Factor
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ABSTRACT: Succinobucol (succinyl ester of probucol) is a lipid-lowering compound with anti-inflammatory and antioxidant properties. Recent experimental evidence has highlighted the potential neuroprotective effects of succinobucol. In the present study, cultured neuroblastoma (SH-SY5Y) cells were used to investigate mechanisms mediating the potential protective effect of succinobucol against mitochondrial metabolic impairment and oxidative stress induced by 3-nitropropionic acid (3-NP), a succinate dehydrogenase inhibitor that has been used in experimental models of the Huntington disease (HD). 3-NP decreased cellular viability after 24 h of incubation. This decline in cellular viability was preceded by (i) reduced mitochondrial complex II activity, (ii) increased reactive species generation, (iii) decreased mitochondrial membrane potential (ΔΨm), and (iv) diminished glutathione (GSH) levels. Succinobucol pretreatment (6 days) significantly prevented 3-NP-induced loss of cellular viability, generation of reactive oxygen species, and decrease of ΔΨm. However, succinobucol pretreatment did not protect against 3-NP-induced inhibition of mitochondrial complex II activity, pointing to the mitigation of secondary events resultant from mitochondrial complex II inhibition. Succinobucol pretreatment (6 days) significantly increased (50 %) the levels of GSH in SH-SY5Y cells, and this event was paralleled by significant increases in glutamate cysteine ligase messenger RNA (mRNA) expression and activity (GCL; the first enzyme in the GSH biosynthesis). The present findings are the first to show that succinobucol increases GSH levels via upregulation of GCL activity (possibly through the activation of the nuclear (erythroid-derived 2)-related factor (Nrf2)/antioxidant response element (ARE) pathway), displaying protective effects against mitochondrial dysfunction-derived oxidative stress.
Molecular Neurobiology 01/2015; DOI:10.1007/s12035-014-9086-x · 5.14 Impact Factor
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ABSTRACT: As with sharks and horseshoe crabs, some designs of nature need only minor evolutionary adjustments over the millennia to remain superbly adapted. Such is the case at the molecular level for the nuclear receptors (NR), which appear to have originated concomitantly with the earliest metazoan lineage of animals. A wide array of NR persists today throughout all animal phyla with many different functions, yet they share a highly conserved protein structure, a testament to their having evolved through numerous gene duplications. Of particular interest for this readership are the estrogen-related receptors (ERR), which have significant supportive roles in energy creation and regulation, mitochondrial function and biogenesis, development, tissue repair, hypoxia and cancer. Thus placed at the nexus of energetics and homeostasis, ERR (in association with the coregulatory molecules peroxisome proliferator-activated receptor-gamma coactivator-1 (PGC-1[alpha] and -[beta]) can facilitate repair from injury and adaptations to stressful environments. While it is curious that ERR and some other NR exist as "orphans" by virtue of having no known cognate ligand, increasing interest in ER has led to development of synthetic ligands and screening for naturally-occurring molecules, either capable of modulating ERR activity. Thus what's needed now is a nomenclature update for the ERR to focus the mind on energetics and metabolism, the most compromised and crucial systems following trauma and shock.
Shock 02/2015; 44(1). DOI:10.1097/SHK.0000000000000364 · 3.05 Impact Factor
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