大麻二酚对应激大鼠肺部损伤的预防保护作用
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摘要
目的建立应激性肺部损伤大鼠模型,观察大麻二酚(CBD)对大鼠应激性肺损伤的保护作用,并探讨其可能的机制。方法使用水浸束缚SD大鼠的方法制备大鼠应激模型,将40只SD大鼠随机分为正常组、模型组、CBD低、中、高剂量组(12、36、108 mg/kg,ig),每组8只,造模前开始进行早晚2次CBD预防性给药,连续灌胃给药3 d。大鼠经过48 h水浸束缚应激造模后(中途解绑短暂休息,自由饮水),麻醉处死并解剖取材。取全肺检测肺脏器系数及肺部湿干质量比(wet/dry ratio,W/D)检测肺水肿程度;HE染色法观察左肺肺组织形态学变化;ELISA法测定血清皮质酮(CORT)、TNF-α及IL-1β含量。结果模型组肺脏器系数和W/D值相对正常组显著升高(P<0.01),CBD中、高剂量组均相对模型组显著降低(P<0.05);病理切片HE染色结果发现,中、高剂量的CBD预防性给药能减少应激产生的肺部损伤;ELISA检测结果显示,中、高剂量组的CBD能显著降低模型组大鼠血清中CORT、TNF-α及IL-1β的水平(P<0.05),且其抗应激激素升高水平和抗炎水平呈现剂量依赖性。结论 CBD可显著减轻大鼠急性应激产生的肺组织损伤程度,其机制可能是通过抑制HPA轴的激活,并下调TNF-α和IL-1β的表达而保护应激大鼠的肺脏。
Objective To investigate the protective effect of cannabidiol(CBD) on stress-induced lung injury in rat model,and its possible mechanism. Methods Rat stress model was prepared by using water-immersion restraint SD rats. 40 SD rats were randomly divided into the normal group,the model group,and CBD experimental-L,CBD experimental-M and CBD experimental-H groups(12,36,108 mg/kg,ig). Preventive administration of CBD was started twice in the morning and evening before modeling for three days. Rats were subjected to 48-hour water-immersion restraint stress(small break in the middle,free to drink water),anesthetized and anatomically sampled. The pulmonary organ coefficient and wet/dry(W/D) ratio were measured by whole lung to detect the degree of pulmonary edema. HE staining was used to observe the morphological changes of left lung and lung tissue. Serum levels of corticosterone,TNF-α and IL-1β were measured by ELISA. Results The lung organ coefficient and W/D value were significantly higher in the model group than that of the normal group(P<0.01),which was obviously decreased in CBD experimental-H and experimental-M groups(P<0.05). Pathological sections showed that middle and high doses of CBD administration reduced lung damages caused by stress. ELISA results showed that CBD significantly reduced the serum levels of CORT,TNF-α and IL-1β increased by stress(P<0.01). Conclusion Cannabidiol can alleviate the lung injury caused by acute stress in rats,in which the mechanism may be related to inhibition of the activation of HPA axis and down-regulation of the expression of TNF-α and IL-1β.
Objective To investigate the protective effect of cannabidiol(CBD) on stress-induced lung injury in rat model,and its possible mechanism. Methods Rat stress model was prepared by using water-immersion restraint SD rats. 40 SD rats were randomly divided into the normal group,the model group,and CBD experimental-L,CBD experimental-M and CBD experimental-H groups(12,36,108 mg/kg,ig). Preventive administration of CBD was started twice in the morning and evening before modeling for three days. Rats were subjected to 48-hour water-immersion restraint stress(small break in the middle,free to drink water),anesthetized and anatomically sampled. The pulmonary organ coefficient and wet/dry(W/D) ratio were measured by whole lung to detect the degree of pulmonary edema. HE staining was used to observe the morphological changes of left lung and lung tissue. Serum levels of corticosterone,TNF-α and IL-1β were measured by ELISA. Results The lung organ coefficient and W/D value were significantly higher in the model group than that of the normal group(P<0.01),which was obviously decreased in CBD experimental-H and experimental-M groups(P<0.05). Pathological sections showed that middle and high doses of CBD administration reduced lung damages caused by stress. ELISA results showed that CBD significantly reduced the serum levels of CORT,TNF-α and IL-1β increased by stress(P<0.01). Conclusion Cannabidiol can alleviate the lung injury caused by acute stress in rats,in which the mechanism may be related to inhibition of the activation of HPA axis and down-regulation of the expression of TNF-α and IL-1β.
引文
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[2] 郭蓉,陈璇,郭鸿彦.四氢大麻酚和大麻二酚的药理研究进展[J].天然产物研究与开发,2017(8):189-193.
[3] AMAR M B.Cannabinoids in medicine:a review of their thera-peutic potential[J].J Ethnopharmacol,2006,105(1/2):1-25.
[4] JOSé ALEXANDRE S C A,DERENUSSON G N,FERRARI T B,et al.Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder:a preliminary report[J].J Psychopharmacol,2011,25(1):121-130.
[5] KURINA L M,SCHNEIDER B,WAITE L J .Stress,symptoms of depression and anxiety,and cortisol patterns in working parents[J].Stress Health,2004,20(2):53-63.
[6] BIELAS H,MEISTER-LANGRAF R E,SCHMID J P,et al.Acute stress disorder and C-reactive protein in patients with acute myocardial infarction[J].Eur J Prev Cardiol,2018,25(3):298-305.
[7] FERNáNDEZ ó.THC:CBD in daily practice:available data from uk,germany and spain[J].Eur Neurol,2016,75(1):1-3.
[8] RIBEIRO A,FERRAZ-DE-PAULA V,PINHEIRO M L,et al.Cannabidiol,a non-psychotropic plant-derived cannabinoid,decreases inflammation in a murine model of acute lung injury:role for the adenosine A2A receptor[J].Eur J Pharmacol,2012,678(1/3):78-85
[9] SEGEV A,AKIRAV I .Cannabinoids and glucocorticoids in the basolateral amygdala modulate hippocampal-accumbens plasti-city after stress.[J].Neuropsychopharmacology,2015,41(4):1066.
[10] CRIPPA J A S,DERENUSSON G N,FERRARI T B,et al.Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder:a preliminary report[J].J Psychopharmacol,2011,25(1):121-130.