title: Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis.
abstract: Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by a progressive loss of lower motor neurons in the spinal cord. The incretin hormone, glucagon-like peptide-1 (GLP-1), facilitates insulin signaling, and the long acting GLP-1 receptor agonist exendin-4 (Ex-4) is currently used as an anti-diabetic drug. GLP-1 receptors are widely expressed in the brain and spinal cord, and our prior studies have shown that Ex-4 is neuroprotective in several neurodegenerative disease rodent models, including stroke, Parkinson's disease and Alzheimer's disease. Here we hypothesized that Ex-4 may provide neuroprotective activity in ALS, and hence characterized Ex-4 actions in both cell culture (NSC-19 neuroblastoma cells) and in vivo (SOD1 G93A mutant mice) models of ALS. Ex-4 proved to be neurotrophic in NSC-19 cells, elevating choline acetyltransferase (ChAT) activity, as well as neuroprotective, protecting cells from hydrogen peroxide-induced oxidative stress and staurosporine-induced apoptosis. Additionally, in both wild-type SOD1 and mutant SOD1 (G37R) stably transfected NSC-19 cell lines, Ex-4 protected against trophic factor withdrawal-induced toxicity. To assess in vivo translation, SOD1 mutant mice were administered vehicle or Ex-4 at 6-weeks of age onwards to end-stage disease via subcutaneous osmotic pump to provide steady-state infusion. ALS mice treated with Ex-4 showed improved glucose tolerance and normalization of behavior, as assessed by running wheel, compared to control ALS mice. Furthermore, Ex-4 treatment attenuated neuronal cell death in the lumbar spinal cord; immunohistochemical analysis demonstrated the rescue of neuronal markers, such as ChAT, associated with motor neurons. Together, our results suggest that GLP-1 receptor agonists warrant further evaluation to assess whether their neuroprotective potential is of therapeutic relevance in ALS.
authors.affiliation: Laboratory of Neurosciences, Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States of America.
authors.forename: Yazhou
authors.initials: Y
authors.lastname: Li
authors.forename: Srinivasulu
authors.initials: S
authors.lastname: Chigurupati
authors.forename: Harold W
authors.initials: HW
authors.lastname: Holloway
authors.forename: Mohamed
authors.initials: M
authors.lastname: Mughal
authors.forename: David
authors.initials: D
authors.lastname: Tweedie
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Bruestle
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Brandon K
authors.initials: BK
authors.lastname: Harvey
authors.forename: Balmiki
authors.initials: B
authors.lastname: Ray
authors.forename: Debomoy K
authors.initials: DK
authors.lastname: Lahiri
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
mesh_terms: D000690:Amyotrophic Lateral Sclerosis / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis; D002460:Cell Line; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D004195:Disease Models, Animal; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D005951:Glucose Tolerance Test / Q000379:methods; D006861:Hydrogen Peroxide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism; D008297:Male; D051379:Mice; D009046:Motor Neurons / Q000378:metabolism*; D018384:Oxidative Stress; D010455:Peptides / Q000494:pharmacology*; D013116:Spinal Cord / Q000378:metabolism; D019311:Staurosporine / Q000494:pharmacology; D013482:Superoxide Dismutase / Q000378:metabolism; D000072105:Superoxide Dismutase-1; D014688:Venoms / Q000494:pharmacology*
chemical_list: D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D006861:Hydrogen Peroxide; C000606291:Sod1 protein, mouse; D013482:Superoxide Dismutase; D000072105:Superoxide Dismutase-1; D002795:Choline O-Acetyltransferase; D019311:Staurosporine