Department of Experimental Neuroendocrinology, Institute of Pharmacology, Polish Academy of Science, 31-343 Krakow, Poland.
Brain Behav Immun. 2013 Jul;31:96-104. doi: 10.1016/j.bbi.2013.01.001. Epub 2013 Jan 9.
Chronic activation of immune-inflammatory and oxidative and nitrosative stress (O&NS) pathways plays an important role in the pathophysiology of clinical depression. Increased IgA responses directed against LPS of gram-negative bacteria, indicating increased bacterial translocation, may be one of the drivers underpinning these pathways. There is a strong association between signs of bacterial translocation and chronicity of depression and O&NS, but not pro-inflammatory cytokines. The aims of the present study were to: (1) develop a new neurobehavioral model of (chronic) depression (anhedonic behavior) that may reflect chronic LPS stimulation and is associated with increased oxidative stress, and (2) to delineate the effects of fluoxetine on this new depression model. We established that in female mice repeated LPS injections once daily for 5 days (from 750 μg/kg to a maximal dose 1250 μg/kg; increasing doses for the first three days which were then gradually decreased on day 4 and 5) at a one-month interval and this repeated for 4 consecutive months induced chronic anhedonia (estimated by the preference to drink a 1% sucrose) lasting for at least 7 weeks. Chronic LPS administration significantly decreased thymus weight, proliferative activity of splenocytes, production of interferon (IFN)γ and interleukin-(IL)10, and increased superoxide and corticosterone production. Treatment with fluoxetine for 3 weeks abolished the neurobehavioral effects of LPS. The antidepressant effect of fluoxetine was accompanied by increased production of IL-10 and reduced superoxide and corticosterone production. Our results suggest that repeated intermittent LPS injections to female mice may be a useful model of chronic depression and in particular for the depressogenic effects of long standing activation of the toll-like receptor IV complex.
慢性激活免疫炎症和氧化及硝化应激（O&NS）途径在临床抑郁症的病理生理学中起着重要作用。针对革兰氏阴性菌 LPS 的 IgA 反应增加，表明细菌易位增加，可能是这些途径的驱动因素之一。细菌易位的迹象与抑郁症和 O&NS 的慢性存在之间存在强烈关联，但与促炎细胞因子无关。本研究的目的是：（1）开发一种新的神经行为模型（慢性）抑郁症（快感缺失行为），该模型可能反映慢性 LPS 刺激并与氧化应激增加有关，（2）阐明氟西汀对这种新的抑郁症模型的影响。我们发现，雌性小鼠在一个月的间隔时间内每天重复注射一次 LPS（从 750μg/kg 增加到 1250μg/kg 的最大剂量；前三天逐渐增加剂量，然后在第四天和第五天逐渐减少），连续 4 个月重复注射，会导致慢性快感缺失（通过饮用 1%蔗糖的偏好来估计）持续至少 7 周。慢性 LPS 给药显著降低了胸腺重量、脾细胞增殖活性、干扰素（IFN）γ和白细胞介素（IL）-10 的产生，并增加了超氧化物和皮质酮的产生。氟西汀治疗 3 周可消除 LPS 的神经行为作用。氟西汀的抗抑郁作用伴随着 IL-10 的产生增加和超氧化物及皮质酮产生的减少。我们的结果表明，雌性小鼠反复间歇性 LPS 注射可能是慢性抑郁症的有用模型，特别是对 Toll 样受体 IV 复合物长期激活的致抑郁作用。
