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Abstract
Diarrheal diseases are a leading cause of non-cardiovascular death worldwide with infants and children in developing countries being the primary victims. While oral rehydration therapy has been very effective in reducing the mortality associated with infectious diarrhea, there remains an urgent need for safe and economical drugs that can help prevent or combat the disease effectively. In the present study I have examined the efficacy of two classes of PPAR ligands in suppressing intestinal chloride secretion both in vivo and in vitro. The first class of drugs is the PPARα agonists, fenofibrate and clofibrate. My results demonstrate that these drugs promptly and persistently inhibit intestinal chloride secretion without affecting intestinal absorptive capacity. The mechanism of action does not involve PPARα, but is a direct blockade of the basolateral KCNQ1/KCNE3 channel complex. Because of their rapid, persistent and comprehensive inhibitory action on intestinal ion transport, these compounds have the potential to be developed as a remedy for acute secretory diarrhea. The second part of this study focused on the effect of the PPARγ ligands rosiglitazone (Ro) and pioglitazone (Po) on intestinal chloride secretion. I have found that both of these drugs suppress intestinal Cl- secretion both in vivo and in vitro. Ro was also effective in reducing cholera toxin–induced fluid secretion in a mouse model of secretory diarrhea. The mechanism by which Ro inhibits Cl - secretion involves a downregulation of the expression of CFTR, KCNQ1 and NKCC1 proteins. The full inhibitory effect of Ro/Po required at least 3 days to manifest and this fact makes Ro better suited for treating patients suffering from chronic diarrhea. This study identifies two classes of drugs that are potent suppressors of intestinal Cl- secretion. All of these drugs are known to be safe for use in humans and are easily available. Given the urgent need for safe and economical drugs or adjuncts to ORT that may help in mitigating the loss of life due to diarrhea, these findings are very promising and significant.
