Pretreatment with lovastatin prevents N-methyl-D-aspartate-induced neurodegeneration in the magnocellular nucleus basalis and behavioral dysfunction.
Besides a beneficial cardiovascular effect, it was recently suggested that statins can also exert neuroprotective actions. In a previous study, we provided in vitro evidence that lovastatin treatment abates excitotoxic cell death in primary cortical neurons. Here, we investigated the neuroprotective effect of lovastatin in an in vivo mouse model. We found that administration of lovastatin (20 mg/kg) significantly protects cholinergic neurons and their cortical projections against N-methyl-D-aspartate (60 nmol)-induced cell death in the magnocellular nucleus basalis, a neuronal cell group that is characteristically affected in Alzheimer's disease. Furthermore, lovastatin-mediated neuroprotection was shown to be dependent on protein kinase B (PKB)/Akt signaling since treatment with the PKB/Akt inhibitor LY294002 blocked the lovastatin-induced neuroprotective effect. The loss of cholinergic neurons after the lesion in the magnocellular nucleus basalis resulted in memory impairment as tested in a passive avoidance paradigm. This was reverted by pre-lesion lovastatin treatment. From these studies we conclude that treatment with lovastatin may provide protection against neuronal injury in excitotoxic conditions associated with neurodegenerative diseases including Alzheimer's disease.
Dolga
Amalia M
AM
Department of Molecular Neurobiology, Graduate School of Behavioral and Cognitive Neurosciences, University of Groningen, Haren, The Netherlands.
Granic
Ivica
I
Nijholt
Ingrid M
IM
Nyakas
Csaba
C
van der Zee
Eddy A
EA
Luiten
Paul G M
PG
Eisel
Ulrich L M
UL
D000704:Analysis of Variance; D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D020532:Basal Nucleus of Meynert / Q000187:drug effects / Q000473:pathology*; D001526:Behavioral Symptoms / Q000139:chemically induced / Q000517:prevention & control*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D002867:Chromones / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D008148:Lovastatin / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009025:Morpholines / Q000494:pharmacology; D016202:N-Methylaspartate / Q000633:toxicity; D019636:Neurodegenerative Diseases / Q000139:chemically induced / Q000473:pathology* / Q000517:prevention & control*; D011930:Reaction Time / Q000187:drug effects
D002867:Chromones; D004791:Enzyme Inhibitors; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009025:Morpholines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D016202:N-Methylaspartate; D008148:Lovastatin; D002795:Choline O-Acetyltransferase