Introduction: Neonatal Hypoxia-Ischemia (HI) is a major cause of morbidity and mortality, and is frequently associated with short and long-term neurologic and cognitive impairments. The HI injury causes mitochondrial damage leading to increased production of reactive oxygen species (ROS). Phytoestrogens are non-steroidal plant substances structurally and functionally similar to estrogen. Coumestrol is a potent isolavonoid with a protective efect against ischemic brain damage in adult rats. Our aim was to determine if coumestrol treatment following neonatal HI attenuates the long-term cognitive deicits induced by neonatal HI, as well as to investigate one possible mechanism underlying its potential efect. Methods: On the 7th postnatal day, male Wistar rats were submitted to the Levine-Rice HI model. Intraperitoneal injections of 20 mg/kg of coumestrol, or vehicle, were administered immediately pre-hypoxia or 3 h post-hypoxia. At 12 h after HI the mitochondrial status and ROS levels were determined. At 60th postnatal day the cognitive deicits were revealed in the Morris water maze reference and working spatial memories. Following behavioral analysis, histological assessment was performed and reactive astrogliosis was measured by GFAP expression. Results: Results demonstrate that both pre-and post-HI administration of coumestrol were able to counteract the long-term cognitive and morphological impairments caused by HI, as well as to block the late reactive astrogliosis. The pre-HI administration of coumestrol was able to prevent the early mitochondrial dysfunction in the hippocampus of injured rat pups. Conclusion: Present data suggest that coumestrol exerts protection against experimental neonatal brain hypoxiaischemia through, at least in part, early modulation of mitochondrial function.
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