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

Abstract

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 (ERα)/estrogen receptor β (ERβ) 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 ERα and ERβ were detected in vitro and in vivo, respectively. ICA pretreatment was also supplemented with the autophagy inhibitor 3-methyladenine (3-MA), ERα inhibitor methylpiperidino pyrazole (MPP), and ERβ 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 ERα/ERβ 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 ERα and ERβ proteins in HIBD newborn mice. Both MPP and PHTPP administration significantly inhibited the expression levels of the ERα and ERβ 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 ERα and ERβ pathways, thus reducing the apoptosis induced by HIBD and exerting a neuroprotective effect on neonatal mice with HIBD.

Chinese herbal medicine and its active compounds in attenuating renal injury via regulating autophagy in diabetic kidney disease

“…Icariin is a flavonoid glycoside extracted from the medicinal plant Epimedium (184). Icariin exerts renal protection through multiple bioactivities such as anti-fibrosis (50, 185), anti-inflammatory (186,187), and anti-oxidative stress (186).…”

TrkB-mediated neuroprotection in female hippocampal neurons is autonomous, estrogen receptor alpha-dependent, and eliminated by testosterone: a proposed model for sex differences in neonatal hippocampal neuronal injury

“…In addition to adult models of ischemia, other investigators have shown that ERα plays a role in neuroprotection during the neonatal period. Ircariin, which is a flavonoid glycoside, exerts a neuroprotective effect both in P7 mice following the Vannucci’s model of HI and in a mouse hippocampal neuronal cell line (HT22) during OGD by activating ERα and reducing apoptosis [ 25 ]. When P6 rat pups or the immature oligodendroglia cell line (OLN-93) is exposed to hypoxia estradiol prevents neonatal oxygen-induced white matter injury [ 26 ].…”