Neuroprotective Effect of Nor-Prenylated Acylphloroglucinols from Hypericum perforatum L. (St John’s Wort) in the MPTP-Induced Zebrafish Model

<i>Hypericum perforatum</i> L. (St John's wort) has been widely studied and used for antidepressant treatment, as well as, rarely, featuring in studies on its chemical composition for Parkinson's disease (PD) treatment. Five new <i>nor</i>-prenylated acylphloroglucinols with a cyclohexanone core, norperforatums A-E (<b>1</b>-<b>5</b>), together with four known analogs [(2<i>R</i>,3<i>R</i>,4<i>S</i>,6<i>R</i>)-3-methyl-4,6-di(3-methyl-2-butenyl)-2-(2-methyl-1-oxopropyl)-3-(4-methyl-3-pentenyl)cyclohexanone (<b>6</b>), hyperscabrin B (<b>7</b>), (2<i>R</i>,3<i>R</i>,4<i>S</i>,6<i>R</i>)-6-methoxycarbonyl-3-methyl-4,6-di(3-methyl-2-butenyl)-2-(2-methyl-1-oxopropyl)-3-(4-methyl-3-pentenyl)cyclohexanone (<b>8</b>), and hyperscabin K (<b>9</b>)], were isolated from the aerial parts of <i>H. perforatum</i>. The structures and absolute configurations of the new compounds were characterized by multiple spectroscopic means, including nuclear magnetic resonance (NMR), high-resolution electrospray ionization mass spectrometry (HR-ESI-MS), ultraviolet visible absorption spectroscopy (UV), infrared spectroscopy (IR), calculated electronic circular dichroism (ECD) data, and X-ray signal crystal diffraction. In addition, the efficacy of these isolations was evaluated against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD in zebrafish larvae. Compound <b>9</b> had the best therapeutic effect, by significantly increasing the total distance traveled and the mean speed of movement in PD dyskinesia zebrafish larvae. Moreover, it enhanced superoxide dismutase (SOD) activity and inhibited reactive oxygen species (ROS) production in a dose-dependent manner. These results suggest that compound <b>9</b> may have ameliorative effects on PD symptoms by inhibiting oxidative stress. This study provides new insights into the treatment of <i>H. perforatum</i> for PD.