Dexmedetomidine Combined With Fluoxetine Attenuate PTSD-Like Behaviors By Inhibiting ERS And Alleviating Apoptosis Of Hippocampal Neurons In Mice

Objective: Post-traumatic stress disorder(PTSD)is a chronic mental illness that usually occurs after life-threatening events such as wars,car accidents,natural disasters and other death threats or severe traumatic events.The drugs currently approved for the treatment of PTSD are not effective in the treatment of PTSD due to their low effective rate and long onset time.Therefore,there is an urgent need to explore combined drug regimens.At present,studies have shown that both dexmedetomidine(DEX)and fluoxetine(FLX)can exert neuroprotective effects by inhibiting ERS and alleviating apoptosis,but whether the combination of the two drugs will have a positive effect and the mechanism of the effect is unclear.This study aims to evaluate the combined use of dexmedetomidine.Whether DEX and FLX can improve the symptoms of PTSD compared with single drug,and further discuss the possible mechanism of their effect is related to the apoptosis mediated by endoplasmic reticulum stress.Methods: In this study,a mouse model of PTSD was induced by SPS&S.80 mice were randomly divided into five groups:(1)Sham group(2)SPS&S group(3)DEX group(4)FLX group(5)DEX+FLX group,among the 16 mice in each group,8 mice were used for open field and elevated plus maze experiments,and 8 mice were used for Morris water maze experiments,The reason for doing this is to better reduce the interference between neuroethology.In the DEX group,20 μg/kg dexmedetomidine was injected every day for 7 consecutive days.The FLX group was orally administered fluoxetine 10 mg/kg per day for seven consecutive days.The DEX+FLX group was treated with dexmedetomidine and fluoxetine as above.The sham group was given the same amount of normal saline by intraperitoneal injection and gavage at the same time.We used open field test,elevated plus maze test to evaluate the anxiety state of mice,and Morris water maze to evaluate the spatial memory and learning ability of mice.The apoptosis of hippocampus CA1 area was evaluated by TUNEL method.The expressions of endoplasmic reticulum stress-related proteins GRP78 and CHOP were detected by immunofluorescence technology,and the expressions of GRP78,CHOP,Caspase-12,Caspase-3,Bcl-2 and Bax proteins were detected by Western blot and qRT-PCR.Results: Although dexmedetomidine and fluoxetine alone can improve the anxiety state and learning and memory ability of SPS& S mice(P<0.01),the combination of dexmedetomidine and fluoxetine can achieve better therapeutic effect(P<0.001).After drug treatment,the number of apoptotic neurons in the hippocampal CA1 area of the combined dexmedetomidine and fluoxetine group was significantly less than that of other groups(P<0.01),and the expression of anti-apoptotic protein Bcl-2 was compared with that of other groups significantly increased(P<0.001),and the expressions of pro-apoptotic proteins Caspase-3,Bax,and Caspase-12 were significantly lower compared with other groups(P<0.01).Similarly,in terms of the expression of endoplasmic reticulum stress marker proteins,compared with other groups,the expression of CHOP and GRP78 in the combined drug group was significantly lower(P<0.01).Conclusion: Dexmedetomidine combined with Fluoxetine attenuate PTSD-like behaviors by inhibiting ERS and alleviating apoptosis of hippocampal neurons in mice.