The recognition, most effectively forwarded by Jim Roberts and Chris Redman more than 20 years ago, that the maternal endothelial dysfunction that underlies the maternal signs and symptoms of preeclampsia were caused, at least in part, by excessive oxidative stress offered opportunities for developing novel therapies based on mitigating oxidative stress. Not surprisingly, the field received with much enthusiasm the results of Lucy Chappell’s small “proof-of-principle” study that suggested that supplementation with vitamins C and E reduced the recurrence risk of preeclampsia in women at high risk. We now know, of course, that subsequently large randomised controlled trials failed to confirm this effect and, indeed, suggested that, if anything vitamin C and E might worsen the disease in those who developed it. The metaphorical knuckles of the “antioxidant” enthusiasts had been soundly rapped and further clinical research has been sparse. That’s a pity.
However, using their RUPP rat model of preeclampsia, Joey Grainger and his team in Jackson, Mississippi have confirmed that excessive placental and endothelial oxidative stress are central to maternal hypertension. They have also shown that vitamin C does not mitigate the endothelial dysfunction. There is a lesson for all there – that experimental research can be used to better direct clinical research.
We have recently shown that increased endothelial NADP(H) oxidase-2 (NOX2) activity causes the endothelial oxidative stress and dysfunction in preeclampsia and that this is amenable to therapeutic targeting. We have been assessing an array of anti-oxidant and pro-oxidant therapies that target both NOX and Nrf2, an antioxidant transcription factor, with a view to improving endothelial function. In this talk we will summarise both preclinical and clinical data on the use of melatonin and the next generation of adjuvant therapies for preeclampsia that target oxidative stress pathways.