Neuroprotective effect of pretreatments with different doses of esketamine on ischemic brain injury in mice
Objective To investigate the neuroprotective role of pretreatments with different doses of esketamine in mice with ischemic brain injury and explore its potential mechanisms.Methods Forty-four adult male C57BL/6 mice were randomly divided into sham-operation group,model group,low-dose group and high-dose group,with 11 mice in each group.The focal cerebral ischemia models were established in model group,low-dose group and high-dose group by permanent ligation of the right middle cerebral artery and temporary occlusion of the bilateral common carotid arteries.The mice in sham-operation group were only exposed the arteries without any occlusion treatment.The mice in low-dose group and high-dose group were respectively intraperitoneally injected with 6 and 12 mg/kg of esketamine before clamping the bilateral common carotid arteries,and the mice in sham-operation group and model group were intraperitoneally injected with equivalent volume of normal saline.At 24 h after model establishment,both the Longa score and double-sided sticker removal experiment were used to observe the neurobehavioral changes in four groups.Real-time fluorescence quantitative PCR was used to detect the relative expressions of inducible nitric oxide synthase(iNOS),arginase-1(Arg-1)and Beclin 1 mRNAs in the ischemic cerebral tissues.At 72 h after model establishment,TTC staining was performed to observe the cerebral infarct area.Results(1)The Longa score was significantly higher in model group(2.36±0.51)than that in sham-operation group(0),low-dose group(1.27±0.47)and high-dose group(1.91±0.54)(P＜0.05),higher in low-dose and high-dose groups than that in sham-operation group(P＜0.05),and higher in high-dose group than that in low-dose group(P＜0.05).The time for touching sticker and time for removing stickers were longer in model group[(23.18±2.36),(26.36±1.96)s]than those in sham-operation group[(5.27± 1.42),(6.73±1.95)s],low-dose group[(6.73±1.42),(8.82±1.89)s]and high-dose group[(15.65±3.08),(18.91±3.11)s](P＜0.05),were longer in high-dose group than those in sham-operation and low-dose groups(P＜0.05),and showed no significant difference between sham-operation and low-dose groups(P＞0.05).(2)The cerebral infarct area was larger in high-dose group[(23.45±0.84)％]than that in sham-operation group(0),model group[(19.03±0.99)％]and low-dose group[(15.98±0.97)％](P＜0.05),larger in model and low-dose groups than that in sham-operation group(P＜0.05),and larger in model group than that in low-dose group(P＜0.05).(3)The relative expressions of Arg-1 and iNOS mRNAs in the ischemic cerebral tissues were lower in sham-operation group(0.99±0.15,1.00±0.29)than those in model group(12.37±2.99,4.17±0.76),low-dose group(17.16±3.78,2.02±0.21)and high-dose group(5.64±0.51,1.94±0.21)(P＜0.05).The relative expression of Arg-1 mRNA was lower in model group and high-dose group than that in low-dose group(P＜0.05),and lower in high-dose group than that in model group(P＜0.05).The relative expression of iNOS mRNA was lower in low-dose and high-dose groups than that in model group(P＜0.05),and showed no significant difference between low-dose and high-dose groups(P＞0.05).The relative expression of Beclin 1 mRNA was lower in low-dose group(0.35±0.03)than that in sham-operation group(0.73±0.18),model group(0.91±0.08)and high-dose group(0.87±0.06)(P＜0.05),was higher in model group than that in sham-operation group(P＜0.05),and showed no significant difference between model and high-dose groups(P＞0.05)and between high-dose and sham-operation groups(P＞0.05).Conclusions A low-dose esketamine can exert neuroprotection by promoting transformation of microglia from phenotype Ml to M2,inhibiting neuroinflammatory response and decreasing autophagy in the ischemic cerebral area.However,a high-dose esketamine has no significant protection against ischemic brain injury.
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