Abstract Details

Title An Analog of gamma-Glutamyl-Cysteine Is a More Stable Drug for the Potential Treatment of Stroke

Topic Cerebrovascular Disease and Interventional Neurology

Presentation(s) P01 - (-)

Poster/Presentation
Number 248

Objective

Background BACKGROUND: The treatment for ischemic stroke involves utilization of a thrombolytic agent to re-establish blood flow in affected areas of the brain. However, delayed reperfusion has been associated with damage to brain capillaries, resulting in cerebral bleeding and death (i.e., hemorrhagic transformation). Initial evidence from our laboratory, utilizing a rat model, has shown that intravascular pretreatment with a combination of experimental drugs, including the antioxidant gamma-L-glutamyl-L-cysteine (Gamma-Glu-Cys), stabilizes the cerebral vasculature following thrombolysis for ischemic stroke, and thus may prevent hemorrhagic transformation. Subsequent pharmacokinetic studies showed that the analog, gamma-L-glutamyl-D-cysteine (Gamma-Glu-D-Cys), is more stable to hydrolysis and oxidation in rat serum than Gamma-Glu-Cys. To determine the potential stability of these drugs in humans, they were incubated in human serum in vitro, and degradation was quantified by high pressure liquid chromatography (HPLC) as a function of time.

Design/Methods DESIGN/METHODS: Gamma-Glu-Cys and its analog, Gamma-Glu-D-Cys, were incubated in human serum at a concentration of 6.25 mM for intervals of time over 180 mins, after which the presence and concentration of the peptides and metabolites were quantified by high pressure liquid chromatography (HPLC).

Results RESULTS: These studies show that: 1) Gamma-Glu-Cys and Gamma-Glu-D-Cys are degraded both by hydrolysis and oxidation, 2) the analog, Gamma-Glu-D-Cys, is more stable than Gamma-Glu-Cys in human serum, and 3) both peptides express an equal antioxidant capacity in an in vitro assay.

Conclusions CONCLUSIONS: The data suggest that the D-analog of Gamma-Glu-Cys may serve as a more stable therapeutic agent.

Authors/Disclosures
Rachel Forman, MD (Yale Neurology) PRESENTER	Dr. Forman has nothing to disclose.
	No disclosure on file
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