The HMG-CoA reductase inhibitor lovastatin reverses the learning and attention deficits in a mouse model of neurofibromatosis type 1.
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.
Li
Weidong
W
Department of Neurobiology, University of California, Los Angeles, Los Angeles, California 90095, USA.
Cui
Yijun
Y
Kushner
Steven A
SA
Brown
Robert A M
RA
Jentsch
J David
JD
Frankland
Paul W
PW
Cannon
Tyrone D
TD
Silva
Alcino J
AJ
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
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008148:Lovastatin; D020928:Mitogen-Activated Protein Kinases; D016283:Proto-Oncogene Proteins p21(ras)