Phytoestrogen coumestrol attenuates brain mitochondrial dysfunction and long-term cognitive deficits following neonatal hypoxia–ischemia

• Published in: International journal of developmental neuroscience 2019-12, Vol.79 (1), p.86-95
• Main Authors: Anastacio, Janine Beatriz Ramos, Sanches, Eduardo Farias, Nicola, Fabrício, Odorcyk, Felipe, Fabres, Rafael Bandeira, Netto, Carlos Alexandre
• Format: Article
• Language: English
• Subjects: Animals; Astrocytes; Brain; Brain - drug effects; Brain - metabolism; Brain damage; Brain injury; Cognition - drug effects; Cognitive ability; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - metabolism; Coumestrol; Coumestrol - pharmacology; Coumestrol - therapeutic use; Estrogens; Glial fibrillary acidic protein; Gliosis; Hippocampus; Hypoxia; Hypoxia-Ischemia, Brain - drug therapy; Hypoxia-Ischemia, Brain - metabolism; Injury prevention; Ischemia; Male; Maze Learning - drug effects; Mitochondria; Mitochondria - drug effects; Mitochondria - metabolism; Morbidity; Neonatal hypoxia-ischemia; Neonates; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Phytoestrogens; Phytoestrogens - pharmacology; Phytoestrogens - therapeutic use; Rats; Rats, Wistar; Reactive oxygen species; Reactive Oxygen Species - metabolism; Rodents; Spatial analysis
• ISSN: 0736-5748; 1873-474X
• DOI: 10.1016/j.ijdevneu.2019.10.009

•Neonatal hypoxia-ischemia (HI) is one of the main causes of permanent brain damage.•Coumestrol has promising effects against cell damage caused by neonatal HI.•Coumestrol administration blocked the late reactive astrogliosis after HI insult.•A possible mechanism of coumestrol is the maintenance of mitochondrial function.•This the first study to report neuroprotection by Coumestrol in rat neonatal HI. 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 isoflavonoid with a protective effect against ischemic brain damage in adult rats. Our aim was to determine if coumestrol treatment following neonatal HI attenuates the long-term cognitive deficits induced by neonatal HI, as well as to investigate one possible mechanism underlying its potential effect. 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 deficits 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 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. Present data suggest that coumestrol exerts protection against experimental neonatal brain hypoxia-ischemia through, at least in part, early modulation of mitochondrial function.