奥氮平通过抑制NLRP3炎症小体激活对抑郁症模型大鼠海马神经元的保护作用

岳凌峰; 仲照希; 马敬; 王宁

奥氮平通过抑制NLRP3炎症小体激活对抑郁症模型大鼠海马神经元的保护作用

The Protective Effect of Olanzapine on the Hippocampal Neuron of Depression Model Rats via Inhibiting NLRP3 Inflammasome Activation

摘要

摘要:
目的探究奥氮平(OLA)对抑郁症模型大鼠海马神经元的影响及作用机制。
方法将大鼠分为对照组、慢性不可预见性应激(CUS)组、OAL (0.5、1、2 mg/kg)组、si-Atg5及OAL (2 mg/kg)+si-Atg5组，旷场实验及糖水偏好实验评估大鼠行为学表现，Tunnel检测细胞凋亡，ELISA检测白介素(IL)-1β、IL-18质量浓度，Western blot检测cleaved Caspase-3，cleaved Caspase-9，自噬相关蛋白LC3、Beclin1、P62，炎症小体NLRP3及cleaved Caspase-1表达水平。
结果 0.5、1、2 mg/kg OAL均可增加CUS大鼠自发活动总路程、糖水消耗量及偏好率，降低大鼠IL-18血清质量浓度，海马CA3区凋亡细胞百分比，cleaved Caspase-9、cleaved Caspase-1、NLRP3表达；0.5 mg/kg OAL对cleaved Caspase-3表达及IL-1β血清质量浓度无影响，1、2 mg/kg OAL可降低cleaved Caspase-3表达及IL-1β血清质量浓度。si-Atg5可减小CUS大鼠自发活动总路程、糖水消耗量及偏好率，提高cleaved Caspase-3、cleaved Caspase-9、cleaved Caspase-1、NLRP3表达，并减弱2 mg/kg OAL产生的影响。同时，0.5、1、2 mg/kg OAL均可提高大鼠海马CA3区LC3Ⅱ/LC3Ⅰ比值及Beclin1表达；0.5 mg/kg OAL对P62表达无影响，1、2 mg/kg OAL可降低P62表达。si-Atg5可降低LC3Ⅱ/LC3Ⅰ比值及Beclin1的表达, 并减弱2 mg/kg OAL产生的作用。
结论 OAL可通过抑制NLRP3炎症小体激活对CUS大鼠海马神经元产生保护作用。

Abstract:
Objective To determine the impact olanzapine (OLA) on the hippocampal neuron of model rats with depression.
Methods Rats were divided into five groups: control, chronic unpredicted stress (CUS), OAL (0.5, 1, 2 mg/kg), si-Atg5, and OAL (2 mg/kg)+si-Atg5. Open field and sucrose preference tests were performed to evaluate rat behaviors. Cell apoptosis was detected with Tunnel. The concentrations of interleukin (IL)-1β and IL-18 were determined by ELISA. The expressions of cleaved Caspase-3, cleaved Caspase-9, LC3, Beclin1, P62, NLRP3 and cleaved Caspase-1 were measured by Western blot.
Results OAL (0.5, 1, 2 mg/kg) increased the total moving distance, sucrose consumption and preference rate of CUS rats, and decreased serum IL-18, cell apoptosis and the expressions of cleaved Caspase-9, cleaved Caspase-1 and NLRP3 in the CA3 region of hippocampus. Although OAL (1, 2 mg/kg) decreased the expression of cleaved Caspase-3 and serum IL-1β, OAL (0.5 mg/kg) showed no detectable effects. Si-Atg5 decreased the total moving distance, sucrose consumption and preference rate of CUS rats, enhanced the expressions of cleaved Caspase-3, cleaved Caspase-9, cleaved Caspase-1 and NLRP3, and weakened the effect of OAL (2 mg/kg). OAL (0.5, 1, 2 mg/kg) also increased the LC3Ⅱ/LC3Ⅰ ratio and the expression of Beclin1 in the CA3 region of hippocampus. OAL (1, 2 mg/kg) reduced the expression of p62, but not when it was reduced to 0.5 mg/kg. Si-Atg5 reduced the LC3Ⅱ/LC3Ⅰ ratio and the expression of Beclin1, and weakened the function of OAL (2 mg/kg).
Conclusion OAL can protect the hippocampal neuron of CUS rats via inhibiting NLRP3 inflammasome activation.

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