Increasing the Biological Stability Profile of a New Chemical Entity, UPEI-104, and Potential Use as a Neuroprotectant Against Reperfusion-Injury

Brain Sciences

Tarek M. Saleh¹  Barry J. Connell¹  Inan Kucukkaya²  Alaa S. Abd-El-Aziz² 

[1] Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown, PE C1A 4P3, Canada; E-Mail:;Department of Chemistry, University of Prince Edward Island, Charlottetown, PE C1A 4P3, Canada; E-Mails:

关键词: stroke;    ischemia/reperfusion;    middle cerebral artery occlusion;    antioxidant therapy;    neuroprotection;    bio cleavage-resistance;   

DOI  :  10.3390/brainsci5020130

来源: mdpi

【 摘 要 】

Previous work in our laboratory demonstrated the utility of synthetic combinations of two naturally occurring, biologically active compounds. In particular, we combined two known anti-oxidant compounds, lipoic acid and apocynin, covalently linked via an ester bond (named UPEI-100). In an animal model of ischemia-reperfusion injury (tMCAO), UPEI-100 was shown to produce equivalent neuroprotection compared to each parent compound, but at a 100-fold lower dose. However, it was determined that UPEI-100 was undetectable in any tissue samples almost immediately following intravenous injection. Therefore, the present investigation was done to determine if biological stability of UPEI-100 could be improved by replacing the ester bond with a more bio cleavage-resistant bond, an ether bond (named UPEI-104). We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as liver microsomes. Our results demonstrated that both UPEI-100 and UPEI-104 could be detected in human plasma for over 120 min; however, only UPEI-104 was detectable for an average of 7 min following incubation with human liver microsomes. This increased stability did not affect the biological activity of UPEI-104 as measured using our tMCAO model. Our results suggest that combining compounds using an ether bond can improve stability while maintaining biological activity.

【 授权许可】

CC BY   
© 2015 by the authors; licensee MDPI, Basel, Switzerland.