The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1.

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.

• Authors: Weidong Li, Yijun Cui, Steven A Kushner, Robert A M Brown, J David Jentsch, Paul W Frankland, Tyrone D Cannon, Alcino J Silva
• Journal: Current biology : CB (Curr Biol) Vol. 15 Issue 21 Pg. 1961-7 (Nov 08 2005) ISSN: 0960-9822 [Print] England
• PMID: 16271875 (Publication Type: Comparative Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

• Analysis of Variance
• Animals
• Attention Deficit Disorder with Hyperactivity (drug therapy, etiology)
• Blotting, Western
• Excitatory Postsynaptic Potentials (drug effects)
• Hippocampus (drug effects)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (pharmacology, therapeutic use)
• Learning Disabilities (drug therapy, etiology)
• Long-Term Potentiation (drug effects)
• Lovastatin (pharmacology, 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)