Neurocytoprotective Effects of Aliphatic Hydroxamates from Lovastatin, a Secondary Metabolite from <i>Monascus</i>-Fermented Red Mold Rice, in 6‑Hydroxydopamine (6-OHDA)-Treated Nerve Growth Factor (NGF)-Differentiated PC12 Cells

Lovastatin, a secondary metabolite isolated from <i>Monascus</i>-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 <b>3a</b>, <b>3d</b>, <b>3e</b>, and <b>3f</b>, significantly enhanced cell viability. In particular, compound <b>3f</b> 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 <b>3f</b> reduced 6-OHDA-induced apoptosis in PC12 cells. Compound <b>3f</b> 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 <b>3f</b> also stabilized mitochondrial membrane potential. Thus, compound <b>3f</b> may be used as a neurocytoprotective agent. Future studies should investigate its potential application as a treatment for Parkinson’s disease