The HMG-CoA Reductase Inhibitor Lovastatin Reverses the Learning and Attention Deficits in a Mouse Model of Neurofibromatosis Type 1

Curr Biol. 2005 Nov 8;15(21):1961-7. doi: 10.1016/j.cub.2005.09.043.

Abstract

Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP). Importantly, NF1 causes learning disabilities and attention deficits. A previous study showed that the learning and memory deficits of a mouse model of NF1 (nf1+/-) appear to be caused by excessive p21Ras activity leading to impairments in long-term potentiation (LTP), a cellular mechanism of learning and memory. Here, we identify lovastatin as a potent inhibitor of p21Ras/Mitogen Activated Protein Kinase (MAPK) activity in the brain. Lovastatin is a specific inhibitor of three-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, used commonly for the treatment of hypercholesterolemia. We report that lovastatin decreased the enhanced brain p21Ras-MAPK activity of the nf1+/- mice, rescued their LTP deficits, and reversed their spatial learning and attention impairments. Therefore, these results demonstrate that lovastatin may prove useful in the treatment of Neurofibromatosis Type 1.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analysis of Variance
  • Animals
  • Attention Deficit Disorder with Hyperactivity / drug therapy*
  • Attention Deficit Disorder with Hyperactivity / etiology
  • Blotting, Western
  • Excitatory Postsynaptic Potentials / drug effects
  • Hippocampus / drug effects
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / pharmacology
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use*
  • Learning Disabilities / drug therapy*
  • Learning Disabilities / etiology
  • Long-Term Potentiation / drug effects
  • Lovastatin / pharmacology
  • Lovastatin / therapeutic use*
  • Maze Learning / drug effects
  • Mice
  • Mice, Mutant Strains
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Neurofibromatosis 1 / complications*
  • Proto-Oncogene Proteins p21(ras) / antagonists & inhibitors

Substances

  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Lovastatin
  • Mitogen-Activated Protein Kinases
  • Proto-Oncogene Proteins p21(ras)