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

Saleh TM, Connell BJ, Kucukkaya I, Abd-El-Aziz AS - Brain Sci (2015)

Bottom Line: We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown, PE C1A 4P3, Canada. tsaleh@upei.ca.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus

(A) Representative photomicrographs of 2,3,5-triphenol tetrazolium chloride (TTC)-stained, 1 mm thick coronal sections through the rat brain. Lack of staining (white regions) in the tissue from both vehicle and UPEI-104-treated rats indicates areas of infarct; (B) Bar graph demonstrating the effect of UPEI-104 treatment on infarct volume as a function of dose in Sprague-Dawley rats that were treated with the compound (0.001–0.1 mg/kg) 30 min prior to the middle cerebral artery (MCA) was occluded to induce a stroke. Numbers inside bars indicate the number of animals/dose group. (* Asterisk indicates significantly different from vehicle group; p < 0.05; ANOVA).
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brainsci-05-00130-f002: (A) Representative photomicrographs of 2,3,5-triphenol tetrazolium chloride (TTC)-stained, 1 mm thick coronal sections through the rat brain. Lack of staining (white regions) in the tissue from both vehicle and UPEI-104-treated rats indicates areas of infarct; (B) Bar graph demonstrating the effect of UPEI-104 treatment on infarct volume as a function of dose in Sprague-Dawley rats that were treated with the compound (0.001–0.1 mg/kg) 30 min prior to the middle cerebral artery (MCA) was occluded to induce a stroke. Numbers inside bars indicate the number of animals/dose group. (* Asterisk indicates significantly different from vehicle group; p < 0.05; ANOVA).

Mentions: Pre-treatment with UPEI-104 at 30 min prior to MCA occlusion resulted in a dose-dependent reduction in infarct volume when measured following ischemia/reperfusion. Infarct volume was significantly lower in rats treated with 0.1 mg/kg UPEI-104 (Figure 2). This dose was equal to that previously observed with the parent compound, UPEI-100, when tested using the same in vivo model of reperfusion-injury in our laboratory [27].


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

Saleh TM, Connell BJ, Kucukkaya I, Abd-El-Aziz AS - Brain Sci (2015)

(A) Representative photomicrographs of 2,3,5-triphenol tetrazolium chloride (TTC)-stained, 1 mm thick coronal sections through the rat brain. Lack of staining (white regions) in the tissue from both vehicle and UPEI-104-treated rats indicates areas of infarct; (B) Bar graph demonstrating the effect of UPEI-104 treatment on infarct volume as a function of dose in Sprague-Dawley rats that were treated with the compound (0.001–0.1 mg/kg) 30 min prior to the middle cerebral artery (MCA) was occluded to induce a stroke. Numbers inside bars indicate the number of animals/dose group. (* Asterisk indicates significantly different from vehicle group; p < 0.05; ANOVA).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4493460&req=5

brainsci-05-00130-f002: (A) Representative photomicrographs of 2,3,5-triphenol tetrazolium chloride (TTC)-stained, 1 mm thick coronal sections through the rat brain. Lack of staining (white regions) in the tissue from both vehicle and UPEI-104-treated rats indicates areas of infarct; (B) Bar graph demonstrating the effect of UPEI-104 treatment on infarct volume as a function of dose in Sprague-Dawley rats that were treated with the compound (0.001–0.1 mg/kg) 30 min prior to the middle cerebral artery (MCA) was occluded to induce a stroke. Numbers inside bars indicate the number of animals/dose group. (* Asterisk indicates significantly different from vehicle group; p < 0.05; ANOVA).
Mentions: Pre-treatment with UPEI-104 at 30 min prior to MCA occlusion resulted in a dose-dependent reduction in infarct volume when measured following ischemia/reperfusion. Infarct volume was significantly lower in rats treated with 0.1 mg/kg UPEI-104 (Figure 2). This dose was equal to that previously observed with the parent compound, UPEI-100, when tested using the same in vivo model of reperfusion-injury in our laboratory [27].

Bottom Line: We then compared the stability of UPEI-104 to the original parent compound UPEI-100 in human plasma as well as 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Sciences, Atlantic Veterinary College, Charlottetown, PE C1A 4P3, Canada. tsaleh@upei.ca.

ABSTRACT
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.

No MeSH data available.


Related in: MedlinePlus