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.

Original languageEnglish
Pages (from-to)716-724
Number of pages9
JournalACS Chemical Neuroscience
Volume6
Issue number5
DOIs
Publication statusPublished - May 20 2015

Fingerprint

Monascus
Lovastatin
Oxidopamine
PC12 Cells
Nerve Growth Factor
Metabolites
Fungi
Staining and Labeling
Parkinson Disease
Caspase 8
Propidium
Fluorescein-5-isothiocyanate
Mitochondrial Membrane Potential
Annexin A5
Blood-Brain Barrier
Neuroblastoma
Caspase 3
Toxicity
Reactive Oxygen Species
Cell Survival

Keywords

  • 6-hydroxydopamine
  • Lovastatin-derived hydroxamate
  • mitochondrial membrane potential
  • neurocytoprotective
  • Parkinson's disease

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Physiology
  • Cognitive Neuroscience

Cite this

@article{cf392bd1fb6b4ed584051965dd5946ce,
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.",
keywords = "6-hydroxydopamine, Lovastatin-derived hydroxamate, mitochondrial membrane potential, neurocytoprotective, Parkinson's disease",
author = "Chien-Min Lin and Lin, {Yi Tzu} and Lin, {Rong Dih} and Wei-Jan Huang and Mei-Hsien Lee",
year = "2015",
month = "5",
day = "20",
doi = "10.1021/cn500275k",
language = "English",
volume = "6",
pages = "716--724",
journal = "ACS Chemical Neuroscience",
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T1 - 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

AU - Lin, Chien-Min

AU - Lin, Yi Tzu

AU - Lin, Rong Dih

AU - Huang, Wei-Jan

AU - Lee, Mei-Hsien

PY - 2015/5/20

Y1 - 2015/5/20

N2 - 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.

AB - 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.

KW - 6-hydroxydopamine

KW - Lovastatin-derived hydroxamate

KW - mitochondrial membrane potential

KW - neurocytoprotective

KW - Parkinson's disease

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