Glucagon-like peptide-1 protects NSC-34 motor neurons against glucosamine through Epac-mediated glucose uptake enhancement.

Abstract

Bioenergetic deficits are considered a common cause of neurodegenerative diseases. Although creatine supplementation has been shown to be effective in certain neurodegenerative disorders, it is less effective in amyotrophic lateral sclerosis, a disease that primarily affects motor neurons. These neurons are particularly vulnerable to a cellular energy deficit. Using the ATP-depleting drug glucosamine, we evaluated whether the incretin hormone glucagon-like peptide (GLP)-1 protects motor neurons against glucosamine-induced cytotoxicity. Undifferentiated NSC-34 cells were differentiated into glutamate-sensitive motor neurons by a modified serum deprivation technique. Glucosamine inhibited the viability of differentiated NSC-34 cells in a time- and dose-dependent manner. Glucosamine also acutely reduced cellular glucose uptake, glucokinase activity and intracellular ATP levels. As a result, the activity of AMP-activated protein kinase as well as endoplasmic reticulum stress increased. Pretreatment with GLP-1 significantly alleviated glucosamine-mediated neurotoxicity by restoring cellular glucose uptake, glucokinase activity and intracellular ATP levels. The protective effect of GLP-1 was replicated by Exendin-4 but not Exendin-9, and not blocked by inhibitors of phosphoinositide-3 kinase, protein kinase A, cSrc, or epidermal growth factor receptor, but it was blocked by an adenylate cyclase inhibitor. A selective activator for exchange proteins directly activated by cAMP (Epac), but not a selective activator for protein kinase A, mimicked the GLP-1 effect. Therefore GLP-1 may exert its effect mainly through cAMP-dependent, Epac-mediated restoration of glucose uptake that is typically impaired by glucosamine. These findings indicate that GLP-1 could be employed therapeutically to protect motor neurons that are susceptible to bioenergetic deficits.

• Authors: Jung-Geun Lim, Jang-Jun Lee, Sung-Hee Park, Jae-Hyung Park, Sun-Joo Kim, Ho-Chan Cho, Won-Ki Baek, Dae-Kwang Kim, Dae-Kyu Song
• Journal: Neuroscience letters (Neurosci Lett) Vol. 479 Issue 1 Pg. 13-7 (Jul 19 2010) ISSN: 1872-7972 [Electronic] Ireland
• PMID: 20471453 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Epac protein, mouse
• Guanine Nucleotide Exchange Factors
• Peripheral Nervous System Agents
• Glucagon-Like Peptide 1
• Adenosine Triphosphate
• Glucokinase
• AMP-Activated Protein Kinases
• Glucose
• Glucosamine

Topics

• AMP-Activated Protein Kinases (metabolism)
• Adenosine Triphosphate (metabolism)
• Animals
• Cell Line, Tumor
• Cell Survival (drug effects)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum (drug effects, enzymology, metabolism)
• Glucagon-Like Peptide 1 (metabolism)
• Glucokinase (metabolism)
• Glucosamine (administration & dosage, toxicity)
• Glucose (metabolism)
• Guanine Nucleotide Exchange Factors (metabolism)
• Hybrid Cells
• Mice
• Motor Neurons (drug effects, enzymology, metabolism)
• Peripheral Nervous System Agents (administration & dosage, toxicity)
• Stress, Physiological (drug effects, physiology)
• Time Factors