Department of Pharmacy, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong 226001, Jiangsu Province, China.
Department of Pharmacology, Nantong Health College of Jiangsu Province, #288 Zhenxing East Road, Nantong 226010, Jiangsu Province, China.
Prog Neuropsychopharmacol Biol Psychiatry. 2020 Jul 13;101:109931. doi: 10.1016/j.pnpbp.2020.109931. Epub 2020 Mar 19.
The decrease of microglia in the hippocampus is a novel mechanism for depression onset. Reversal of this decrease can ameliorate stress-induced depression-like behaviors in rodents. However, the property of this therapeutic strategy remains unclear. We addressed this issue by designing a series of behavioral experiments. Results showed that a single lipopolysaccharide (LPS) injection at the dose of 75 and 100 μg/kg, but not at 30 or 50 μg/kg, produced obvious antidepressant effects in chronic unpredictable stress (CUS) mice at 5 h after the drug administration. In the time-dependent experiment, a single LPS injection (100 μg/kg) ameliorated the CUS-induced depression-like behaviors in mice at 5 and 8 h, but not at 3 h, after the drug administration. The antidepressant effect of a single LPS injection persisted at least 10 days and disappeared at 14 days after the drug administration. 14 days after the first injection, a second LPS injection (100 μg/kg) still produced antidepressant effects in chronically-stressed mice who re-displayed depression-like behaviors at 5 h after the drug administration. The antidepressant effect of LPS appears to be dependent on microglia, as at 5 h after LPS administration (100 μg/kg), the CUS-induced decrease in microglial numbers and Iba-1 mRNA levels in the hippocampus was reversed markedly, and inhibition of microglia by minocycline (40 mg/kg) or PLX33297 (290 mg/kg) prevented the antidepressant effect of LPS in CUS mice. These results indicate that a single LPS injection displays rapid and sustained antidepressant effects in chronically stressed mice likely through stimulating hippocampal microglia.
海马区小胶质细胞减少是抑郁症发病的新机制。逆转这种减少可以改善应激诱导的抑郁样行为。然而，这种治疗策略的特性尚不清楚。我们通过设计一系列行为实验来解决这个问题。结果表明，单次注射脂多糖（LPS）剂量为 75 和 100μg/kg，但 30 或 50μg/kg 剂量不会产生明显的抗抑郁作用，在药物给药后 5 小时在慢性不可预测应激（CUS）小鼠中。在时间依赖性实验中，单次 LPS 注射（100μg/kg）在药物给药后 5 和 8 小时改善了 CUS 诱导的抑郁样行为，但在 3 小时时没有改善。单次 LPS 注射的抗抑郁作用至少持续 10 天，给药后 14 天消失。第一次注射后 14 天，第二次 LPS 注射（100μg/kg）仍在慢性应激小鼠中产生抗抑郁作用，这些小鼠在药物给药后 5 小时重新出现抑郁样行为。LPS 的抗抑郁作用似乎依赖于小胶质细胞，因为在 LPS 给药后 5 小时（100μg/kg），CUS 诱导的海马区小胶质细胞数量和 Iba-1 mRNA 水平明显减少，米诺环素（40mg/kg）或 PLX33297（290mg/kg）抑制小胶质细胞可预防 LPS 在 CUS 小鼠中的抗抑郁作用。这些结果表明，单次 LPS 注射在慢性应激小鼠中表现出快速和持续的抗抑郁作用，可能通过刺激海马小胶质细胞。
