Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
Int Immunopharmacol. 2023 Jul;120:110347. doi: 10.1016/j.intimp.2023.110347. Epub 2023 Jun 2.
We recently reported that intraperitoneal injection of a low dose of lipopolysaccharide (LPS) reversed depression-like behavior in mice induced by chronic stress by stimulating microglia in the hippocampus. In this study, we found that a single intranasal administration of LPS at a dose of 5 or 10 μg/mouse, but not at a dose of 1 μg/mouse, rapidly reversed depression-like behavior in mice stimulated with chronic unpredictable stress (CUS). In the time-dependent experiment, a single intranasal administration of LPS (10 μg/mouse) reversed CUS-induced depression-like behavior in mice 5 and 8 h but not 3 h after drug administration. The antidepressant effect of a single intranasal LPS administration (10 μg/mouse) lasted at least 10 days and disappeared 14 days after administration. Fourteen days after the first intranasal LPS administration, a second intranasal LPS administration (10 μg/mouse) still reversed the increased immobility time in TST and FST and the decreased sucrose uptake in SPT in CUS mice, which again exhibited depression-like behaviors 5 h after LPS administration. The antidepressant effect of intranasal LPS administration was dependent on microglial activation, because inhibition of microglia by pretreatment with minocycline (40 mg/kg) or depletion of microglia by pretreatment with PLX3397 (290 mg/kg) prevented the antidepressant effect of intranasal LPS administration in CUS mice. These results suggest that stimulation of the microglia-mediated innate immune response by intranasal administration of LPS can produce rapid and sustained antidepressant effects in animals under chronic stress conditions.
我们最近报道，腹腔内注射低剂量脂多糖（LPS）通过刺激海马中的小胶质细胞逆转了慢性应激诱导的小鼠抑郁样行为。在这项研究中，我们发现，单次鼻腔内给予 LPS 剂量为 5 或 10μg/小鼠，但不是 1μg/小鼠，可迅速逆转慢性不可预测应激（CUS）刺激的小鼠的抑郁样行为。在时间依赖性实验中，单次鼻腔内给予 LPS（10μg/小鼠）可在给药后 5 和 8 小时但不能在 3 小时逆转 CUS 诱导的小鼠抑郁样行为。单次鼻腔内给予 LPS（10μg/小鼠）的抗抑郁作用至少持续 10 天，并在给药后 14 天消失。第一次鼻腔内给予 LPS 后 14 天，第二次鼻腔内给予 LPS（10μg/小鼠）仍可逆转 CUS 小鼠 TST 和 FST 中不动时间的增加和 SPT 中蔗糖摄取的减少，这再次导致 LPS 给药后 5 小时出现抑郁样行为。鼻腔内给予 LPS 的抗抑郁作用依赖于小胶质细胞的激活，因为预先给予米诺环素（40mg/kg）抑制小胶质细胞或预先给予 PLX3397（290mg/kg）耗竭小胶质细胞可防止 CUS 小鼠鼻腔内给予 LPS 的抗抑郁作用。这些结果表明，鼻腔内给予 LPS 刺激小胶质细胞介导的固有免疫反应可在慢性应激条件下的动物中产生快速和持续的抗抑郁作用。
