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

W Li, Y Cui, SA Kushner, RAM Brown, JD Jentsch… - Current Biology, 2005 - cell.com
Current Biology, 2005cell.com
Summary Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by
mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein
(GAP)[1]. Importantly, NF1 causes learning disabilities and attention deficits [2, 3]. 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)[4], a cellular mechanism of learning and memory [5–7]. Here, we identify …
Summary
Neurofibromatosis Type 1 (NF1) is a common neurological disorder caused by mutations in the gene encoding Neurofibromin, a p21Ras GTPase Activating Protein (GAP) [1]. Importantly, NF1 causes learning disabilities and attention deficits [2, 3]. 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) [4], a cellular mechanism of learning and memory [5–7]. Here, we identify lovastatin as a potent inhibitor of p21Ras/Mitogen Activated Protein Kinase (MAPK) activity [8, 9] 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 [10]. 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.
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