title: Tacrine-silibinin codrug shows neuro- and hepatoprotective effects in vitro and pro-cognitive and hepatoprotective effects in vivo.
abstract: A codrug of the anti-Alzheimer drug tacrine and the natural product silibinin was synthesized. The codrug's biological and pharmacological properties were compared to an equimolar mixture of the components. The compound showed potent acetyl- and butyrylcholinesterase inhibition. In a cellular hepatotoxicity model, analyzing the influence on viability and mitochondria of hepatic stellate cells (HSC), the toxicity of the codrug was markedly reduced in comparison to that of tacrine. Using a neuronal cell line (HT-22), a neuroprotective effect against glutamate-induced toxicity could be observed that was absent for the 1:1 mixture of components. In subsequent in vivo experiments in rats, in contrast to the effects seen after tacrine treatment, after administration of the codrug no hepatotoxicity and no induction of the cytochrome P450 system were noticed. In a scopolamine-induced cognitive impairment model using Wistar rats, the codrug was as potent as tacrine in reversing memory dysfunction. The tacrine-silibinin codrug shows high AChE and BChE inhibition, neuroprotective effects, lacks tacrine's hepatotoxicity in vitro and in vivo, and shows the same pro-cognitive effects in vivo as tacrine, being superior to the physical mixture of tacrine and silibinin in all these regards.
authors.affiliation: Institut für Pharmazie, Universität Regensburg, Universitätsstraße 31, D-93053 Regensburg, Germany.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Chen
authors.forename: Katharina
authors.initials: K
authors.lastname: Zenger
authors.forename: Amelie
authors.initials: A
authors.lastname: Lupp
authors.forename: Beata
authors.initials: B
authors.lastname: Kling
authors.forename: Jörg
authors.initials: J
authors.lastname: Heilmann
authors.forename: Christian
authors.initials: C
authors.lastname: Fleck
authors.forename: Birgit
authors.initials: B
authors.lastname: Kraus
authors.forename: Michael
authors.initials: M
authors.lastname: Decker
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000494:Allosteric Regulation; D000818:Animals; D002091:Butyrylcholinesterase / Q000378:metabolism; D002452:Cell Count; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D003071:Cognition / Q000187:drug effects*; D004524:Eels; D005260:Female; D018698:Glutamic Acid / Q000494:pharmacology; D055166:Hepatic Stellate Cells / Q000166:cytology / Q000187:drug effects; D006736:Horses; D015227:Lipid Peroxidation / Q000187:drug effects; D008099:Liver / Q000166:cytology / Q000187:drug effects*; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D000077385:Silybin; D012838:Silymarin / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity; D013619:Tacrine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000494:pharmacology / Q000633:toxicity
chemical_list: D002800:Cholinesterase Inhibitors; D018696:Neuroprotective Agents; D012838:Silymarin; D018698:Glutamic Acid; D000077385:Silybin; D013619:Tacrine; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase