Cytoprotective Effect of Acetyl-l-Carnitine Evidenced by Analysis of Gene Expression in the Rat Brain

Traina, Giovanna; Federighi, Giuseppe; Brunelli, Marcello; Scuri, Rossana

doi:10.1007/s12035-009-8056-1

Cited by 17 publications

(20 citation statements)

References 37 publications

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“…We reported before that, in the skeletal muscles of unloaded rats, ALCAR treatment was able to prevent a huge decay of mRNAs level for two kinases AMPK and CaMK2beta able to transduce, respectively, metabolic and neuronal stimuli into PGC-1alpha mitochondrial biogenesis and to increase the mRNAs levels of factors involved in mitochondrial biogenesis cascade. The ability of this molecule to act on gene expression [12,31,75] seems to be supported by the fact that mitochondrial acetylcarnitine provides acetyl groups for nuclear histone acetylation [76]. Furthermore, ALCAR treatment prevented the decrease in old rats of the protein level of factors involved in mitochondrial biogenesis cascade [31,32,77].…”

Section: Resultsmentioning

confidence: 99%

Rat liver mitochondrial proteome: Changes associated with aging and acetyl-L-carnitine treatment

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Capelli

Pesce

et al. 2011

Journal of Proteomics

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Section: Resultsmentioning

confidence: 99%

Rat liver mitochondrial proteome: Changes associated with aging and acetyl-L-carnitine treatment

Musicco

Capelli

Pesce

et al. 2011

Journal of Proteomics

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“…In this case, ALC prevents the decay of two kinases of the neuronal (CaMKIIb) and metabolic (AMPK) stimuli axes, localized upstream the PGC1-a signalig pathway. ALC was shown to regulate gene expression in brain and heart (Gadaleta et al 1990;Traina et al 2009). Mitochondrial ALC has been reported to provide acetyl groups for nuclear histone acetylation suggesting this as one of its mechanisms of action (Madiraju et al 2009).…”

Section: Mitochondria-targeted Chemopreventionmentioning

confidence: 99%

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

et al. 2010

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Oxidative stress is a phenotypic hallmark in several genetic disorders characterized by cancer predisposition and/or propensity to premature ageing. Here we review the published evidence for the involvement of oxidative stress in the phenotypes of Ataxia-Telangiectasia (A-T), Down Syndrome (DS), Fanconi Anaemia (FA), and Werner Syndrome (WS), from the viewpoint of mitochondrial dysfunction. Mitochondria are recognized as both the cell compartment where energetic metabolism occurs and as the first and most susceptible target of reactive oxygen species (ROS) formation. Thus, a critical evaluation of the basic mechanisms leading to an in vivo pro-oxidant state relies on elucidating the features of mitochondrial impairment in each disorder. The evidence for different mitochondrial dysfunctions reported in A-T, DS, and FA is reviewed. In the case of WS, clear-cut evidence linking human WS phenotype to mitochondrial abnormalities is lacking so far in the literature. Nevertheless, evidence relating mitochondrial dysfunctions to normal ageing suggests that WS, as a progeroid syndrome, is likely to feature mitochondrial abnormalities. Hence, ad hoc research focused on elucidating the nature of mitochondrial dysfunction in WS pathogenesis is required. Based on the recognized, or reasonably suspected, role of mitochondrial abnormalities in the pathogenesis of these disorders, studies of chemoprevention with mitochondria-targeted supplements are warranted.

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“…Besides the afore mentioned role on mitochondrial bioenergetics, which allows brain cells to restore altered redox balance [3,45], ALC is neuroprotective through a variety of other effects such as the increase in PKC activity [41], and modulation of synaptic plasticity via NMDA receptor expression and increase in the production of neurotrophins [202]. Importantly, treatment with ALC induces up-regulation of the gene coding for Hsp72 explaining its protective effects in inflammation, neurodegenerative disorders, and aging [203][204][205]. Another gene identified that is positively modulated by acetylcarnitine in the brain is the mitochondrial voltage-dependent anion channel (VDAC) protein [206].…”

Section: The Carnitine System: Physiological Roles Insufficiency Andmentioning

confidence: 99%

Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

et al. 2010

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The widely accepted oxidative stress theory of aging postulates that aging results from accumulation of oxidative damage. A prediction of this theory is that, among species, differential rates of aging may be apparent on the basis of intrinsic differences in oxidative damage accrual. Although widely accepted, there is a growing number of exceptions to this theory, most contingently related to genetic model organism investigations. Proteins are one of the prime targets for oxidative damage and cysteine residues are particularly sensitive to reversible and irreversible oxidation. The adaptation and survival of cells and organisms requires the ability to sense proteotoxic insults and to coordinate protective cellular stress response pathways and chaperone networks related to protein quality control and stability. The toxic effects that stem from the misassembly or aggregation of proteins or peptides, in any cell type, are collectively termed proteotoxicity. Despite the abundance and apparent capacity of chaperones and other components of homeostasis to restore folding equilibrium, the cell appears poorly adapted for chronic proteotoxic stress which increases in cancer, metabolic and neurodegenerative diseases. Pharmacological modulation of cellular stress response pathways has emerging implications for the treatment of human diseases, including neurodegenerative disorders, cardiovascular disease, and cancer. A critical key to successful medical intervention is getting the dose right. Achieving this goal can be extremely challenging due to human inter-individual variation as affected by age, gender, diet, exercise, genetic factors and health status. The nature of the dose response in and adjacent to the therapeutic zones, over the past decade has received considerable advances. The hormetic dose-response, challenging long-standing beliefs about the nature of the dose-response in a lowdose zone, has the potential to affect significantly the design of pre-clinical studies and clinical trials as well as strategies for optimal patient dosing in the treatment of numerous diseases. Given the broad cytoprotective properties of the heat shock response there is now strong interest in discovering and developing pharmacological agents capable of inducing stress responses, including carnitines. This paper describes in mechanistic detail how hormetic dose responses are mediated for endogenous cellular defense pathways, including the possible signaling mechanisms by which the carnitine system, by interplaying metabolism, mitochondrial energetics and activation of critical vitagenes, modulates signal transduction cascades that confer cytoprotection against chronic degenerative damage associated to aging and neurodegenerative disorders.

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Cytoprotective Effect of Acetyl-l-Carnitine Evidenced by Analysis of Gene Expression in the Rat Brain

Cited by 17 publications

References 37 publications

Rat liver mitochondrial proteome: Changes associated with aging and acetyl-L-carnitine treatment

Rat liver mitochondrial proteome: Changes associated with aging and acetyl-L-carnitine treatment

Mitochondrial dysfunction in some oxidative stress-related genetic diseases: Ataxia-Telangiectasia, Down Syndrome, Fanconi Anaemia and Werner Syndrome

Cellular Stress Responses, Mitostress and Carnitine Insufficiencies as Critical Determinants in Aging and Neurodegenerative Disorders: Role of Hormesis and Vitagenes

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