Maternal hydroxytyrosol administration improves neurogenesis and cognitive function in prenatally stressed offspring

Prenatal stress is known to induce emotional and cognitive dysfunction in the offspring of both humans and experimental animals. Hydroxytyrosol (HT), a major polyphenol in olive oil with reported ability modulating oxidative stress and mitochondrial function, was performed to investigate its preventive effect on prenatal stress-induced behavioral and molecular alterations in offspring. Rats were exposed to restraint stress on days 14-20 of pregnancy. HT was given at doses of 10 and 50 mg/kg/day. The spontaneous alternation performance and Morris water maze confirmed the impaired learning capacity and memory performance induced by prenatal stress in both male and female offspring, and these effects were markedly restored in the HT supplement groups. Through tissue analysis of the hippocampi of male offspring, we found that the stress-induced downregulation of neural proteins, including BDNF, GAP43, synaptophysin, NMDAR1, NMDANR2A and NMDANR2B, was prevented by HT. Prenatal stress-induced low expression of glucocorticoid receptor was also increased by HT, although basal fetal serum corticosterone levels were not different among the four groups. Oxidative stress and mitochondrial dysfunction in prenatally stressed rats were confirmed with changes in protein oxidation, SOD activity, the expression of mitochondrial complexes and mitochondrial DNA copy number. Meanwhile, HT significantly increased transcription factors FOXO1 and FOXO3, as well as phase II enzyme-related proteins, including Nrf2 and HO-1, which may contribute to the decreased oxidative stress and increased mitochondrial function shown with HT supplementation. Taken together, these findings suggest that HT is an efficient maternal nutrient protecting neurogenesis and cognitive function in prenatally stressed offspring.