糖皮质激素治疗对单纯疱疹病毒性脑炎预后的影响

Delayed Dexamethasone Treatment in Combination with Acyclovir Protect Experimental Herpes Simplex Encephalitis in Mice

目的探讨不同时间点糖皮质激素联合抗病毒药物治疗对单纯疱疹病毒性脑炎预后的影响。方法小鼠随机分为对照组、HSV-1感染组(感染组)、阿昔洛韦治疗组(阿昔洛韦组)、地塞米松早期干预组(早期干预组)和地塞米松延迟干预组(延迟干预组)5组。采用流式细胞术测定脑组织小胶质细胞表面抗原CD11b,并用反转录-聚合酶链反应(RT-PCR)检测促炎性细胞因子TNF-αI、L-6表达,通过脑组织病理切片观察组织形态学变化。病毒感染后第5天对小鼠进行神经功能评分,2周后应用Kaplan-Meier法对各组小鼠进行生存率分析。结果病毒感染后第7天,与对照组比较,感染组脑组织CD11b阳性细胞及促炎性细胞因子明显增多(P<0.01),小胶质细胞激活,早期干预组可见小胶质细胞明显激活伴大量促炎性细胞因子产生(P<0.05);与感染组比较,阿昔洛韦组和延迟干预组小胶质细胞激活减少(P<0.01),促炎性细胞因子降至正常水平。延迟干预组与阿昔洛韦组相比小胶质激活减少(P<0.01),促炎性细胞因子表达及生存率无显著差异(P>0.05);与早期干预组比较,延迟干预组CD11b及促炎性细胞因子表达均明显减少(P<0.01),小鼠脑组织病理改变减轻,神经功能评分与生存率均明显提高(P<0.05)。结论在抗病毒治疗基础上,延迟给予糖皮质激素治疗可改善单纯疱疹病毒性脑炎预后。

Objective To evaluate the effects of early versus delayed glucocorticoid administration in combination with antivirus drug in a model of herpes simplex encephalitis. Methods Mice were randomly assigned to 5 groups with 15 mice in each： normal control group（NC）, HSV 1 infected group（HC）, Acyclovir treated group （HA）, early dexamethasone administration group （DE）, delayed dexamethasone administration group（DD）. Flow cytometry was adopted to detect CD11b expression in the brain tissue. We used semiquantitative reverse transcription polymerase chain reaetion（RT-PCR） to detect proinflammatory cytokines TNF-α and IL-6. Pathologic slices of brain tissues of mice were used to identify tissue morphology differences.Neurological score was quantified using an established neurological scale on 5 d after HSV-1 encephalitis. Differences in cumulative survival among the groups were analyzed according to Kaplan-Meier followed by a logrank test 2 weeks after viral infection. Results After HSV-1 infection, brain tissue CD11b and cytokines were significantly increased compare with NC group （P〈0.01）, meaning that microglial cells were activated. DE group （started immediately after infection） showed still obviously microglial activation associated with vigorous eytokines production compare with NC group. CD11b expression in HA and DD group were decreased compare with HC group （P〈0.01）, cytokines reduced to normal levels. CD11b in HA group was higher than DD group （P〈0.01）, however there were no significant difference of cytokines expression and cumulative survival （P〉0.05）. DD group （started 3 d after infection） inhibited CD11b and attenuated proinflammatory cytokines expression （P〈0.01）, and also showed attenuated brain tissue pathological changes compare with DE group. Neurological score and cumulative survival were higher in DD group than in DE group （P〈0.05）. Conclusions Delayed but not early dexamethasone treatment in combination with acyclovir protect experimental HSV-1 encephalitis in mice.