FAD012, a ferulic acid derivative, improves cerebral blood flow and enhances swallowing reflux in a rat chronic cerebral hypoperfusion model

Abstract

Dysphagia is the major complication of stroke and often leads to lethal aspiration pneumonia in the patients. In the present study, we investigated the effects of FAD012, a synthetic derivate of ferulic acid (FA), against the swallowing dysfunction induced by bilateral common carotid artery occlusion (2VO) in rats.

Male adult Sprague-Dawley rats (11 week old) were continuously treated with FAD012 or FA (3 or 10 mg/kg daily, p.o.) from one week before 2VO. The rats were anaesthetized with isoflurane, and their bilateral common carotid arteries were exposed and ligated using 6-0 silk suture. Chronological changes in cerebral blood flow (CBF) in the cortex were measured using laser Doppler flowmetry. Two weeks after 2VO, swallowing reflux was evoked under urethane anesthesia by injection of stimulating solution (50 μL of water or citric acid) into the laryngopharyngeal region and was identified by electromyogram activity of the mylohyoid muscle. To evaluate impairment of nigrostriatal dopamine-SP system by chronic cerebral hypoperfusion, the expression of tyrosine hydroxylase (TH) and substance P (SP, a key molecule triggering the swallowing reflex) 14 days after 2VO was analyzed by immunohistochemical staining.

In vehicle group, CBF decreased to 46.0% of the baseline after 2VO. Pretreatment with FAD012 suppressed the 2VO-induced decrease in CBF (67.0%) and increased the survival rate after 2VO. FA had no effect on the survival rate or CBF in 2VO rats. 2VO rats had an attenuated swallowing reflux; they showed a smaller number of swallows with a longer onset latency compared with the sham-operated rats. FAD012 dose-dependently increased the number of swallows and reduced the latency in 2VO rats, and these effects were more potent than those of FA. In 2VO rats, the expression of striatal TH and SP decreased, suggesting that 2VO impaired the nigrostriatal dopamine-SP system. Treatment with FAD012 preserved TH and SP expression in 2VO rats. These results suggest that oral treatment with FAD012 preserves CBF even under cerebral hypoperfusion and improves swallowing reflex by protecting the nigrostriatal dopamine-SP system in 2VO rats.