Acetyl-l-carnitine provides effective in vivo neuroprotection over 3,4-methylenedioximethamphetamine-induced mitochondrial neurotoxicity in the adolescent rat brain

Alves, Emanuele Amorim; Binienda, Zbigniew; Carvalho, Félix; Alves, Cecília J.; Fernandes, Eduarda; Bastos, Maria de Lourdes; Tavares, M. A.; Summavielle, Teresa

doi:10.1016/j.neuroscience.2008.10.041

Cited by 78 publications

(62 citation statements)

References 59 publications

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“…Although the author did not monitor the effects of the antioxidants in body temperature, these results are also consistent with the postulate that MDMA-induced neurotoxicity involves oxidative stress. Subsequent works in rats confirmed that other antioxidants were able to avoid MDMA-induced neurotoxicity without modifying MDMAinduced hyperthermia, namely, alpha-lipoic acid [291], ascorbic acid [481], and acetyl-L-carnitine [482]. Consistent with the importance of MDMA metabolism to the neurotoxic events is the fact that fluoxetine pretreatment may provide protection against MDMAinduced long-term neurotoxicity by decreasing the metabolic transformation of MDMA and MDA to neurotoxic metabolites [427].…”

Section: Apoptosis Apoptosis Apoptosis Apoptosismentioning

confidence: 85%

Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

et al. 2009

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"Ecstasy" [(+/-)-3,4-methylenedioxymethamphetamine, MDMA, XTC, X, E] is a psychoactive recreational hallucinogenic substance and a major worldwide drug of abuse. Several reports raised the concern that MDMA has the ability to induce neurotoxic effects both in laboratory animals and humans. Despite more than two decades of research, the mechanisms by which MDMA is neurotoxic are still to be fully elucidated. MDMA induces serotonergic terminal loss in rats and also in some mice strains, but also a broader neuronal degeneration throughout several brain areas such as the cortex, hippocampus, and striatum. Meanwhile, in human "ecstasy" abusers, there are evidences for deficits in seronergic biochemical markers, which correlate with long-term impairments in memory and learning. There are several factors that contribute to MDMA-induced neurotoxicity, namely, hyperthermia, monoamine oxidase metabolism of dopamine and serotonin, dopamine oxidation, the serotonin transporter action, nitric oxide, and the formation of peroxinitrite, glutamate excitotoxicity, serotonin 2A receptor agonism, and, importantly, the formation of MDMA neurotoxic metabolites. The present review covered the following topics: history and epidemiology, pharmacological mechanisms, metabolic pathways and the influence of isoenzyme genetic polymorphisms, as well as the acute effects of MDMA in laboratory animals and humans, with a special focus on MDMA-induced neurotoxic effects at the cellular and molecular level. The main aim of this review was to contribute to the understanding of the cellular and molecular mechanisms involved in MDMA neurotoxicity, which can help in the development of therapeutic approaches to prevent or treat the long-term neuropsychiatric complications of MDMA abuse in humans.

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Section: Apoptosis Apoptosis Apoptosis Apoptosismentioning

confidence: 85%

Molecular and Cellular Mechanisms of Ecstasy-Induced Neurotoxicity: An Overview

et al. 2009

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“…Increasing mitochondrial antioxidant activities by elevating mitochondrial reducing power is considered as an important mechanism of neuroprotection by several naturally occurring compounds, including ketone bodies, pyruvate, and acyl-carnitines (Ryu et al, 2004;Zanelli et al, 2005;Gasior et al, 2006;Zhao et al, 2006b;Jarrett et al, 2008;Rosca et al, 2009;Alves et al, 2009;Jones et al, 2010;Zhang et al, 2010). This mechanism of action might be particularly important during reperfusion after cerebral ischemia, when the mitochondrial redox state is hyperoxidized, ROS production is elevated, and there are increased markers of oxidative molecular modification (Perez-Pinzon et al, 1999;Fiskum et al, 2004).…”

Section: Protection Against Mitochondrial Oxidative Stressmentioning

confidence: 99%

Novel Mitochondrial Targets for Neuroprotection

Pérez-Pinzón

Stetler

Fiskum

2012

J Cereb Blood Flow Metab

126

108

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Mitochondrial dysfunction contributes to the pathophysiology of acute neurologic disorders and neurodegenerative diseases. Bioenergetic failure is the primary cause of acute neuronal necrosis, and involves excitotoxicity-associated mitochondrial Ca 2 + overload, resulting in opening of the inner membrane permeability transition pore and inhibition of oxidative phosphorylation. Mitochondrial energy metabolism is also very sensitive to inhibition by reactive O 2 and nitrogen species, which modify many mitochondrial proteins, lipids, and DNA/RNA, thus impairing energy transduction and exacerbating free radical production. Oxidative stress and Ca 2 + -activated calpain protease activities also promote apoptosis and other forms of programmed cell death, primarily through modification of proteins and lipids present at the outer membrane, causing release of proapoptotic mitochondrial proteins, which initiate caspase-dependent and caspase-independent forms of cell death. This review focuses on three classifications of mitochondrial targets for neuroprotection. The first is mitochondrial quality control, maintained by the dynamic processes of mitochondrial fission and fusion and autophagy of abnormal mitochondria. The second includes targets amenable to ischemic preconditioning, e.g., electron transport chain components, ion channels, uncoupling proteins, and mitochondrial biogenesis. The third includes mitochondrial proteins and other molecules that defend against oxidative stress. Each class of targets exhibits excellent potential for translation to clinical neuroprotection.

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“…ALCAR participates in maintenance and repair processes in neurons, is able to attenuate the rate of neuronal mortality (Manfridi et al 1992) and to decrease the neurotoxicity evoked by mitochondrial uncoupling factors or inhibitors (Virmani et al 1995). ALCAR is also able to reduce the oxidative stress induced at the mitochondrial level by stimulant drug as 3,4-methylenedioximethamphetamine (Alves et al 2009). ALCAR is reported to have beneficial effects in major depressive disorders especially in elderly subjects (Garzya et al 1990;Pettegrew et al 2000;Pettegrew et al 2002).…”

Section: Introductionmentioning

confidence: 99%