Therapeutic potential of N-acetyl-glucagon-like peptide-1 in primary motor neuron cultures derived from non-transgenic and SOD1-G93A ALS mice

Cell Mol Neurobiol. 2013 Apr;33(3):347-57. doi: 10.1007/s10571-012-9900-9. Epub 2012 Dec 28.

Abstract

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by the death of motor neurons (MN) in the motor cortex, brain stem, and spinal cord. In the present study, we established an ALS in vitro model of purified embryonic MNs, derived from non-transgenic and mutant SOD1-G93A transgenic mice, the most commonly used ALS animal model. MNs were cultured together with either non-transgenic or mutant SOD1-G93A astrocyte feeder layers. Cell viability following exposure to kainate as excitotoxic stimulus was assessed by immunocytochemistry and calcium imaging. We then examined the neuroprotective effects of N-acetyl-GLP-1(7-34) amide (N-ac-GLP-1), a long-acting, N-terminally acetylated, C-terminally truncated analog of glucagon-like peptide-1 (GLP-1). GLP-1 has initially been studied as a treatment for type II diabetes based on its function as insulin secretagogue. We detected neuroprotective effects of N-ac-GLP-1 in our in vitro system, which could be attributed to an attenuation of intracellular calcium transients, not only due to these antiexcitotoxic capacities but also with respect to the increasing knowledge about metabolic deficits in ALS which could be positively influenced by N-ac-GLP-1, this compound represents an interesting novel candidate for further in vivo evaluation in ALS.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / drug therapy*
  • Amyotrophic Lateral Sclerosis / metabolism
  • Amyotrophic Lateral Sclerosis / pathology*
  • Animals
  • Astrocytes / drug effects
  • Astrocytes / metabolism
  • Astrocytes / pathology
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Cells, Cultured
  • Coculture Techniques
  • Cytosol / drug effects
  • Cytosol / metabolism
  • Female
  • Fluorometry
  • Glucagon-Like Peptide 1 / pharmacology
  • Glucagon-Like Peptide 1 / therapeutic use*
  • Glucagon-Like Peptide-1 Receptor
  • Humans
  • Intracellular Space / metabolism
  • Kainic Acid / toxicity
  • Male
  • Mice
  • Mice, Transgenic
  • Motor Neurons / drug effects
  • Motor Neurons / metabolism
  • Motor Neurons / pathology*
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Neurotoxins / toxicity
  • Receptors, Glucagon / metabolism
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism

Substances

  • GLP1R protein, human
  • Glp1r protein, mouse
  • Glucagon-Like Peptide-1 Receptor
  • Neuroprotective Agents
  • Neurotoxins
  • Receptors, Glucagon
  • Glucagon-Like Peptide 1
  • Superoxide Dismutase
  • Kainic Acid
  • Calcium