米诺环素对CCI大鼠抑郁样行为的影响及机制研究
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摘要
目的:观察海马CA1区注射米诺环素对坐骨神经慢性缩窄性损伤(CCI)大鼠的抑郁样行为、海马和前额叶皮层小胶质细胞激活的影响并分析其机制。方法:成年SD雄性大鼠随机分为:对照组、假手术组、CCI模型组、CCI+米诺环素组。糖水偏好及旷场实验检测大鼠抑郁样行为;免疫组化观察海马以及前额叶皮层Iba-1表达;取海马以及前额叶皮层组织,real-time PCR观察Iba-1、NLRP3和caspase1 mRNA表达,ELISA测定IL-1β和IL-18含量。结果:与假手术组相比,CCI大鼠7、10 d和14 d的糖水偏好明显降低(P <0. 05),旷场中央活动距离和中央活动时间明显减少(P <0. 05);与CCI组相比,CA1区注射米诺环素后CCI大鼠7 d和14 d的糖水偏好明显升高(P <0. 05),旷场中央活动距离和中央活动时间明显增加(P <0. 05)。与假手术组相比,CCI组大鼠海马CA1、CA3及DG区和前额叶皮层Iba-1阳性细胞数目显著增多(P <0. 05),Iba-1、NLRP3和caspase1 mRNA表达明显上调; IL-1β和IL-18含量也明显升高(P <0. 05)。与CCI组相比,注射米诺环素后,CCI大鼠海马CA1、CA3及DG区和前额叶皮层Iba-1阳性细胞数目减少(P <0. 05),Iba-1、NLRP3和caspase1 mRNA表达降低(P <0. 05),IL-1β和IL-18含量降低(P <0. 05)。结论:海马CA1区注射米诺环素明显抑制CCI大鼠的抑郁样行为;其机制可能是抑制海马和前额叶皮层小胶质细胞激活,下调NLRP3和caspase1表达,从而使IL-1β和IL-18产生减少。
Objective: To investigate the effect of intra-CA1( cornu ammonis 1) administration of minocycline on the depressive-like behaviors and the activation of microglia in hippocampus and prefrontal cortex of rats with chronic constriction injury( CCI) of the sciatic nerve,and explored the possible mechanisms of CCI-induced depression-like behavior.Methods: Sprague-Dawley male rats were randomized into four groups: control group,sham group,CCI group,and CCI+ minocycline group. The sucrose preference test and open field test were evaluated the depression-like behaviors. The expression of Iba-1 in the hippocampus and prefrontal cortex of the rat was detected by immunohistochemistry. The expression of Iba-1,NLRP3 and caspase1 mRNA in the hippocampus and prefrontal cortex were examined by RT-PCR.The content of IL-1β and IL-18 in the hippocampus and prefrontal cortex were examined by ELISA. Results: Compared with the sham group,the sucrose consumption test evaluatedat 7,10 and 14 days after surgery in the CCI model group decreased significantly( P < 0. 05) and the time and distances in the center zone in open field test was obviously decneas-ed( P < 0. 05). Compared with the CCI group,the sucrose consumption test was evaluatedat 7 and 14 days after surgery in rats with intra-CA1 injection of minocycline group increased significantly( P < 0. 05) and rats spent significantly more time and longer distances in the center zone( P < 0. 05). Numbers of Iba1-positive cells in CA1,CA3,DG and PFC were significantly increased in the CCI group compared to the sham group,and the numbers of Iba1-positive cells were significantly decreased after intra-CA1 injection of minocycline( P < 0. 05). The expression of Iba-1,NLRP3 and caspase1 mRNA in the hippocampus and prefrontal cortex was markedly enhanced after nerve injury( P < 0. 05).Compared with the CCI group,intra-CA1 injection of minocycline obviously suppressed the increased expression of Iba-1,NLRP3 and caspase1 mRNA( P < 0. 05). Compared with sham group,the content of IL-1β and IL-18 in the hippocampus and prefrontal cortex were significantly increased in CCI rats( P < 0. 05). Compared with the CCI group,intra-CA1 injection of minocycline obviously suppressed the increased content of IL-1β and IL-18. Conclusion: Intra-hippocampal CA1 injection of minocycline can significantly attenuate CCI-induced depressive-like behaviors; suggesting that minocycline may attenuate CCI-induced depressive-like behaviors by inhibition of hippocampus and prefrontal cortex microglia activation and the decreased expression of Iba-1,NLRP3 and caspase1 mRNA and results in the decreased production of IL-1β and IL-18.
Objective: To investigate the effect of intra-CA1( cornu ammonis 1) administration of minocycline on the depressive-like behaviors and the activation of microglia in hippocampus and prefrontal cortex of rats with chronic constriction injury( CCI) of the sciatic nerve,and explored the possible mechanisms of CCI-induced depression-like behavior.Methods: Sprague-Dawley male rats were randomized into four groups: control group,sham group,CCI group,and CCI+ minocycline group. The sucrose preference test and open field test were evaluated the depression-like behaviors. The expression of Iba-1 in the hippocampus and prefrontal cortex of the rat was detected by immunohistochemistry. The expression of Iba-1,NLRP3 and caspase1 mRNA in the hippocampus and prefrontal cortex were examined by RT-PCR.The content of IL-1β and IL-18 in the hippocampus and prefrontal cortex were examined by ELISA. Results: Compared with the sham group,the sucrose consumption test evaluatedat 7,10 and 14 days after surgery in the CCI model group decreased significantly( P < 0. 05) and the time and distances in the center zone in open field test was obviously decneas-ed( P < 0. 05). Compared with the CCI group,the sucrose consumption test was evaluatedat 7 and 14 days after surgery in rats with intra-CA1 injection of minocycline group increased significantly( P < 0. 05) and rats spent significantly more time and longer distances in the center zone( P < 0. 05). Numbers of Iba1-positive cells in CA1,CA3,DG and PFC were significantly increased in the CCI group compared to the sham group,and the numbers of Iba1-positive cells were significantly decreased after intra-CA1 injection of minocycline( P < 0. 05). The expression of Iba-1,NLRP3 and caspase1 mRNA in the hippocampus and prefrontal cortex was markedly enhanced after nerve injury( P < 0. 05).Compared with the CCI group,intra-CA1 injection of minocycline obviously suppressed the increased expression of Iba-1,NLRP3 and caspase1 mRNA( P < 0. 05). Compared with sham group,the content of IL-1β and IL-18 in the hippocampus and prefrontal cortex were significantly increased in CCI rats( P < 0. 05). Compared with the CCI group,intra-CA1 injection of minocycline obviously suppressed the increased content of IL-1β and IL-18. Conclusion: Intra-hippocampal CA1 injection of minocycline can significantly attenuate CCI-induced depressive-like behaviors; suggesting that minocycline may attenuate CCI-induced depressive-like behaviors by inhibition of hippocampus and prefrontal cortex microglia activation and the decreased expression of Iba-1,NLRP3 and caspase1 mRNA and results in the decreased production of IL-1β and IL-18.
引文
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[14]Zhang G,Zhao BX,Hua R,et al. Hippocampal microglial activation and glucocorticoid receptor down-regulation precipitate visceral hypersensitivity induced by colorectal distension in rats[J]. Neuropharmacology,2016,102:295-303. DOI:10. 1016/j. neuropharm. 2015. 11. 028.
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[16]曾俊伟,刘晓红,蒋慧,等.脊髓背角P2Y_(12)受体/P38MAPK参与MRS2395对CCI大鼠的镇痛作用[J].中国疼痛医学杂志,2015,21(1):15-20. DOI:10. 3969/j. issn. 1006-9852. 2015. 01. 005.
[17]Lu Y,Xiao G,Luo W. Minocycline suppresses NLRP3 inflammasome activation in experimental ischemic stroke[J]. Neuroimmunomodulation, 2016, 23(4):230-238. DOI:10. 1159/000452172.
[18]Zhu W,Cao FS,Feng J,et al. NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide[J]. Neuroscience,2017,343:77-84. DOI:10. 1016/j. neuroscience. 2016. 11. 037.
[19]Swaroop S,Mahadevan A,Shankar SK,et al. HSP60 critically regulates endogenous IL-1βproduction in activated microglia by stimulating NLRP3 inflammasome pathway[J]. J Neuroinflammat ion,2018,15(1):177. DOI:10. 1186/s12974-018-1214-5.
[20]Ma Q,Chen S,Hu Q,et al. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage[J]. Ann Neurol,2014,75(2):209-219. DOI:10. 1002/ana. 24070.
[21]Wu T,Liang X,He K,et al. MPA-modified CdTe quantum dots increased interleukin-1beta secretion through My D88-dependent Toll-like receptor pathway and NLRP3 inflammasome activation in microglia[J]. Toxicol In Vitro,2018,52:41-51. DOI:10.1016/j. tiv. 2018. 05. 014.
[22]Song MT,Ruan J,Zhang RY,et al. Astragaloside IV ameliorates neuroinflammation-induced depressive-like behaviors in mice via the PPARgamma/NF-kappaB/NLRP3 inflammasome axis[J]. Acta Pharmacol Sin,2018,39(10):1559-1570. DOI:10. 1038/aps.2017. 208.
[2]Dellarole A,Morton P,Brambilla R,et al. Neuropathic pain-induced depressive-like behavior and hippocampal neurogenesis and plasticity are dependent on TNFR1 signaling[J]. Brain Behav Immun,2014,41:65-81. DOI:10. 1016/j. bbi. 2014. 04. 003.
[3]Wang YL,Han QQ,Gong WQ,et al. Microglial activation mediates chronic mild stress-induced depressive-and anxiety-like behavior in adult rats[J]. J Neuroinflammat,2018,15(1):21. DOI:10.1186/s12974-018-1054-3.
[4]Lei Y,Chen CJ,Yan XX,et al. Early-life lipopolysaccharide exposure potentiates forebrain expression of NLRP3 inflammasome proteins and anxiety-like behavior in adolescent rats[J]. Brain Res,2017,1671:43-54. DOI:10. 1016/j. brainres. 2017. 06. 014.
[5]Hu XF,Dong YL,Jin XH,et al. The novel and potent anti-depressive action of triptolide and its influences on hippocampal neuroinflammation in a rat model of depression comorbidity of chronic pain[J]. Brain Behav Immun,2017,64:180-194. DOI:10. 1016/j. bbi. 2017. 03. 005.
[6]Cardoso-Cruz H,Lima D,Galhardo V. Impaired spatial memory performance in a rat model of neuropathic pain is associated with reduced hippocampus-prefrontal cortex connectivity[J]. J Neuroscience,2013,33(6):2465. DOI:10. 1523/JNEUROSCI. 5197-12. 2013.
[7]刘雯,郭文洁,徐强,等. NLRP3炎症小体调控机制研究进展[J].药学学报,2016,51(10):1505-1512. DOI:10.16438/j. 0513-4870. 2016-0380.
[8] Cheng J,Dong S,Yi L,et al. Magnolol abrogates chronic mild stress-induced depressive-like behaviors by inhibiting neuroinflammation and oxidative stress in the prefrontal cortex of mice[J]. Int Immunopharmacol,2018,59:61-67. DOI:10. 1016/j. intimp.2018. 03. 031.
[9]Burke NN,Kerr DM,Moriarty O,et al. Minocycline modulates neuropathic pain behaviour and cortical M1-M2 microglial gene expression in a rat model of depression[J]. Brain Behav Immun,2014,42:147-156. DOI:10. 1016/j. bbi. 2014. 06. 015.
[10]Xu N,Tang XH,Pan W,et al. Spared nerve injury increases the expression of microglia M1 markers in the prefrontal cortex of rats and provokes depression-like behaviors[J]. Front Neurosci,2017,11:209. DOI:10. 3389/fnins. 2017. 00209.
[11]王功伍,蔡景霞.海马-前额叶神经回路与工作记忆[J].动物学研究,2010,31(1):50-56. DOI:10. 3724/SP. J. 1141.2010. 01050.
[12]Barr JL,Forster GL. Serotonergic neurotransmission in the ventral hippocampus is enhanced by corticosterone and altered by chronic amphetamine treatment[J]. Neuroscience,2011,182:105-114.DOI:10. 1016/j. neuroscience. 2011. 03. 020.
[13]周佩洋,任自敬,孙成林,等.脑缺血中一氧化氮前体/供体的作用研究[J].中国药业,2017,26(12):4-7. DOI:10.3969/j. issn. 1006-4931. 2017. 24. 002.
[14]Zhang G,Zhao BX,Hua R,et al. Hippocampal microglial activation and glucocorticoid receptor down-regulation precipitate visceral hypersensitivity induced by colorectal distension in rats[J]. Neuropharmacology,2016,102:295-303. DOI:10. 1016/j. neuropharm. 2015. 11. 028.
[15]陆国能,陆永经,韦理萍,等.炎症在慢性疼痛与抑郁共病过程中的作用[J].中国疼痛医学杂志,2014,20(12):896-898. DOI:10. 3969/j. issn. 1006-9852. 2014. 12. 013.
[16]曾俊伟,刘晓红,蒋慧,等.脊髓背角P2Y_(12)受体/P38MAPK参与MRS2395对CCI大鼠的镇痛作用[J].中国疼痛医学杂志,2015,21(1):15-20. DOI:10. 3969/j. issn. 1006-9852. 2015. 01. 005.
[17]Lu Y,Xiao G,Luo W. Minocycline suppresses NLRP3 inflammasome activation in experimental ischemic stroke[J]. Neuroimmunomodulation, 2016, 23(4):230-238. DOI:10. 1159/000452172.
[18]Zhu W,Cao FS,Feng J,et al. NLRP3 inflammasome activation contributes to long-term behavioral alterations in mice injected with lipopolysaccharide[J]. Neuroscience,2017,343:77-84. DOI:10. 1016/j. neuroscience. 2016. 11. 037.
[19]Swaroop S,Mahadevan A,Shankar SK,et al. HSP60 critically regulates endogenous IL-1βproduction in activated microglia by stimulating NLRP3 inflammasome pathway[J]. J Neuroinflammat ion,2018,15(1):177. DOI:10. 1186/s12974-018-1214-5.
[20]Ma Q,Chen S,Hu Q,et al. NLRP3 inflammasome contributes to inflammation after intracerebral hemorrhage[J]. Ann Neurol,2014,75(2):209-219. DOI:10. 1002/ana. 24070.
[21]Wu T,Liang X,He K,et al. MPA-modified CdTe quantum dots increased interleukin-1beta secretion through My D88-dependent Toll-like receptor pathway and NLRP3 inflammasome activation in microglia[J]. Toxicol In Vitro,2018,52:41-51. DOI:10.1016/j. tiv. 2018. 05. 014.
[22]Song MT,Ruan J,Zhang RY,et al. Astragaloside IV ameliorates neuroinflammation-induced depressive-like behaviors in mice via the PPARgamma/NF-kappaB/NLRP3 inflammasome axis[J]. Acta Pharmacol Sin,2018,39(10):1559-1570. DOI:10. 1038/aps.2017. 208.