Document Detail


The role of glycolysis and gluconeogenesis in the cytoprotection of neuroblastoma cells against 1-methyl 4-phenylpyridinium ion toxicity.
MedLine Citation:
PMID:  12564389     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
1-Methyl-4-phenylpyridinium (MPP+) is a mitochondrial Complex I inhibitor and is frequently used to investigate the pathological degeneration of neurons associated with Parkinson's disease (PD). In vitro, extracellular concentration of glucose is one of the most critical factors in establishing the vulnerability of neurons to MPP+ toxicity. While glucose is the primary energy fuel for the brain, central nervous system (CNS) neurons can also take up and utilize other metabolic intermediates for energy. In this study, we compared various monosaccharides, disaccharides, nutritive/non-nutritive sugar alcohols, glycolytic and gluconeogenic metabolic intermediates for their cytoprotection against MPP+ in murine brain neuroblastoma cells. Several monosaccharides were effective against MMP+ (500 microM) including glucose, fructose and mannose, which restored cell viability to 109 +/- 5%, 70 +/- 5%, 99 +/- 3% of live controls, respectively. Slight protective effects were observed in the presence of 3-phosphoglyceric acid and glucose-6-phosphate; however, no protective effects were exhibited by galactose, sucrose, sorbitol, mannitol, glycerol or various gluconeogenic and ketogenic amino acids. On the other hand, fructose 1,6 bisphosphate and gluconeogenic energy intermediates [pyruvic acid, malic acid and phospho(enol)pyruvate (PEP)] were neuroprotective against MPP+. The gluconeogenic intermediates elevated intracellular levels of ATP and reduced propidium iodide (PI) nucleic acid staining to live controls, but did not alter the MPP(+)-induced loss of mitochondrial O2 consumption. These data indicate that malic acid, pyruvic acid and PEP contribute to anaerobic substrate level phosphorylation. The use of hydrazine sulfate to impede gluconeogenesis through PEP carboxykinase (PEPCK) inhibition heightened the protective effects of energy substrates possibly due to attenuated ATP demands from pyruvate carboxylase (PC) activity and pyruvate mitochondrial transport. It was concluded from these studies that several metabolic intermediates are effective in fueling anaerobic glycolysis during mitochondrial inhibition by MPP+.
Authors:
Elizabeth Mazzio; Karam F A Soliman
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Publication Detail:
Type:  Comparative Study; Journal Article; Research Support, U.S. Gov't, P.H.S.    
Journal Detail:
Title:  Neurotoxicology     Volume:  24     ISSN:  0161-813X     ISO Abbreviation:  Neurotoxicology     Publication Date:  2003 Jan 
Date Detail:
Created Date:  2003-02-04     Completed Date:  2003-03-21     Revised Date:  2007-11-14    
Medline Journal Info:
Nlm Unique ID:  7905589     Medline TA:  Neurotoxicology     Country:  Netherlands    
Other Details:
Languages:  eng     Pagination:  137-47     Citation Subset:  IM    
Affiliation:
College of Pharmacy and Pharmaceutical Sciences, Florida A & M University, Tallahassee, FL 32307, USA.
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MeSH Terms
Descriptor/Qualifier:
1-Methyl-4-phenylpyridinium / toxicity*
Animals
Cell Survival / drug effects,  physiology
Cytoprotection / drug effects,  physiology*
Dose-Response Relationship, Drug
Gluconeogenesis / drug effects,  physiology*
Glycolysis / drug effects,  physiology*
Mice
Models, Biological
Monosaccharides / pharmacology
Neuroblastoma / metabolism*
Tumor Cells, Cultured
Grant Support
ID/Acronym/Agency:
GM 08111/GM/NIGMS NIH HHS; NCRR 03020/RR/NCRR NIH HHS
Chemical
Reg. No./Substance:
0/Monosaccharides; 48134-75-4/1-Methyl-4-phenylpyridinium

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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