Treatment with sildenafil prevents impairment of learning in rats born to pre-eclamptic mothers

Abstract

Pre-eclampsia is an important hypertensive pregnancy disorder and a main cause of maternal and fetal morbidity and mortality. Children born from mothers with pre-eclampsia may present cognitive deficits. The mechanisms leading to this cognitive impairment remain unclear and no treatments to improve it have been tested. Pre-eclampsia is associated with impaired regulation of the nitric oxide-3‵-5‵guanosine monophosphate cyclic (cGMP) pathway, which modulates some cognitive functions. We hypothesized that alterations in the NO-cGMP pathway would be involved in the mechanisms leading to cognitive impairment in rats born to pre-eclamptic mothers and that treatment with sildenafil, an inhibitor of the phosphodiesterase that degrades cGMP, could restore their cognitive function. To test these hypotheses, we used an animal model of pre-eclampsia in rats: pregnant rats treated with l-nitro-arginine methyl ester, an inhibitor of nitric oxide synthase. Using this model, we assessed: (1) whether rats born to pre-eclamptic mothers show reduced learning ability and/or altered motor activity or coordination when they are 2 months-old; (2) whether cognitive impairment is associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo; and (3) whether treatment of the mothers with sildenafil prevents this cognitive and motor alterations. The results reported show that the ability to learn a conditional discrimination task in a Y maze is reduced in rats born to pre-eclamptic mothers. This impairment was associated with reduced function of the glutamate-NO-cGMP pathway in brain in vivo, as assessed by microdialysis in freely moving rats. Treatment with sildenafil restores the function of this pathway and learning ability.