"Preconditioning" with latrepirdine, an adenosine 5'-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1(G93A) mice

Neurobiol Aging. 2015 Feb;36(2):1140-50. doi: 10.1016/j.neurobiolaging.2014.09.022. Epub 2014 Sep 26.


Adenosine 5'-monophosphate-activated protein kinase (AMPK) is a master regulator of energy balance. As energy imbalance is documented as a key pathologic feature of amyotrophic lateral sclerosis (ALS), we investigated AMPK as a pharmacologic target in SOD1(G93A) mice. We noted a strong activation of AMPK in lumbar spinal cords of SOD1(G93A) mice. Pharmacologic activation of AMPK has shown protective effects in neuronal "preconditioning" models. We tested the hypothesis that "preconditioning" with a small molecule activator of AMPK, latrepirdine, exerts beneficial effects on disease progression. SOD1(G93A) mice (n = 24 animals per group; sex and litter matched) were treated with latrepirdine (1 μg/kg, intraperitoneal) or vehicle from postnatal day 70 to 120. Treatment with latrepirdine increased AMPK activity in primary mouse motor neuron cultures and in SOD1(G93A) lumbar spinal cords. Mice "preconditioned" with latrepirdine showed a delayed symptom onset and a significant increase in life span (p < 0.01). Our study suggests that "preconditioning" with latrepirdine may represent a possible therapeutic strategy for individuals harboring ALS-associated gene mutations who are at risk for developing ALS.

Keywords: AMPK; Amyotrophic lateral sclerosis; Bioenergetics; Motoneuron degeneration; Pre-conditioning; SOD1; Spinal cord.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • AMP-Activated Protein Kinases / physiology
  • Amyotrophic Lateral Sclerosis / enzymology
  • Amyotrophic Lateral Sclerosis / genetics*
  • Amyotrophic Lateral Sclerosis / prevention & control*
  • Animals
  • Cell Survival / drug effects
  • Cells, Cultured
  • Disease Progression
  • Energy Metabolism
  • Enzyme Activation / drug effects
  • Female
  • Indoles / administration & dosage*
  • Injections, Intraperitoneal
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Motor Neurons / enzymology
  • Motor Neurons / pathology
  • Mutation
  • Risk
  • Spinal Cord / enzymology
  • Superoxide Dismutase / genetics*
  • Superoxide Dismutase / metabolism
  • Superoxide Dismutase-1


  • Indoles
  • Sod1 protein, mouse
  • Superoxide Dismutase
  • Superoxide Dismutase-1
  • AMP-Activated Protein Kinases
  • latrepirdine