Corticotropin releasing factor-1 receptor antagonism alters the biochemical, but not behavioral effects of repeated interleukin-1β administration.
Corticotropin releasing factor-1 receptor antagonism alters the biochemical, but not behavioral effects of repeated interleukin-1β administration.
复制标题
促肾上腺皮质激素释放因子-1 受体拮抗作用改变生化，但不改变重复白细胞介素-1β 给药的行为影响。
DOI：
10.1016/j.neuropharm.2011.07.040
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发表时间：
2012
影响因子：
4.7
通讯作者：
Loftis,JenniferM
中科院分区：
文献类型：
--
作者：
Wilhelm,ClareJ;Murphy-Crews,Aaron;Menasco,DanielJ;Huckans,MarilynS;Loftis,JenniferM
通过给予细胞因子激活免疫系统用于治疗慢性病毒感染，如丙型肝炎和对放射治疗有抗性的癌症。基于细胞因子的治疗诱导一系列“疾病”行为（例如抑郁、焦虑、疼痛、厌食和疲劳）。通过诱导促肾上腺皮质激素释放因子（CRF）激活下丘脑垂体-肾上腺轴可能是这些不良副作用的基础。本研究使用反复全身注射促炎细胞因子白细胞介素-1 β（IL-1β）来模拟疾病行为和免疫系统激活的生化效应。我们评估了CRF I型受体（CRF 1）拮抗剂减少IL-1β治疗诱导的疾病生化和行为体征的能力。将40只Wistar大鼠分为4组：1）生理盐水+溶剂; 2）生理盐水+DMP 904（CRF 1拮抗剂）; 3）IL-1β+溶剂; 4）IL-1β+ DMP 904。大鼠接受腹膜内注射DMP 904或媒介物和IL-1β或盐水六天。使用体重评估和强迫游泳试验（FST）评价疾病行为。收集血液和脑样品，使用多重技术测量细胞因子、p38丝裂原活化蛋白激酶（MAPK）和磷酸化p38 MAPK水平。与IL-1β给药相关的体重和FST不动时间显著降低。给予IL-1β的大鼠血清IL-10水平显著升高，但干扰素-γ水平不升高。在海马内，IL-1β降低了p38 MAPK的水平，但除了在存在DMP 904的情况下，对磷酸化p38 MAPK的水平没有影响。当单独给药时，DMP 904对海马中的p38 MAPK或磷酸化p38 MAPK没有显著影响，但当与IL-1β一起给药时，导致p38 MAPK的磷酸化增加。IL-1β和DMP 904降低了下丘脑内p38 MAPK的水平，而IL-1β和DMP 904的联合给药则消除了单独使用任何一种药物的作用。IL-1β减少FST中的不动时间，并导致体重减轻，血清细胞因子水平和海马和下丘脑内p38 MAPK调节的变化。DMP 904阻断了IL-1β的一些神经化学作用，但不影响行为测量或血清细胞因子。因此，需要进一步的研究来确定CRF 1拮抗剂是否是一种有效的治疗奎宁引起的疾病。这篇文章是题为“焦虑和抑郁”的特刊的一部分。
Activation of the immune system via administration of cytokines is used for the treatment of chronic viral infections such as hepatitis C and for cancers resistant to radiotherapy. Cytokine-based treatments induce a range of “sickness” behaviors (e.g. depression, anxiety, pain, anorexia, and fatigue). Activation of the hypothalamic pituitary-adrenal axis via the induction of corticotropin releasing factor (CRF) may underlie these unwanted side effects. This study used repeated systemic injections of the pro-inflammatory cytokine interleukin-1β (IL-1β) to model the sickness behaviors and biochemical effects of immune system activation. We assessed the ability of CRF type I receptor (CRF1) antagonism to reduce biochemical and behavioral signs of sickness induced by IL-1β treatment. Forty Wistar rats were assigned to one of four groups: 1) saline+vehicle; 2) saline+DMP904 (CRF1antagonist); 3) IL-1β+vehicle; 4) IL-1β+DMP904. Rats received intraperitoneal injections of either DMP904 or vehicle and of IL-1β or saline for six days. Sickness behavior was evaluated using body weight assessments and forced swim testing (FST). Blood and brain samples were collected to measure cytokine, p38 mitogen-activated protein kinase (MAPK), and phospho-p38 MAPK levels using multiplex techniques. There were significant reductions in body weights and FST immobility times associated with IL-1β administration. Rats administered IL-1β had significantly higher serum levels of IL-10, but not interferon-γ. Within the hippocampus, IL-1β reduced levels of p38 MAPK, but had no impact on levels of phospho-p38 MAPK except in the presence of DMP904. When administered alone, DMP904 had no significant effect on p38 MAPK or phospho-p38 MAPK in the hippocampus, but when given with IL-1β led to increased phosphorylation of p38 MAPK. IL-1β and DMP904 reduced levels of p38 MAPK within the hypothalamus, while co-administration of IL-1β and DMP904 abolished the effects of either drug alone. IL-1β decreased immobility time in the FST, and led to reductions in body weight, changes in serum cytokine levels and p38 MAPK regulation within the hippocampus and hypothalamus. DMP904 blocked some of the neurochemical effects of IL-1β, but did not impact the behavioral measures, or serum cytokines. Thus, additional studies will be needed to determine whether CRF1antagonism is an effective treatment for cytokine-induced sickness. This article is part of a Special Issue entitled ‘Anxiety and Depression’.