Study On The Relationship Between Histone Acetylation And Depression And Antidepressant Effect Of Sodium Valproate

【Objective】 To investigate the relationship between histone acetylationand depression and the antidepressant effect of sodium valproate (VPA) in achronic unpredicted stress induced rat depression model【Methods】Sixty Male Sprague-Dawley (SD) rats were divided intocontrol group (CG), model group (MG), VPA-treated model group (VPAM)and VPA-treated control group (VPAC). The depression model wasestablished by chronic unpredicted stress (CUS) with solitary feed. VPA(300mg/kg once daily) was administered to rats (VPAM and VPAC) byintragastric gavage, and the same volume of vehicle was given to rats in theVM and VC groups. Open field test (OFT), forced swim test (FST) wereused to evaluate the depressant behavior. Hippocampus pathomorphologywas observed with HE staining. Malondialdehyde (MDA) level, superoxidedismutase (SOD) and catalase (CAT) activities in the serum, cortex andhippocampus, corticosterone (CORT) level in the serum, mRNA expressionof TH, TPH in the cortex and TH, TPH, BDNF, MAO-A, IDO and GSK-3βin the hippocampus and CRF in the hypothalamus, as well as protein expression of acH3K9, acH3K14, acH4K12, HDAC5, TH and TPH in thehippocampus, TH and TPH in the cortex and CRF in the hypothalamuswere determined.【Results】1. Compared with control rats, model rats showed a significant decrease ofhorizontal and vertical movements scores in OFT and more immobilityin FST. VPA administration obviously prevented rats from decreasingactivities, compared with model rats. However VPA administration hadno significant influences on behaviors of control rats.2. Compared with control rats, model rats showed a significant increase inthe MDA levels, distinct decrease in SOD and CAT activities in theserum, hippocampus and cortices, and a significant increase in CORTlevel in the serum. VPA administration markedly inhibited thesechanges but it had no effects on control rats.3. The expression of acH3K9, acH3K14and acH4K12showed significantdecrease but HDAC5showed increase in the hippocampus of model rats,compared with control rats. VPA administration significantly preventedthe changes of acH3K9, acH3K14and HDAC5but it had no effects onacH4K12. VPA administration had no influence on control rats.4. Compared with control rats, the TH, TPH expression in the hippocampusand cortex and BDNF expression in the hippocampus showed decrease,but the MAO-A, IDO and GSK-3β expression in the hippocampus and CRF expression in the hypothalamus showed increase significantly inmodel rats. VPA treatment markedly inhibited these changes but it hadno effects on control rats.5. The layer of hippocampus pyramidal cells became thinner withkaryopyknosis and chromatin concentration were observed in modelrats, compared with control rats. VPA treatment was beneficial in themodel rats but had no influence on control rats.【C onclusion】1. CUS with solitary feed can induce depression-like behaviors of ratswith pathomophorlogical changes of hippocampal neurocytes.2. The mechanisms may involve the imbalance of oxidative stress andanti-oxidative stress systems, HPA axis dysfunction, inhibition ofhistone acetylation modification (acH3K9, acH3K14, acH4K12),decrease of BDNF, TH and TPH expression, and increase of IDO,MAO-A and GSK-3β expression.3. VPA can improve depression-like behaviors in CUS rats, themechanisms may involve reversing oxidative stress and anti-oxidativestress systems imbalance and improving HPA axis function, besidesinhibiting HDAC5, elevating histone avetylation modification, inducingBDNF, TH and TPH expression, and inhibiting IDO, MAO-A andGSK-3β overexpression.