Neuroprotective Mechanism of Icariin on Hypoxic Ischemic Brain Damage in Neonatal Mice.

Objective: Our previous results showed that icariin (ICA) could inhibit apoptosis and provide neuroprotection against hypoxic-ischemic brain damage (HIBD) in neonatal mice, but the specific mechanism of its neuroprotective effect remains unknown. This study aims at exploring whether ICA plays a neuroprotective role in apoptosis inhibition by regulating autophagy through the estrogen receptor α (ER α )/estrogen receptor β (ER β ) pathway in neonatal mice with HIBD.

Methods: A neonatal mouse model of HIBD was constructed in vivo, and an oxygen and glucose deprivation (OGD) model in HT22 cells from the hippocampal neuronal system was constructed in vitro. The effects of ICA pretreatment on autophagy and the expression of ER α and ER β were detected in vitro and in vivo, respectively. ICA pretreatment was also supplemented with the autophagy inhibitor 3-methyladenine (3-MA), ER α inhibitor methylpiperidino pyrazole (MPP), and ER β inhibitor 4-(2-phenyl-5,7-bis (trifluoromethyl) pyrazolo [1,5-a] pyramidin-3-yl) phenol (PHTPP) to further detect whether ICA pretreatment can activate the ER α /ER β pathway to promote autophagy and reduce HIBD-induced apoptosis to play a neuroprotective role against HIBD in neonatal mice.

Results: ICA pretreatment significantly promoted autophagy in HIBD mice. Treatment with 3-MA significantly inhibited the increase in autophagy induced by ICA pretreatment, reversed the neuroprotective effect of ICA pretreatment, and promoted apoptosis. Moreover, ICA pretreatment significantly increased the expression levels of the ER α and ER β proteins in HIBD newborn mice. Both MPP and PHTPP administration significantly inhibited the expression levels of the ER α and ER β proteins activated by ICA pretreatment, reversed the neuroprotective effects of ICA pretreatment, inhibited the increase in autophagy induced by ICA pretreatment, and promoted apoptosis.

Conclusion: ICA pretreatment may promote autophagy by activating the ER α and ER β pathways, thus reducing the apoptosis induced by HIBD and exerting a neuroprotective effect on neonatal mice with HIBD.

Competing Interests: The authors declare that they have no conflict of interest.

(Copyright © 2022 Mengxia Wang et al.)