Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, 226001, Jiangsu Province, China.
Invasive Technology Department, Nantong First People's Hospital, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong, 226001, Jiangsu Province, China.
Neuropharmacology. 2019 Jun;151:33-44. doi: 10.1016/j.neuropharm.2019.04.005. Epub 2019 Apr 4.
Chronic stress-induced decline in microglia in the hippocampus is a newly hypothesized mechanism of depression, and reversal of this decline by microglial activators has been shown to suppress depression-like behaviors in mice. This suggests that activation of immune cells in the hippocampus may be a potential strategy for depression therapy. Since amphotericin B, an anti-fungal medication, is known to activate macrophages and microglia, we investigated whether conventional amphotericin B or its liposomal form displays antidepressant activity. Our results showed that both amphotericin B and its liposomal form at various doses induced obvious depression-like behaviors in naïve mice, likely owing to increased serum interleukin-6 (IL-6) and IL-1β levels. However, under stressed conditions, amphotericin B liposome, but not amphotericin B itself, reversed chronic unpredictable stress (CUS)-induced increase in immobility time in the tail suspension test and forced swim test as well as CUS-induced decrease in sucrose intake in the sucrose preference test and the time spent in the center region of the open field test in a dose-dependent manner. Immunofluorescence analysis showed that amphotericin B liposome reversed the CUS-induced decline in dentate gyrus (DG) microglia, and inhibition or ablation of microglia in the hippocampus by minocycline (40 mg/kg) or PLX3397 pre-treatment (290 mg/kg) abrogated the antidepressant effect of the amphotericin B liposome in CUS-treated mice. These results not only identify a novel pharmacological effect of amphotericin B liposome, but further support the notion that microglial activation in the hippocampus is a potential strategy for depression therapy.
慢性应激引起的海马小胶质细胞减少是抑郁症的一种新假设机制，小胶质细胞激活剂逆转这种减少已被证明可抑制小鼠的抑郁样行为。这表明海马免疫细胞的激活可能是抑郁症治疗的一种潜在策略。由于两性霉素 B 是一种抗真菌药物，已知它可以激活巨噬细胞和小胶质细胞，我们研究了两性霉素 B 及其脂质体形式是否具有抗抑郁活性。我们的结果表明，两性霉素 B 及其脂质体形式在不同剂量下均会引起未处理小鼠明显的抑郁样行为，这可能是由于血清白细胞介素 6 (IL-6) 和白细胞介素 1β (IL-1β) 水平升高所致。然而，在应激条件下，两性霉素 B 脂质体而非两性霉素 B 本身可逆转慢性不可预测应激 (CUS) 引起的悬尾试验和强迫游泳试验中不动时间的增加，以及蔗糖偏好试验和旷场试验中蔗糖摄入量的减少，且呈剂量依赖性。免疫荧光分析表明，两性霉素 B 脂质体逆转了 CUS 诱导的海马齿状回 (DG) 小胶质细胞减少，而预先用米诺环素 (40mg/kg) 或 PLX3397 (290mg/kg) 抑制或消融海马中的小胶质细胞可消除两性霉素 B 脂质体在 CUS 处理小鼠中的抗抑郁作用。这些结果不仅确定了两性霉素 B 脂质体的一种新的药理学作用，而且进一步支持了这样一种观点，即海马中微胶质细胞的激活是抑郁症治疗的一种潜在策略。
