Abstract
The neurotoxicity induced by the mitochondrial inhibitor 3-nitropropionic acid (3-NPA) is associated with a decrease of ATP synthesis and an increase of free radical production which can lead to apoptosis or necrosis. We have used the PC12, neuron-like rat pheochromocytoma cell line, to study further the mechanism of 3-NPA-evoked neurotoxicity and the effects of acetyl-L-carnitine (ALC) which has neuroprotective actions against various types of mitochondrial inhibitors.Cultured PC 12 cells were exposed to a low dose of 3-NPA 50 (microM) in the presence or absence of 5 mM ALC. The dose of 3-NPA was sub toxic and no changes in pro-apoptotic Bax or anti-apoptotic Bcl-2 gene expression were observed. We followed specific genetic markers to look for changes evoked by 3-NPA toxicity and also changes associated with neuroprotection exerted by the ALC treatment, using RT-PCR arrays (delta-delta method). 3-NPA exposure evoked a decrease in expression of the Tp53 gene. This down regulation was prevented by pretreatment of the cells with ALC. The Tp53 gene responds to cellular stresses and the effects seen here are possibly associated with the 3-NPA evoked changes in mitochondrial metabolism. Other genes associated with stress and apoptosis, Parp-1, Bcl-2, and Bax were not affected by 3-NPA or ALC. The decrease of inflammatory response Il-10 gene expression due to 3-NPA was further lowered by presence of ALC. Other inflammation related genes, Il1rn, Nr3c1 and Cxcr4 were not affected. Interestingly, the glutamate transporter slc17a7, carnitine-acylcarnitine translocase Slc25a20 and heat shock proteins genes, Hsp27, Hmox1 (Hsp32, HO1) as well as Hspa 1a (Hsp 70) increased only when both ALC and small dose of 3-NPA were present. The alterations in gene expression detected in this study suggest role of several intracellular pathways in the neurotoxicity of 3-NPA and the neuroprotection against 3-NPA-induced neurotoxicity by ALC.
Highlights
The mitochondrial inhibitor, 3-nitropropionic acid (3NPA), induces cellular energy deficit through inactivation of electron transport chain complex II
The neurotoxicity induced by the mitochondrial inhibitor 3-nitropropionic acid (3-NPA) is associated with a decrease of ATP synthesis and an increase of free radical production which can lead to apoptosis or necrosis
The present study was designed to investigate an effect of sub toxic doses of 3-NPA on expression of selected genes, representing pathways involved in metabolism of carnitine, glutamate transport, apoptosis, heat shock, and inflammatory responses
Summary
The mitochondrial inhibitor, 3-nitropropionic acid (3NPA), induces cellular energy deficit through inactivation of electron transport chain complex II (succinate dehydrogenase). A decrease of ATP synthesis and an increase of free radical production followed by apoptosis or necrosis caused by secondary excitotoxicity are major features of 3-NPA generated neurotoxicity [1]. These changes are associated with a decrease of body temperature and a decrease of dopamine production in susceptible brain regions in animal model of 3-NPA neurotoxicity [2, 3]. The neuron-like rat pheochromocytoma cell line, PC12, has been used to study mechanism of neurotoxicity and neuroprotection in dopaminergic neurons [5, 6]. The application of energy metabolism enhancers such as acetyl-L-carnitine (ALC) or coenzyme
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