Impacts of donepezil combined with Madopar on neuronal apoptosis and cognitive function in Parkinson's disease rats
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.
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