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Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease.
J Neurosci Res. 2006 Aug 01; 84(2):398-408.JN

Abstract

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tangles in brain. Amyloid-beta peptide, particularly the 42-amino-acid peptide (Abeta(1-42)), is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. The AD brain is under significant oxidative stress, and Abeta(1-42) peptide is known to cause oxidative stress in vitro and in vivo. Acetyl-L-carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps to maintain mitochondrial bioenergetics and lowers the increased oxidative stress associated with aging. Glutathione (GSH) is an important endogenous antioxidant, and its levels have been shown to decrease with aging. Administration of ALCAR increases cellular levels of GSH in rat astrocytes. In the current study, we investigated whether ALCAR plays a protective role in cortical neuronal cells against Abeta(1-42)-mediated oxidative stress and neurotoxicity. Decreased cell survival in neuronal cultures treated with Abeta(1-42) correlated with an increase in protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (4-hydroxy-2-nonenal) formation. Pretreatment of primary cortical neuronal cultures with ALCAR significantly attenuated Abeta(1-42)-induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Addition of ALCAR to neurons also led to an elevated cellular GSH and heat shock proteins (HSPs) levels compared with untreated control cells. Our results suggest that ALCAR exerts protective effects against Abeta(1-42) toxicity and oxidative stress in part by up-regulating the levels of GSH and HSPs. This evidence supports the pharmacological potential of acetyl carnitine in the management of Abeta(1-42)-induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD.

Authors+Show Affiliations

Department of Chemistry, Center for Membrane Sciences, University of Kentucky, Lexington, 40506, USA.No affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

16634066

Citation

Abdul, Hafiz Mohmmad, et al. "Acetyl-L-carnitine-induced Up-regulation of Heat Shock Proteins Protects Cortical Neurons Against Amyloid-beta Peptide 1-42-mediated Oxidative Stress and Neurotoxicity: Implications for Alzheimer's Disease." Journal of Neuroscience Research, vol. 84, no. 2, 2006, pp. 398-408.
Abdul HM, Calabrese V, Calvani M, et al. Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. J Neurosci Res. 2006;84(2):398-408.
Abdul, H. M., Calabrese, V., Calvani, M., & Butterfield, D. A. (2006). Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. Journal of Neuroscience Research, 84(2), 398-408.
Abdul HM, et al. Acetyl-L-carnitine-induced Up-regulation of Heat Shock Proteins Protects Cortical Neurons Against Amyloid-beta Peptide 1-42-mediated Oxidative Stress and Neurotoxicity: Implications for Alzheimer's Disease. J Neurosci Res. 2006 Aug 1;84(2):398-408. PubMed PMID: 16634066.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Acetyl-L-carnitine-induced up-regulation of heat shock proteins protects cortical neurons against amyloid-beta peptide 1-42-mediated oxidative stress and neurotoxicity: implications for Alzheimer's disease. AU - Abdul,Hafiz Mohmmad, AU - Calabrese,Vittorio, AU - Calvani,Menotti, AU - Butterfield,D Allan, PY - 2006/4/25/pubmed PY - 2006/9/20/medline PY - 2006/4/25/entrez SP - 398 EP - 408 JF - Journal of neuroscience research JO - J Neurosci Res VL - 84 IS - 2 N2 - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by loss of memory and cognition and by senile plaques and neurofibrillary tangles in brain. Amyloid-beta peptide, particularly the 42-amino-acid peptide (Abeta(1-42)), is a principal component of senile plaques and is thought to be central to the pathogenesis of the disease. The AD brain is under significant oxidative stress, and Abeta(1-42) peptide is known to cause oxidative stress in vitro and in vivo. Acetyl-L-carnitine (ALCAR) is an endogenous mitochondrial membrane compound that helps to maintain mitochondrial bioenergetics and lowers the increased oxidative stress associated with aging. Glutathione (GSH) is an important endogenous antioxidant, and its levels have been shown to decrease with aging. Administration of ALCAR increases cellular levels of GSH in rat astrocytes. In the current study, we investigated whether ALCAR plays a protective role in cortical neuronal cells against Abeta(1-42)-mediated oxidative stress and neurotoxicity. Decreased cell survival in neuronal cultures treated with Abeta(1-42) correlated with an increase in protein oxidation (protein carbonyl, 3-nitrotyrosine) and lipid peroxidation (4-hydroxy-2-nonenal) formation. Pretreatment of primary cortical neuronal cultures with ALCAR significantly attenuated Abeta(1-42)-induced cytotoxicity, protein oxidation, lipid peroxidation, and apoptosis in a dose-dependent manner. Addition of ALCAR to neurons also led to an elevated cellular GSH and heat shock proteins (HSPs) levels compared with untreated control cells. Our results suggest that ALCAR exerts protective effects against Abeta(1-42) toxicity and oxidative stress in part by up-regulating the levels of GSH and HSPs. This evidence supports the pharmacological potential of acetyl carnitine in the management of Abeta(1-42)-induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD. SN - 0360-4012 UR - https://www.unboundmedicine.com/medline/citation/16634066/Acetyl_L_carnitine_induced_up_regulation_of_heat_shock_proteins_protects_cortical_neurons_against_amyloid_beta_peptide_1_42_mediated_oxidative_stress_and_neurotoxicity:_implications_for_Alzheimer's_disease_ L2 - https://doi.org/10.1002/jnr.20877 DB - PRIME DP - Unbound Medicine ER -