Role of ω-3 polyunsaturated fatty acids and selenium in hypertension and cognitive function

Submission note: A thesis submitted in total fulfilment of the requirements for the degree of Doctor of Philosophy to the School of Psychological Science, Faculty of Science, Technology and Engineering, La Trobe University, Bundoora.

Dietary omega-3 fatty acid deficiency has been demonstrated to induce hypertension and cognitive impairment. However, the effects of multiple generations of omega-3 fatty acid deficiency on hypertension and cognitive impairment in animals remain inconclusive. In addition, oxidative stress may also play a role in the development of hypertension. This thesis aims, through a number of studies, to explore the effects of dietary omega-3 fatty acid deficiency on hypertension and cognitive impairment in animals. The first and second experiments were concerned with the effects of three generations of omega-3 fatty acid deficiency on blood pressure and cognitive function in mice. In addition, these studies examined the hypothesis that increased blood pressure and cognitive impairment in mice on omega-3 fatty acid deficient diet is due to increased prostaglandin activity by eicosanoid production from an arachidonic acid (AA)-cyclooxygenase (COX) pathway. Therefore, naproxen, a COX inhibitor was used in these studies as a treatment to inhibit prostaglandin activity. The third experiment examined whether elimination of the antioxidant Se in the omega-3 fatty acid deficient diet would lead to development of hypertension at an earlier age than when given only an omega-3 fatty acid deficient diet. In experiment 1 and 2, male and female C57BL/6J mice were bred through three generations on diets either deficient or sufficient in omega-3 fatty acids. At postnatal day 21, the third[-]generation mice were maintained on the dam’s diet or switched from the dam’s diet to the opposite diet, creating four groups. In addition, two groups that remained on the dam’s diet were treated with naproxen, a COX inhibitor. The systolic blood pressure of the third[-]generation mice was assessed by xiii CODA (Non-Invasive Blood Pressure Measurement) non-invasive blood pressure measure at 25-weeks of age and the spatial recognition memory was tested using the Y-maze task at 19-weeks of age. In experiment 3, rats were divided into four groups and placed on diets either sufficient or deficient in omega-3 fatty acids and Se. After maintaining them on these diets for 18-weeks, tail cuff blood pressure was assessed using an IITC (IITC Life Science Instruments) blood pressure system. Findings from the first study provides the first evidence that when mice were placed on an omega-3 fatty acid deficient diet for three generations they showed an increased systolic blood pressure compared to the mice that were maintained on an omega-3 fatty acid sufficient diet for three generations. Furthermore, the systolic blood pressure of the mice fed with an omega-3 fatty acid deficient diet over three generations was higher compared to that of the mice maintained on an omega-3 fatty acid deficient for one generation. Hypertension caused by omega-3 fatty acid deficiency over three generations can be prevented by feeding the third[-]generation mice an omega-3 fatty acid sufficient diet for 22 weeks. Findings from the second study showed that mice maintained on an omega-3 fatty acid deficient diet for three generations demonstrated impaired spatial recognition memory compared to the mice that were maintained on an omega-3 fatty acid sufficient diet for three generations. This spatial recognition memory impairment can be prevented by feeding the third[-]generation mice an omega-3 fatty acid sufficient diet for 16 weeks. However, spatial recognition memory of mice maintained on an omega-3 fatty acid sufficient diet for three generations was impaired when they were fed with an omega-3 fatty acid deficient diet for 16 weeks. In addition, their cognitive performances were not different from the mice that were maintained on an omega-3 fatty acid deficient diet for three generations. This suggests that the xiv increased deficit in omega-3 fatty acids resulting from multi-generational maintenance on an omega-3 fatty acid deficient diet does not cause any greater cognitive deficit than that observed within one generation. In addition, hypertension and cognitive impairment of the mice maintained on an omega-3 fatty acid deficient diet for three generations can be prevented by treatment with naproxen. These results suggest that hypertension and cognitive impairment caused by omega-3 fatty acid deficiency over three generations appears to be mediated by products of the AA-COX pathway. Finally, the third study found that rats maintained on a diet deficient both in omega-3 fatty acids and Se developed high blood pressure within 18 weeks. Se deficiency did not alter blood pressure in animals maintained on the omega-3 fatty acid sufficient diet. Thus, it would appear that Se, due to its antioxidant actions, can ameliorate the hypertensive effects that may occur due to an omega-3 fatty acid deficiency.