Tejeda-Martínez A R, Viveros-Paredes J M, Hidalgo-Franco G V, Pardo-González E, Chaparro-Huerta V, González-Castañeda R E, Flores-Soto M E
Laboratorio de Neurobiología Celular y Molecular, División de Neurociencias, Centro de Investigación Biomédica de Occidente (CIBO), Instituto Mexicano del Seguro Social, 44340, Mexico.
Laboratorio de Investigación y Desarrollo Farmacéutico, Departamento de Farmacología, Centro Universitario de Ciencias Exactas e Ingenierías, Universidad de Guadalajara, 44430, Mexico.
Behav Neurol. 2021 Mar 24;2021:6651492. doi: 10.1155/2021/6651492. eCollection 2021.
Symptoms of depressive disorders such as anhedonia and despair can be a product of an aberrant adaptation to stress conditions. Chronic unpredictable stress model (CUS) can generate an increase in the activity of the hypothalamic-pituitary-adrenal axis (HPA) and induce a reduction of neurotrophin signaling and the proliferation of neural progenitors in the adult dentate gyrus, together with increased oxidative stress. Levels of the endocannabinoid anandamide (AEA) seem to affect these depression-by-stress-related features and could be modulated by fatty acid amide hydrolase (FAAH). We aimed to evaluate the effects of FAAH inhibitor, URB597, on depressive-like behavior and neural proliferation of mice subjected to a model of CUS. URB597 was administered intraperitoneally at a dose of 0.2 mg/kg for 14 days after CUS. Depressive-like behaviors, anhedonia, and despair were evaluated in the splash and forced swimming tests, respectively. Alterations at the HPA axis level were analyzed using the relative weight of adrenal glands and serum corticosterone levels. Oxidative stress and brain-derived neurotrophic factor (BDNF) were also evaluated. Fluorescence immunohistochemistry tests were performed for the immunoreactivity of BrdU and Sox2 colabeling for comparison of neural precursors. The administration of URB597 was able to reverse the depressive-like behavior generated in mice after the model. Likewise, other physiological responses associated with CUS were reduced in the treated group, among them, increase in the relative weight of the adrenal glands, increased oxidative stress, and decreased BDNF and number of neural precursors. Most of these auspicious responses to enzyme inhibitor administration were blocked by employing a cannabinoid receptor antagonist. In conclusion, the chronic inhibition of FAAH generated an antidepressant effect, promoting neural progenitor proliferation and BDNF expression, while reducing adrenal gland weight and oxidative stress in mice under the CUS model.
抑郁症的症状，如快感缺乏和绝望，可能是对压力状况异常适应的结果。慢性不可预测应激模型（CUS）可导致下丘脑-垂体-肾上腺轴（HPA）活性增加，并诱导成年齿状回中神经营养因子信号传导减少以及神经祖细胞增殖，同时氧化应激增加。内源性大麻素花生四烯酸乙醇胺（AEA）的水平似乎会影响这些与应激相关的抑郁特征，并且可能受到脂肪酸酰胺水解酶（FAAH）的调节。我们旨在评估FAAH抑制剂URB597对CUS模型小鼠的抑郁样行为和神经增殖的影响。在CUS后，以0.2 mg/kg的剂量腹腔注射URB597，持续14天。分别在溅水试验和强迫游泳试验中评估抑郁样行为、快感缺乏和绝望。使用肾上腺相对重量和血清皮质酮水平分析HPA轴水平的变化。还评估了氧化应激和脑源性神经营养因子（BDNF）。进行荧光免疫组织化学试验，以检测BrdU和Sox2共标记的免疫反应性，用于比较神经前体细胞。URB597的给药能够逆转模型后小鼠产生的抑郁样行为。同样，治疗组中与CUS相关的其他生理反应也有所降低，其中包括肾上腺相对重量增加、氧化应激增加、BDNF减少以及神经前体细胞数量减少。通过使用大麻素受体拮抗剂，大多数这些对酶抑制剂给药的良好反应被阻断。总之，在CUS模型下，长期抑制FAAH产生了抗抑郁作用，促进了神经祖细胞增殖和BDNF表达，同时减轻了肾上腺重量和氧化应激。
