Anti-neurotoxicity Effects Of Oxoisoaporphine-lipoic Acid Hybrids

With the average life expectancy increasing every year, the incidence ofAlzheimer’s disease in worldwide increased significantly, which has been aserious threat to the health of the elderly. The well-accepted pathogenesis ofAlzheimer’s disease include beta-amyloid (Aβ) deposits, reduced synthesis ofthe neurotransmitter acetylcholine,and oxidative stress.Nowdays the mosteffective anti-AD drugs are anti-cholinesterase inhibitors, and its main target isthe catalytic active site of acetylcholinesterase. In recent years, with thediscovery of the peripheral acetylcholinesterase anionic sites and their role inpromoting amyloid deposition revealed, synthesis of multi-target-directedacetylcholinesterase inhibitors become anti-Alzheimer’s disease drug researchhotspot.Our previous study in vitro confirmed Oxoisoaporphine alkaloidsderivatives extracted from Chinese herbs, Menispermum dauricum,possessneuroprotective effects gainst Alzheimer’s disease, and mainly targettheperipheral anionic sites of acetylcholinesterase.In the present study, wechemically synthesize Oxoisoaporphine-Lipoic Acid hybrids,which mayincrease antioxidant activity of oxoisoaporphine,to test its anti-neurotoxicityeffects in vitro and in vivo.Objective: Exploring anti-neurotoxicity effects of Oxoisoaporphine-Lipoic Acidhybrids and its mechanism in vitro and in provide preliminary experimentalbasis for new drugs development for multi-targets-directed acetylcholinesterase inhibitors.Methods: In vitro,the inhibition of AChE and BChE in vitro by the syntheticcompounds was determined using the modified Ellman method.Toxicity andneuroprotective capacity of compounds8-11in SH-SY5Y cells were tested withMTT assay.In vivo,the Aβ42-Elav-GAL4/UAS hybrid Drosophila wasrandomly assigned into five groups (n=100per group): normal control group,blank control group, DMSO solvent control group, and Oxoisoaporphine-LipoicAcid hybrids administrated groups (0.1,10μmol/L).100normal Drosophilawas used as normal control. Observe the following indicators:(1) flies survival,climbing ability;(2) SOD, MDA level detection in Drosophila brain tissue;(3)detection of Drosophila brain tissue ATP levels;(4) HE staining of Drosophilabrain tissue.Results:The hybrids exhibited moderate inhibitory effects on the activity ofacetylcholinesterase (AChE), with IC50values in the micromolar range and lowtoxicity in SH-SY5Y cells. Moreover, the learning and memory abilities,climbing capability, and average life expectancy of the Aβ42transgenicDrosophila were all significantly improved by the hybrids. They also enhancedthe intracephalic antioxidant activity, the metabolism, and the activitycholinesterase in the flies. More strikingly, Aβ42aggregation in thehybrids-treated Drosophila was attenuated with effective neuroprotection.Conclusions: Our results indicate the potential of using theseoxoisoaporphine-lipoic acid hybrids in AD treatments.