title: HMG-CoA reductase inhibitor induces a transient activation of high affinity nerve growth factor receptor, trk, and morphological differentiation with fatal outcome in PC12 cells.
abstract: The present study was aimed at investigating the possible toxicity of simvastatin on a neuronal cell line, PC12 cells. Simvastatin clearly induced a transient morphological differentiation as evidenced by the occurrence of neurite outgrowth with a transient activation of the high affinity nerve growth factor receptor, Trk, but died at 36 h after its addition. Tyrosine autophosphorylation of the Trk protein also disappeared at 36 h after addition. During the morphological differentiation, NGF mRNA expression was upregulated transiently and returned to the basal level at 36 h after addition of simvastatin. These results suggest that simvastatin is neurotoxic and PC12 cells elicited a protective response, involving a transient activation of a Trk-mediated intracellular signal transduction pathway by an autocrine secretion of NGF, although these responses did not persist against pro-apoptotic signals and resulted in an apoptosis of the PC12 cells.
authors.affiliation: Second Department of Internal Medicine, Division of Neurology, Faculty of Medicine, Fukui Medical University, 23-Shimoaizuki, Matsuoka-cho, Fukui, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Kumano
authors.forename: T
authors.initials: T
authors.lastname: Mutoh
authors.forename: H
authors.initials: H
authors.lastname: Nakagawa
authors.forename: M
authors.initials: M
authors.lastname: Kuriyama
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D018929:Cell Culture Techniques; D048429:Cell Size / Q000187:drug effects*; D015801:Helminth Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000633:toxicity*; D016716:PC12 Cells / Q000187:drug effects* / Q000378:metabolism*; D051381:Rats; D018125:Receptors, Transforming Growth Factor beta / Q000187:drug effects* / Q000378:metabolism*; D019821:Simvastatin / Q000633:toxicity*
chemical_list: D015801:Helminth Proteins; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018125:Receptors, Transforming Growth Factor beta; C108876:trk-1 protein, Brugia pahangi; D019821:Simvastatin