Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis

Yazhou Li, Srinivasulu Chigurupati, Harold W. Holloway, Mohamed Mughal, David Tweedie, Daniel A. Bruestle, Mark P. Mattson, Yun Wang, Brandon K. Harvey, Balmiki Ray, Debomoy Lahiri, Nigel H. Greig

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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.

Original languageEnglish
Article numbere32008
JournalPLoS One
Volume7
Issue number2
DOIs
StatePublished - Feb 23 2012

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Nerve Degeneration
Amyotrophic Lateral Sclerosis
Motor Neurons
motor neurons
Neurons
Animals
Animal Models
animal models
spinal cord
choline acetyltransferase
neuroprotective effect
Spinal Cord
neurodegenerative diseases
mutants
Neurodegenerative diseases
agonists
mice
Choline O-Acetyltransferase
hypoglycemic agents
secretin

ASJC Scopus subject areas

  • Agricultural and Biological Sciences(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Li, Y., Chigurupati, S., Holloway, H. W., Mughal, M., Tweedie, D., Bruestle, D. A., ... Greig, N. H. (2012). Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. PLoS One, 7(2), [e32008]. https://doi.org/10.1371/journal.pone.0032008

Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. / Li, Yazhou; Chigurupati, Srinivasulu; Holloway, Harold W.; Mughal, Mohamed; Tweedie, David; Bruestle, Daniel A.; Mattson, Mark P.; Wang, Yun; Harvey, Brandon K.; Ray, Balmiki; Lahiri, Debomoy; Greig, Nigel H.

In: PLoS One, Vol. 7, No. 2, e32008, 23.02.2012.

Research output: Contribution to journalArticle

Li, Y, Chigurupati, S, Holloway, HW, Mughal, M, Tweedie, D, Bruestle, DA, Mattson, MP, Wang, Y, Harvey, BK, Ray, B, Lahiri, D & Greig, NH 2012, 'Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis', PLoS One, vol. 7, no. 2, e32008. https://doi.org/10.1371/journal.pone.0032008
Li, Yazhou ; Chigurupati, Srinivasulu ; Holloway, Harold W. ; Mughal, Mohamed ; Tweedie, David ; Bruestle, Daniel A. ; Mattson, Mark P. ; Wang, Yun ; Harvey, Brandon K. ; Ray, Balmiki ; Lahiri, Debomoy ; Greig, Nigel H. / Exendin-4 ameliorates motor neuron degeneration in cellular and animal models of amyotrophic lateral sclerosis. In: PLoS One. 2012 ; Vol. 7, No. 2.
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