Effects of Orexin-A/OX1R/OX2R on iron death and lipid peroxidation regulation in chronic unpredictable mild stress depressed rats
10.3969/j.issn.1006-5725.2025.16.010
- VernacularTitle:食欲素A、食欲素受体1和2对慢性不可预测轻度应激抑郁大鼠铁死亡及脂质过氧化调控的影响
- Author:
Zhen ZHANG
1
;
Ming CHENG
1
;
Zhaoshu JIANG
1
;
Jie YANG
1
;
Zhenliang LUO
1
;
Feng CAO
1
Author Information
1. 贵州中医药大学中医养生学院(贵州 贵阳 550025)
- Publication Type:Journal Article
- Keywords:
orexin;
depression;
iron death;
lipid peroxidation;
orbitofrontal cortex
- From:
The Journal of Practical Medicine
2025;41(16):2507-2514
- CountryChina
- Language:Chinese
-
Abstract:
Objective To investigate whether orexin A(orexin-A),orexin receptor 1(OX1R)and orexin receptor 2(OX2R)are involved in iron death and lipid peroxidation regulation in chronically unpredictable mild stress(CUMS)depressed rats.Methods Forty rats were randomly divided into a normal group(NC group),a modeling group(Mod group),an exogenous Orexin-A group(Orexin-A group,),and an OX1R/OX2R blocker group(TCS1102 group),with 10 rats in each group.After modeling,behavioral changes were observed using the absent field test(OFT),sugar-water preference test(SPT)and forced swimming test(FST),action potential(PA)and resting membrane potential(Vm)were detected by diaphragm-clamp technique,Orexin-A/OX1R/OX2R protein expression in orbital frontal cortex(OFC)tissues was detected by protein immunoblotting(WB)method,RT-PCR The mRNA expression of glutathione peroxidase 4(GPX4),long chain acyl coenzyme A synthase 4(ACSL4)and cysteine/glutamate transporter light chain(SLC7A11)were detected by RT-PCR method,and the intensity of the expression of rat glial fibrillary acidic protein(GFAP)and lipid peroxidation product 4-hydroxynon-enal(4-HNE)was labeled by immunofluorescence.Results Compared with the NC group,there were significant differences in OFT,SPT and FST behavioral in the Mod group(P<0.01),with lower number of PA issuance(P<0.001),higher Vm(P<0.01),and higher expression of Orexin-A/OX1R/OX2R proteins(P<0.01,P<0.001,and P<0.001).GPX4/SLC7A11 mRNA expression was decreased(P<0.01),ACSL4 mRNA expression was elevated(P<0.01),and the fluorescence intensity expression of both GFAP and 4-HNE was elevated(P<0.001);the number of PA issuance was decreased in the Orexin-A group compared to the Mod group(P<0.05),and the Orexin-A/OX1R/OX2R protein expression was elevated(P<0.05,P<0.01),GPX4/SLC7A11 mRNA ex-pression was decreased(P<0.05),ACSL4 mRNA expression was elevated(P<0.05),and the fluorescence in-tensity of GFAP and 4-HNE expression was elevated(P<0.05,P<0.01);the TCS1102 group had higher expres-sion of GFAP and 4-HNE in the behavioral,Orexin-A/OX1R/OX2R protein expression,PA and Vm,GPX4/SLC7A11/ACSL4 mRNA,and GFAP and 4-HNE fluorescence intensity expression showed a reversed trend.Con-clusions Orexin-A/OX1R/OX2R is involved in the regulation of iron death and lipid peroxidation in CUMS de-pressed rats,and the mechanism may be that Orexin-A enhances the excitability of OFC neurons by activating the OX1R/OX2R signaling pathway,up-regulates the expression of the key factor of iron death,ACSL4/4-HNE,and decreases the expression of GPX4/SLC7A11,which promotes lipid peroxidation and iron death.
