Pretreatment with Lovastatin Prevents N-Methyl-D-Aspartate-Induced Neurodegeneration in the Magnocellular Nucleus Basalis and Behavioral Dysfunction

Article type: Research Article

Authors: Dolga, Amalia M.^a | Granic, Ivica^a | Nijholt, Ingrid M.^a | Nyakas, Csaba^{a; b} | van der Zee, Eddy A.^a | Luiten, Paul G.M.^{a; c} | Eisel, Ulrich L.M.^{a; *}

Affiliations: [a] Department of Molecular Neurobiology, Graduate School of Behavioral and Cognitive Neurosciences, University of Groningen, Haren, The Netherlands | [b] Neuropsychopharmacological Research Group of Semmelweis University and Hungarian Academy of Sciences, Budapest, Hungary | [c] Department of Biological Psychiatry, Graduate School of Behavioral and Cognitive Neurosciences, University of Groningen, Haren, The Netherlands

Correspondence: [*] Corresponding author: Ulrich L.M. Eisel, Department of Molecular Neurobiology, Graduate School of Behavioral and Cognitive Neurosciences, University of Groningen, Haren, The Netherlands. Tel.: +31 50 363 2366; Fax: +31 50 363 2331; E-mail: [email protected].

Note: [] Communicated by Angelika Bierhaus

Abstract: 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.

Keywords: Cholinergic neurons, excitotoxicity, lovastatin, magnocellular nucleus basalis, NMDA, passive avoidance test, PKB/Akt

DOI: 10.3233/JAD-2009-1052

Journal: Journal of Alzheimer's Disease, vol. 17, no. 2, pp. 327-336, 2009