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

  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。

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

  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.