Acupuncture can reduce cognitive deficits in Alzheimer’s disease.However,whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood.Studies have sho...Acupuncture can reduce cognitive deficits in Alzheimer’s disease.However,whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood.Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline.Therefore,we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications.A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks.Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration.Preventive electroacupuncture alleviated memory impairment,decreased tau hyperphosphorylation,and reduced glycogen synthase kinase-3βprotein and mRNA expression levels in the brainstem dorsal raphe nucleus,where intracellular neurofibrillary tangle lesions first occur.In addition,the DNA methylation level in the promoter region of the glycogen synthase kinase-3βgene was increased.The effects of preventive electroacupuncture were stronger than those of preventive acupuncture.Intraperitoneal injection of 0.4 mg/kg 5-aza-2ʹ-deoxycytidine,an inhibitor of DNA methyltransferase that blocks epigenetic modifications,antagonized the effects of preventive electroacupuncture.Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3βgene in the dorsal raphe nucleus.This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine,China(approval No.HUCMS201712001)on November 28,2017.展开更多
Objective:To observe the effect of the early intervention with moxibustion at "Shènshū(肾俞BL23)" on learning and memory of Alzheimer’s disease(AD) rats modeled by ovariectomy and D-Galactose(D-Gal)in...Objective:To observe the effect of the early intervention with moxibustion at "Shènshū(肾俞BL23)" on learning and memory of Alzheimer’s disease(AD) rats modeled by ovariectomy and D-Galactose(D-Gal)injection and the effect on Ca2+/CaMKII/CREB signaling pathway so as to provide the evidence for the acupoint selection in the early intervention with acupuncture and moxibustion for AD.Methods:Sixty female SD rats at the age of 3 months were selected and randomly divided into a normal group,a sham-operation group,a model group,a "BL23" group,a "Wèishū"(胃俞BL21) group,and a non-acupoint group,10 rats in each group.Except in the normal group and the sham-operation group,bilateral ovaries were removed in the other 4 groups.3 days after the operation,D-Gal was injected intraperitoneally at a dose of 150 mg/kg/d for 90 days to establish AD rat model.In the sham-operation group,only the peripheral fat of ovarian was removed and 0.9% normal saline was injected intraperitoneally of the same dose for 90 days.In the "BL23" group,the "BL21" group and the non-acupoints group,since the 2 nd day after ovariectomy,moxibustion was applied at 9:00 a.m.every day in the rats.The rats were fixed on a fixed table,the mild moxibustion with self-prepared moxa stick was applied to bilateral "BL23""BL21" and the non-acupoint of each rat,the ignited end of moxa stick was 2 cm to 3 cm far from skin surface.The infrared thermometer was adopted to measure the temperature of the epidermis of each acupoint from time to time so as to maintain the local temperature to be(41 ± 0.5)℃.Mild moxibustion lasted for 10 min each time,consecutively for 5 days a week and at an interval of 2 days.The total consecutive intervention duration was 12 weeks.In the normal group and the shamoperation group,no moxibustion intervention was performed,but the rats were restricted in a same way during the experiment.At the end of modeling and intervention,water maze test was adopted to detect the learning and memory abilities of rats in each group.The western blotting was used to detect the expressions of p-CREB,p-CaMKII,CaMKII and CREB in hippocampus of rats in each group.Results:(1)Navigation test:since Day 72,compared with the sham-operation group,the escape latencies in all of the consecutive 5 days were longer in the model group(all P <0.05).Since Day 73,compared with the normal group,the escape latency in all of the consecutive 4 days was shorter in the "BL23"group(all P <0.05).(2) Times across platform:compared with the normal group,the number of times consecutively crossing the platform was lower in the model group(P <0.05).After moxibustion,compared with the model group,the number of times across platform was higher in the "BL23"group,indicating a statistical significance(P <0.05).(3)Moving track of water maze spatial probe:the "tendency"strategy was displayed in the normal group and the sham operation group.The "marginal" strategy,which is commonly seen in the AD rats,was displayed in the model group.The "random" strategy was displayed in the "BL23" group.The "marginal" strategy was presented in the "BL21" group and the non-acupoint group.(4) Expressions of hippocampal P-CAMKII,CAMKII,CREB and P-CREB in the rats:compared with the normal group,the phosphorylation degrees of CAMKII and CREB were significantly reduced(both P<0.05) in the model group.In 12 weeks of moxibustion,compared with the model group,the levels of P-CAMKII and P-CREB were increased in the "BL23" group and the "BL21" group(all P <0.05) and the levels in the "BL23" group were higher than that of the "BL21" group and the non-acupoint group(all P<0.05).Conclusion:Moxibustion at "BL23" achieves a better effect in improving the learning and memory of AD rats modeled by ovariectomy and D-Gal injection as compared with moxibustion at "BL21" and the non-acupoint.The effect mechanism is potentially related to the effective activation of Ca2+/CaMKII/CREB signaling pathway.展开更多
基金This work was supported by the National Natural Science Foundation of China,Nos.81373741(to LHK),81473786(to YJD),81873380(to YJD)Sun Guojie Inheritance Base for TCM Acupuncture-Moxibustion of World Federation of Acupuncture-Moxibustion Societies in Wuhan,China(World Federation of Acupuncture-Moxibustion Societies[2019]No.26)(to YJD)and“Wei Yizong Chiropractic Team”Project Founded by Shenzhen of China,No.SZSM201612059(to YFL).
文摘Acupuncture can reduce cognitive deficits in Alzheimer’s disease.However,whether electroacupuncture can prevent or alleviate the cognitive deficits in animal models of aging remains poorly understood.Studies have shown that disordered epigenetic modifications play a critical role in age-related cognitive decline.Therefore,we hypothesized that preventive electroacupuncture might improve cognitive functions during aging by regulating epigenetic modifications.A rat model of aging was produced by intraperitoneal injection of 120 mg/kg D-galactose for 8 weeks.Baihui and Shenshu acupoints were stimulated by electroacupuncture for 8 weeks from the first day of D-galactose administration.Preventive electroacupuncture alleviated memory impairment,decreased tau hyperphosphorylation,and reduced glycogen synthase kinase-3βprotein and mRNA expression levels in the brainstem dorsal raphe nucleus,where intracellular neurofibrillary tangle lesions first occur.In addition,the DNA methylation level in the promoter region of the glycogen synthase kinase-3βgene was increased.The effects of preventive electroacupuncture were stronger than those of preventive acupuncture.Intraperitoneal injection of 0.4 mg/kg 5-aza-2ʹ-deoxycytidine,an inhibitor of DNA methyltransferase that blocks epigenetic modifications,antagonized the effects of preventive electroacupuncture.Our results suggest that preventive electroacupuncture treatment alleviates cognitive impairment in aging rats probably by affecting the epigenetic modification of the glycogen synthase kinase-3βgene in the dorsal raphe nucleus.This study was approved by the Animal Ethics Committee of Hubei University of Chinese Medicine,China(approval No.HUCMS201712001)on November 28,2017.
基金Supported by National Natural Science Foundation of China Project:No.81473786No.81873380。
文摘Objective:To observe the effect of the early intervention with moxibustion at "Shènshū(肾俞BL23)" on learning and memory of Alzheimer’s disease(AD) rats modeled by ovariectomy and D-Galactose(D-Gal)injection and the effect on Ca2+/CaMKII/CREB signaling pathway so as to provide the evidence for the acupoint selection in the early intervention with acupuncture and moxibustion for AD.Methods:Sixty female SD rats at the age of 3 months were selected and randomly divided into a normal group,a sham-operation group,a model group,a "BL23" group,a "Wèishū"(胃俞BL21) group,and a non-acupoint group,10 rats in each group.Except in the normal group and the sham-operation group,bilateral ovaries were removed in the other 4 groups.3 days after the operation,D-Gal was injected intraperitoneally at a dose of 150 mg/kg/d for 90 days to establish AD rat model.In the sham-operation group,only the peripheral fat of ovarian was removed and 0.9% normal saline was injected intraperitoneally of the same dose for 90 days.In the "BL23" group,the "BL21" group and the non-acupoints group,since the 2 nd day after ovariectomy,moxibustion was applied at 9:00 a.m.every day in the rats.The rats were fixed on a fixed table,the mild moxibustion with self-prepared moxa stick was applied to bilateral "BL23""BL21" and the non-acupoint of each rat,the ignited end of moxa stick was 2 cm to 3 cm far from skin surface.The infrared thermometer was adopted to measure the temperature of the epidermis of each acupoint from time to time so as to maintain the local temperature to be(41 ± 0.5)℃.Mild moxibustion lasted for 10 min each time,consecutively for 5 days a week and at an interval of 2 days.The total consecutive intervention duration was 12 weeks.In the normal group and the shamoperation group,no moxibustion intervention was performed,but the rats were restricted in a same way during the experiment.At the end of modeling and intervention,water maze test was adopted to detect the learning and memory abilities of rats in each group.The western blotting was used to detect the expressions of p-CREB,p-CaMKII,CaMKII and CREB in hippocampus of rats in each group.Results:(1)Navigation test:since Day 72,compared with the sham-operation group,the escape latencies in all of the consecutive 5 days were longer in the model group(all P <0.05).Since Day 73,compared with the normal group,the escape latency in all of the consecutive 4 days was shorter in the "BL23"group(all P <0.05).(2) Times across platform:compared with the normal group,the number of times consecutively crossing the platform was lower in the model group(P <0.05).After moxibustion,compared with the model group,the number of times across platform was higher in the "BL23"group,indicating a statistical significance(P <0.05).(3)Moving track of water maze spatial probe:the "tendency"strategy was displayed in the normal group and the sham operation group.The "marginal" strategy,which is commonly seen in the AD rats,was displayed in the model group.The "random" strategy was displayed in the "BL23" group.The "marginal" strategy was presented in the "BL21" group and the non-acupoint group.(4) Expressions of hippocampal P-CAMKII,CAMKII,CREB and P-CREB in the rats:compared with the normal group,the phosphorylation degrees of CAMKII and CREB were significantly reduced(both P<0.05) in the model group.In 12 weeks of moxibustion,compared with the model group,the levels of P-CAMKII and P-CREB were increased in the "BL23" group and the "BL21" group(all P <0.05) and the levels in the "BL23" group were higher than that of the "BL21" group and the non-acupoint group(all P<0.05).Conclusion:Moxibustion at "BL23" achieves a better effect in improving the learning and memory of AD rats modeled by ovariectomy and D-Gal injection as compared with moxibustion at "BL21" and the non-acupoint.The effect mechanism is potentially related to the effective activation of Ca2+/CaMKII/CREB signaling pathway.
基金Project supported by the National Key Research and Development Program(Nos.2018YFC1803100 and 2018YFC1802300)the National Natural Science Foundation of China(No.41877248)the Primary Research&Development Plan of Jiangsu Province(No.BE2017715),China
基金Project supported by the National Natural Science Foundation of China(No.51878160)the National Key Research and Development Program of China(No.2017YFC00703408)the Research Funding from China Huaneng Group Co.Ltd.(No.HNKJ19-H17)。
基金supported by the Innovative Research Team Program of Hainan Natural Science Fund(2018CXTD331)the Natural Science Foundation of Hainan Province(320RC504)Hainan University(KYQD(ZR)1979).