title: 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.affiliation: Department of Neurobiology, University of California, Los Angeles, Los Angeles, California 90095, USA.
authors.forename: Weidong
authors.initials: W
authors.lastname: Li
authors.forename: Yijun
authors.initials: Y
authors.lastname: Cui
authors.forename: Steven A
authors.initials: SA
authors.lastname: Kushner
authors.forename: Robert A M
authors.initials: RA
authors.lastname: Brown
authors.forename: J David
authors.initials: JD
authors.lastname: Jentsch
authors.forename: Paul W
authors.initials: PW
authors.lastname: Frankland
authors.forename: Tyrone D
authors.initials: TD
authors.lastname: Cannon
authors.forename: Alcino J
authors.initials: AJ
authors.lastname: Silva
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001289:Attention Deficit Disorder with Hyperactivity / Q000188:drug therapy* / Q000209:etiology; D015153:Blotting, Western; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D006624:Hippocampus / Q000187:drug effects; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D007859:Learning Disabilities / Q000188:drug therapy* / Q000209:etiology; D017774:Long-Term Potentiation / Q000187:drug effects; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008817:Mice, Mutant Strains; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009456:Neurofibromatosis 1 / Q000150:complications*; D016283:Proto-Oncogene Proteins p21(ras) / Q000037:antagonists & inhibitors
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)