title: Neurocytoprotective Effects of Aliphatic Hydroxamates from Lovastatin, a Secondary Metabolite from Monascus-Fermented Red Mold Rice, in 6-Hydroxydopamine (6-OHDA)-Treated Nerve Growth Factor (NGF)-Differentiated PC12 Cells.
abstract: Lovastatin, a secondary metabolite isolated from Monascus-fermented red rice mold, has neuroprotective activity and permeates the blood-brain barrier. The aim of this study was to enhance the activity of lovastatin for potential use as a treatment for neuronal degeneration in Parkinson's disease. Six lovastatin-derived compounds were semisynthesized and screened for neurocytoprotective activity against 6-hydroxydopamine (6-OHDA)-induced toxicity in human neuroblastoma PC12 cells. Four compounds, designated as 3a, 3d, 3e, and 3f, significantly enhanced cell viability. In particular, compound 3f showed excellent neurocytoprotective activity (97.0 ± 2.7%). Annexin V-FITC and propidium iodide double staining and 4',6-diamidino-2-phenylindole staining indicated that compound 3f reduced 6-OHDA-induced apoptosis in PC12 cells. Compound 3f also reduced caspase-3, -8, and -9 activities, and intracellular calcium concentrations elevated by 6-OHDA in a concentration-dependent manner, without inhibiting reactive oxygen species generation. JC-1 staining indicated that compound 3f also stabilized mitochondrial membrane potential. Thus, compound 3f may be used as a neurocytoprotective agent. Future studies should investigate its potential application as a treatment for Parkinson's disease.
authors.affiliation: †Graduate Institute of Clinical Medicine, Taipei Medical University, Taipei 110, Taiwan.|‡Department of Neurosurgery, Taipei Medical University-Wan Fang Hospital, Taipei 116, Taiwan.|§Department of Neurosurgery, Taipei Medical University-Shuang Ho Hospital, Taipei County 235, Taiwan.
authors.forename: Chien-Min
authors.initials: CM
authors.lastname: Lin
authors.affiliation: ∥Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.
authors.forename: Yi-Tzu
authors.initials: YT
authors.lastname: Lin
authors.affiliation: ⊥Department of Internal Medicine, Heping Branch, Taipei City Hospital, Taipei 100, Taiwan.
authors.forename: Rong-Dih
authors.initials: RD
authors.lastname: Lin
authors.affiliation: ∥Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.|#Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei 110, Taiwan.|∇School of Pharmacy, National Defense Medical Center, Taipei 114, Taiwan.
authors.forename: Wei-Jan
authors.initials: WJ
authors.lastname: Huang
authors.affiliation: ∥Graduate Institute of Pharmacognosy, College of Pharmacy, Taipei Medical University, Taipei 110, Taiwan.|#Ph.D. Program for the Clinical Drug Discovery from Botanical Herbs, Taipei 110, Taiwan.
authors.forename: Mei-Hsien
authors.initials: MH
authors.lastname: Lee
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002454:Cell Differentiation; D002470:Cell Survival / Q000187:drug effects*; D008148:Lovastatin / Q000031:analogs & derivatives*; D008954:Models, Biological; D032741:Monascus; D020932:Nerve Growth Factor; D009474:Neurons / Q000187:drug effects*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D012275:Oryza; D016627:Oxidopamine; D016716:PC12 Cells; D020734:Parkinsonian Disorders; D051381:Rats
chemical_list: D018696:Neuroprotective Agents; D016627:Oxidopamine; D020932:Nerve Growth Factor; D008148:Lovastatin
keywords: 6-hydroxydopamine; Lovastatin-derived hydroxamate; Parkinson’s disease; mitochondrial membrane potential; neurocytoprotective