多奈哌齐联合美多芭对帕金森病大鼠神经细胞凋亡及认知功能的影响OA北大核心CSTPCD
Impacts of donepezil combined with Madopar on neuronal apoptosis and cognitive function in Parkinson's disease rats
目的:探究多奈哌齐联合美多芭对帕金森病(PD)大鼠神经细胞凋亡及认知功能的影响及其可能的作用机制.方法:造模成功的PD大鼠分为模型组(生理盐水)、美多芭组(11.0 mg/kg美多芭)、多奈哌齐组(0.6 mg/kg盐酸多奈哌齐)、多奈哌齐+美多芭组(11.0 mg/kg美多芭+0.6 mg/kg盐酸多奈哌齐),另取12只大鼠作为假手术组(生理盐水).评估各组大鼠运动功能、认知功能;免疫组化检测酪氨酸羟化酶(TH)阳性表达;Western blot检测TH蛋白、细胞凋亡相关蛋白(cleaved caspase-3、Bax、Bcl-2)及PI3K/AKT通路相关蛋白表达水平;TUNEL染色检测细胞凋亡率;商品化试剂盒检测氧化应激指标(MDA、SOD、GSH-Px)和炎症因子(IL-6、IL-18、TNF-α)水平.结果:与假手术组比较,模型组大鼠旋转圈数增加,掉落潜伏期缩短,自发交替行为(SAB)正确率降低,逃避潜伏期延长,跨越原平台次数减少,脑黑质TH阳性表达、TH和Bcl-2蛋白表达水平、SOD和GSH-Px活性及p-PI3K/PI3K、p-AKT/AKT降低,脑黑质神经细胞凋亡率、cleaved caspase-3和Bax蛋白表达水平、MDA含量及IL-6、IL-18、TNF-α水平升高(P<0.05);而美多芭、多奈哌齐及多奈哌齐+美多芭均能够减少PD大鼠的旋转圈数,延长掉落潜伏期,升高SAB正确率,缩短逃避潜伏期,增加跨越原平台次数,升高脑黑质TH阳性表达、TH和Bcl-2蛋白表达水平、SOD和GSH-Px活性及p-PI3K/PI3K、p-AKT/AKT,降低脑黑质神经细胞凋亡率、cleaved caspase-3和Bax蛋白表达水平、MDA含量及IL-6、IL-18、TNF-α水平(P<0.05),且多奈哌齐+美多芭组的作用效果显著优于美多芭组、多奈哌齐组(P<0.05).结论:多奈哌齐联合美多芭可降低PD大鼠氧化应激和炎症反应,提高认知功能,可能通过激活PI3K/AKT通路实现.
Objective:To explore the impacts and possible mechanism of donepezil combined with Madopar on neuronal apop-tosis and cognitive function in Parkinson's disease(PD)rats.Methods:The PD rats with successful modeling were grouped into model group(normal saline),Madopar group(11.0 mg/kg Madopar),donepezil group(0.6 mg/kg donepezil hydrochloride),and donepezil+Madopar group(11.0 mg/kg Medopa+0.6 mg/kg donepezil hydrochloride),another 12 rats were taken as the sham operation group(normal saline).The motor function and cognitive function of the rats in each group were evaluated;the positive expression of tyrosine hydroxylase(TH)was detected by immunohistochemistry;Western blot was used to detect the expression levels of TH protein,apop-tosis related proteins(cleaved caspase-3,Bax,Bcl-2)and PI3K/AKT pathway related proteins;TUNEL staining was used to detect the apoptosis rate;commercial kits were applied to detect the levels of oxidative stress indicators(MDA,SOD,GSH-Px)and inflam-matory factors(IL-6,IL-18,TNF-α).Results:Compared with the sham operation group,the number of rotations in model group was increased,the fall latency was shortened,the spontaneous alternation behavior(SAB)correct rate was reduced,the escape latency was prolonged,and the number of crossing the original platform was reduced,the positive expression of TH in the substantia nigra,the expression levels of TH and Bcl-2 proteins,the activities of SOD and GSH-Px,p-PI3K/PI3K and p-AKT/AKT were decreased,the apoptosis rate of substantia nigra neurons,the expression levels of cleaved caspase-3 and Bax proteins,the content of MDA,the levels of IL-6,IL-18 and TNF-α were increased(P<0.05);the Madopar,donepezil and donepezil+Madopar could reduce the number of rotations,prolong the fall latency,increase the SAB correct rate,shorten the escape latency,and increase the number of crossing the original platform in PD rats,increased the positive expression of TH in the substantia nigra,the expression levels of TH and Bcl-2 proteins,the activities of SOD and GSH-Px,p-PI3K/PI3K and p-AKT/AKT,decreased the apoptosis rate of substantia nigra neurons,the expression levels of cleaved caspase-3 and Bax proteins,the content of MDA,and the levels of IL-6,IL-18 and TNF-α(P<0.05),and the effect of donepezil+Madopar group were significantly better than that of Madopar group and donepezil group(P<0.05).Conclusion:Donepezil combined with Madopar can reduce oxidative stress and inflammatory reaction in PD rats,and improve cogni-tive function,which may be achieved by activating PI3K/AKT pathway.
鲁立颖;王琳
天津市北辰医院神经内科,天津 300400
临床医学
多奈哌齐美多芭帕金森病凋亡认知功能PI3K/AKT通路
DonepezilMadoparParkinson's diseaseApoptosisCognitive functionPI3K/AKT pathway
《中国免疫学杂志》 2024 (010)
2064-2070 / 7
北辰区卫健系统科技项目(SHGY-2021019).
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