Synthesis and Neuroprotective Action of Xyloketal Derivatives in Parkinson’s Disease Models

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease affecting people over age 55. Oxidative stress actively participates in the dopaminergic (DA) neuron degeneration of PD. Xyloketals are a series of natural compounds from marine mangrove fungus strain No. 2508 that have been reported to protect against neurotoxicity through their antioxidant properties. However, their protection versus 1-methyl-4-phenylpyridinium (MPP+)-induced neurotoxicity is only modest, and appropriate structural modifications are necessary to discover better candidates for treating PD. In this work, we designed and synthesized 39 novel xyloketal derivatives (1–39) in addition to the previously reported compound, xyloketal B. The neuroprotective activities of all 40 compounds were evaluated in vivo via respiratory burst assays and longevity-extending assays. During the zebrafish respiratory burst assay, compounds 1, 9, 23, 24, 36 and 39 strongly attenuated reactive oxygen species (ROS) generation at 50 μM. In the Caenorhabditis elegans longevity-extending assay, compounds 1, 8, 15, 16 and 36 significantly extended the survival rates (p < 0.005 vs. dimethyl sulfoxide (DMSO)). A total of 15 compounds were tested for the treatment of Parkinson’s disease using the MPP+-induced C. elegans model, and compounds 1 and 8 exhibited the highest activities (p < 0.005 vs. MPP+). In the MPP+-induced C57BL/6 mouse PD model, 40 mg/kg of 1 and 8 protected against MPP+-induced dopaminergic neurodegeneration and increased the number of DA neurons from 53% for the MPP+ group to 78% and 74%, respectively (p < 0.001 vs. MPP+ group). Thus, these derivatives are novel candidates for the treatment of PD.

Xyloketal B alleviates cerebral infarction and neurologic deficits in a mouse stroke model by suppressing the ROS/TLR4/NF-κB inflammatory signaling pathway

“…We first reported the protective effects of Xyl-B on an oxLDL (oxidatively modified low density lipoprotein)-induced endothelial injury [9] . Furthermore, Xyl-B was shown to have multiple biomedical activities, including neuroprotective effects against toxicity, antioxidant effects on endothelial cells and zebrafish, anti-glioma effects through the inhibition of TRPM7 and the reduction of atherosclerosis plaque formation in apolipoprotein E-deficiency mice [10][11][12][13][14][15][16] . Our previous study also demonstrated that Xyl-B protected against neonatal brain injuries induced by hypoxiaischemia [17] .…”

Perspectives on C. elegans models of human Parkinson’s Disease

“…Molecular modeling of interaction between active compounds and αsynuclein suggests that more potent and selective derivatives might be possible as well as provide insight into the mechanism of anti-aggregation. Xyloketal derivatives have also been developed as potential neuroprotective agents in PD [38]. In C. elegans animals with dopaminergic neuron degeneration produced by 1-methyl-4-phenylpyridinium (MPP+), the survival rate could be significantly increased with several derivatives.…”

Effects of marine compound xyloketal B on neuroprotection and potential drug development

“…Recently, Liu and colleagues demonstrated that novel xyloketal derivatives protected against H 2 O 2 -induced injury in an in-vitro model of oxidative damage [11]. In addition, the same group has previously synthesized xyloketal derivatives that significantly attenuated reactive oxygen species (ROS) production in zebrafish, increased the survival rates of Caenorhabditis elegans and protected against neurodegeneration in C57BL/6 mice in an in-vivo model of PD [12]. These neuroprotective effects are likely mediated by the antioxidative properties of xyloketals.…”