Chen, Xinyu and Zenger, Katharina and Lupp, Amelie and Kling, Beata and Heilmann, Joerg and Fleck, Christian and Kraus, Birgit and Decker, Michael (2012) Tacrine-Silibinin Codrug Shows Neuro- and Hepato protective Effects in Vitro and Pro-Cognitive and Hepatoprotective Effects in Vivo. JOURNAL OF MEDICINAL CHEMISTRY, 55 (11). pp. 5231-5242. ISSN 0022-2623,
Full text not available from this repository. (Request a copy)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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ALZHEIMER DRUG CANDIDATES; OXIDATIVE STRESS; CELL-DEATH; HYBRID MOLECULES; GLUTAMATE TOXICITY; NO-DONOR; DISEASE; HEPATOTOXICITY; BUTYRYLCHOLINESTERASE; SILYBIN; |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical Biology (Prof. Heilmann) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 11 May 2020 12:07 |
| Last Modified: | 11 May 2020 12:07 |
| URI: | https://pred.uni-regensburg.de/id/eprint/18582 |
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