Small GSK-3 Inhibitor Shows Efficacy in a Motor Neuron Disease Murine Model Modulating Autophagy

PLoS One. 2016 Sep 15;11(9):e0162723. doi: 10.1371/journal.pone.0162723. eCollection 2016.

Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive motor neuron degenerative disease that has no effective treatment up to date. Drug discovery tasks have been hampered due to the lack of knowledge in its molecular etiology together with the limited animal models for research. Recently, a motor neuron disease animal model has been developed using β-N-methylamino-L-alanine (L-BMAA), a neurotoxic amino acid related to the appearing of ALS. In the present work, the neuroprotective role of VP2.51, a small heterocyclic GSK-3 inhibitor, is analysed in this novel murine model together with the analysis of autophagy. VP2.51 daily administration for two weeks, starting the first day after L-BMAA treatment, leads to total recovery of neurological symptoms and prevents the activation of autophagic processes in rats. These results show that the L-BMAA murine model can be used to test the efficacy of new drugs. In addition, the results confirm the therapeutic potential of GSK-3 inhibitors, and specially VP2.51, for the disease-modifying future treatment of motor neuron disorders like ALS.

MeSH terms

  • Animals
  • Autophagy*
  • Cell Line
  • Disease Models, Animal*
  • Enzyme Inhibitors / pharmacology*
  • Enzyme Inhibitors / therapeutic use
  • Glycogen Synthase Kinase 3 / antagonists & inhibitors*
  • Mice
  • Motor Neuron Disease / drug therapy*

Substances

  • Enzyme Inhibitors
  • Glycogen Synthase Kinase 3

Grant support

The authors wish to express their gratitude for the expert technical assistance provided by the Animal Facilities of the Biological Science School of Complutense University of Madrid. This work was supported by MINECO (grant no. SAF2012-37979-C03-01), FUNDELA (Spanish Amyotrophic Lateral Sclerosis Foundation) and Association Francaise contre les Myopathies (AFM-16169).