组蛋白乙酰化及抑郁症相关基因表达研究和丙戊酸钠的干预作用
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摘要
【目的】研究组蛋白乙酰化及相关基因表达与慢性不可预见刺激致大鼠抑郁症的关系及丙戊酸钠的干预作用
【方法】雄性SD大鼠60只，随机分为对照组（control group，CG）、模型组（model group，MG）、丙戊酸钠灌胃处理的模型组（sodiumvalproate-treated model group，VPAM）及对照组（sodium valproate-treated control group，VPAC）。丙戊酸钠（300mg/kg/d）及相同体积溶剂分别灌胃给予实验大鼠。采用孤养结合慢性不可预见刺激建立大鼠抑郁症模型。以开场实验、被动游泳实验评价大鼠抑郁行为；采用常规生物化学方法测定大鼠血清、大脑皮质和海马MDA含量及SOD、CAT活力；采用放射免疫法测定血清CORT水平；以HE染色观察海马病理形态学改变；采用Real Time-PCR法检测大脑皮层和海马TH、TPH，海马BDNF、MAO-A、IDO、GSK-3β及下丘脑CRF mRNA表达；以Western Blotting法检测大脑皮层和海马TH、TPH,海马acH3K9、acH3K14、acH4K12、HDAC5及下丘脑CRF蛋白表达。观察丙戊酸钠给予对CUS致大鼠抑郁行为的干预作用以及对正常大鼠的影响。
【结果】
1.模型组大鼠开场实验水平运动、垂直运动得分、被动游泳实验不动时间均显著低于对照组大鼠；丙戊酸钠显著阻遏CUS所致的上述行为学改变而对对照组大鼠行为无明显影响。
2.与对照组大鼠相比，模型组大鼠血清、大脑皮层和海马MDA含量显著升高而SOD、CAT活力显著降低，血清CORT显著升高；丙戊酸钠给予能明显抑制CUS所致的上述改变而对对照组大鼠无明显影响。
3.与对照组大鼠相比，模型组大鼠海马acH3K9、acH3K14、acH4K12表达显著降低而HDAC5表达显著增高；丙戊酸钠给予能显著增加模型组大鼠acH3K9、acH3K14表达而对acH4K12无显著影响，但显著抑制HDAC5表达；丙戊酸钠对对照组大鼠无显著影响。
4.与对照组大鼠相比，模型组大鼠大脑皮层TH、TPH和海马TH、TPH、BDNF表达均显著降低，而海马MAO-A、IDO、GSK-3β及下丘脑CRF表达显著增高。丙戊酸钠给予能明显抑制CUS所致的上述改变而对对照组大鼠无明显影响。
5.与对照组大鼠相比，模型组大鼠海马出现显著的神经细胞核染色质深染、核固缩、核碎裂等病理形态学改变；丙戊酸钠给予能明显阻遏CUS所致的模型组大鼠海马神经细胞损伤而对对照组大鼠无显著影响。
【结论】
1.孤养结合慢性不可预见刺激致大鼠出现明显抑郁症样行为和海马神经细胞病理形态学改变。
2.其发生机制可能与孤养结合慢性不可预见刺激致机体抗氧化应激系统功能失衡，导致HPA轴功能紊乱，组蛋白乙酰化修饰率降低，继而下调BDNF、TH、TPH表达和上调IDO、MAO-A、GSK-3β表达相关。
3.丙戊酸钠灌胃给予可改善大鼠抑郁行为。其机制除抑制HDAC5表达和提升组蛋白乙酰化水平，进而促进BDNF、TH、TPH而抑制IDO、MAO-A、GSK-3β的表达外，还可能涉及纠正氧化-抗氧化应激功能失衡和改善HPA轴功能有关。
【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.
【方法】雄性SD大鼠60只，随机分为对照组（control group，CG）、模型组（model group，MG）、丙戊酸钠灌胃处理的模型组（sodiumvalproate-treated model group，VPAM）及对照组（sodium valproate-treated control group，VPAC）。丙戊酸钠（300mg/kg/d）及相同体积溶剂分别灌胃给予实验大鼠。采用孤养结合慢性不可预见刺激建立大鼠抑郁症模型。以开场实验、被动游泳实验评价大鼠抑郁行为；采用常规生物化学方法测定大鼠血清、大脑皮质和海马MDA含量及SOD、CAT活力；采用放射免疫法测定血清CORT水平；以HE染色观察海马病理形态学改变；采用Real Time-PCR法检测大脑皮层和海马TH、TPH，海马BDNF、MAO-A、IDO、GSK-3β及下丘脑CRF mRNA表达；以Western Blotting法检测大脑皮层和海马TH、TPH,海马acH3K9、acH3K14、acH4K12、HDAC5及下丘脑CRF蛋白表达。观察丙戊酸钠给予对CUS致大鼠抑郁行为的干预作用以及对正常大鼠的影响。
【结果】
1.模型组大鼠开场实验水平运动、垂直运动得分、被动游泳实验不动时间均显著低于对照组大鼠；丙戊酸钠显著阻遏CUS所致的上述行为学改变而对对照组大鼠行为无明显影响。
2.与对照组大鼠相比，模型组大鼠血清、大脑皮层和海马MDA含量显著升高而SOD、CAT活力显著降低，血清CORT显著升高；丙戊酸钠给予能明显抑制CUS所致的上述改变而对对照组大鼠无明显影响。
3.与对照组大鼠相比，模型组大鼠海马acH3K9、acH3K14、acH4K12表达显著降低而HDAC5表达显著增高；丙戊酸钠给予能显著增加模型组大鼠acH3K9、acH3K14表达而对acH4K12无显著影响，但显著抑制HDAC5表达；丙戊酸钠对对照组大鼠无显著影响。
4.与对照组大鼠相比，模型组大鼠大脑皮层TH、TPH和海马TH、TPH、BDNF表达均显著降低，而海马MAO-A、IDO、GSK-3β及下丘脑CRF表达显著增高。丙戊酸钠给予能明显抑制CUS所致的上述改变而对对照组大鼠无明显影响。
5.与对照组大鼠相比，模型组大鼠海马出现显著的神经细胞核染色质深染、核固缩、核碎裂等病理形态学改变；丙戊酸钠给予能明显阻遏CUS所致的模型组大鼠海马神经细胞损伤而对对照组大鼠无显著影响。
【结论】
1.孤养结合慢性不可预见刺激致大鼠出现明显抑郁症样行为和海马神经细胞病理形态学改变。
2.其发生机制可能与孤养结合慢性不可预见刺激致机体抗氧化应激系统功能失衡，导致HPA轴功能紊乱，组蛋白乙酰化修饰率降低，继而下调BDNF、TH、TPH表达和上调IDO、MAO-A、GSK-3β表达相关。
3.丙戊酸钠灌胃给予可改善大鼠抑郁行为。其机制除抑制HDAC5表达和提升组蛋白乙酰化水平，进而促进BDNF、TH、TPH而抑制IDO、MAO-A、GSK-3β的表达外，还可能涉及纠正氧化-抗氧化应激功能失衡和改善HPA轴功能有关。
【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.
引文
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