Inhibition of cognitive decline in mice fed a high-salt and cholesterol diet by the angiotensin receptor blocker, olmesartan

The metabolic syndrome is closely related to dietary habits and seems to be associated with impairment of cognitive function in humans. Angiotensin receptor blockers are widely used with the expectation of preventing cardiovascular events and stroke and potential amelioration of the metabolic syndrome. We examined the diet-induced changes of cognitive function in mice treated with a high-salt and high-cholesterol diet. C57BL/6J mice were fed a high-salt (2% NaCl in drinking water) and high-cholesterol (1.25% cholesterol, 10% coconut oil) diet (HSCD) or a normal diet (ND), and subjected to 20 trials of a passive avoidance task every week from 8 weeks of age. An age-dependent decline of the avoidance rate starting from 10 weeks of age was observed in HSCD mice, whereas the avoidance rate gradually increased in the ND group. Oral administration of an angiotensin receptor blocker, olmesartan, at a dose of 3 mg/kg per day in drinking water from 8 weeks of age prevents this decline of avoidance rate in HSCD mice (49% vs. 82% at 12 weeks of age). Treatment with olmesartan significantly decreased serum glucose and cholesterol levels in HSCD mice, with a slight decrease in blood pressure. Administration of olmesartan in HSCD-fed mice showed a 1.6-fold increase in mRNA expression of a neuroprotective factor, MMS2, compared to HSCD-fed mice without olmesartan. Olmesartan attenuated the increase in superoxide anion production detected by dihydroethidium staining in the brain of HSCD mice. Our results suggest that olmesartan could be therapeutically effective in preventing the impairment of quality of life in persons on a high-fat and high-salt diet.