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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
Author(s) -
Abdul Hafiz Mohmmad,
Calabrese Vittorio,
Calvani Menotti,
Butterfield D. Allan
Publication year - 2006
Publication title -
journal of neuroscience research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.72
H-Index - 160
eISSN - 1097-4547
pISSN - 0360-4012
DOI - 10.1002/jnr.20877
Subject(s) - neurotoxicity , oxidative stress , heat shock protein , disease , amyloid beta , amyloid (mycology) , peptide , neuroscience , chemistry , medicine , biochemistry , biology , toxicity , pathology , gene
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 (Aβ 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 Aβ 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 Aβ 1–42 ‐mediated oxidative stress and neurotoxicity. Decreased cell survival in neuronal cultures treated with Aβ 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 Aβ 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 Aβ 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 Aβ 1–42 ‐induced oxidative stress and neurotoxicity. Therefore, ALCAR may be useful as a possible therapeutic strategy for patients with AD. © 2006 Wiley‐Liss, Inc.