Abstract WP106: Acetazolamide Stabilizes Stroke Induced Respiratory Dysfunction and Improves Longterm Cognitive Outcome

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Abstract

Background: Respiratory dysfunction is a common complication of stroke, with an incidence more than 60% in first time stroke patients, leading to poorer recovery and increased mortality. We developed a mouse model of stroke induced respiratory dysfunction (SIRD) characterized by hypoventilation and apnea. Mice that had the highest incidence of post-stroke apneas developed progressive cognitive decline. Acetazolamide (Act), a carbonic anhydrase inhibitor, promotes metabolic acidosis increasing respiratory activity.

Hypothesis: Acetazolamide will stimulate basal respiratory activity, eliminating apneas and hypoxic events, and will enhance post stroke cognitive outcomes.

Methods: Whole body plethysmography was performed on WT C57/B6 young (2-3 month) male mice to establish baseline breathing frequency, tidal volume, minute ventilation and number of apneas. Mice were subjected to 60 MCAO or sham surgery. Plethysmography was performed on day 3, 7 and weekly thereafter. Act (40mg/kg) continuous administration via SQ implanted Alzet pump or vehicle (n=11/group) was initiated on day 14. Cognitive tests were conducted over six weeks.

Results: Act treatment improved respiratory frequency (152.6±6.49 vs. 318.4±61.9, p<0.05) and decreased the number of apneas (5.4±0.7 vs. 1±0.5, p<0.001) in stroke mice (Fig. 1). Spatial learning/memory assessed on day 42 with Barnes Maze found Act-treated mice had a shorter escape time than vehicle (median escape time 160.48 vs. 14.16s, survival curve for time to escape p=0.0001, Mantel-Cox test).

Summary: Apnea and hypoxia are seen in a murine model of SIRD, the severity of which correlated with post-stroke cognitive decline. These deficits were reversed with chronic Acetazolamide treatment. Research supported by the NCATS Award Number TL1TR000369.

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