Paeoniflorin ameliorates interferon-alpha-induced neuroinflammation and depressive-like behaviors in mice

// Jianwei Li 1, * , Shaohui Huang 1, * , Weiliang Huang 1, * , Wanshan Wang 2, * , Ge Wen 3 , Lei Gao 1 , Xiuqiong Fu 4 , Mengmeng Wang 1 , Weihai Liang 1 , Hiu Yee Kwan 4 , Xiaoshan Zhao 1 , Zhiping Lv 1 1 School of Traditional Chinese Medicine, Southern Medical University, Guangzhou, Guangdong, 510515, China 2 Experimental Animal Center, Southern Medical University, Guangzhou, Guangdong, 510515, China 3 Medical Imaging Department, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, China 4 School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, 999077, China * These authors have contributed equally to this work Correspondence to: Xiaoshan Zhao, email: zhaoxs0609@163.com Zhiping Lv, email: lzp48241@126.com Keywords: depression, interferon, amygdala, neuroinflammation, paeoniflorin Received: October 02, 2016 Accepted: November 24, 2016 Published: December 24, 2016 ABSTRACT Long-term treatment with high-dose Interferon-alpha (IFN-α) has resulted in depression in 30–50% of the patients. Paeoniflorin may ameliorate the IFN-α-induced depression; however, the underlying mechanism is less studied. Here, we investigated the prophylactic antidepressant and anti-neuroinflammatory effects of paeoniflorin on the behaviors and specific emotion-related regions of the brain in mice with IFN-α-induced depression. A series of behavior assessments were conducted to identify the depressive state after subcutaneously IFN-α injections and with or without intragastrically paeoniflorin administration in C57BL/6J mice. Levels of many inflammatory-related cytokines in serum, mPFC, vHi and amygdala were determined by cytokine array analysis. Furthermore, microglia and astrocyte activation in these three regions were evaluated by immunohistochemistry. We found that the mice which were subcutaneously injected IFN-α 15×10 6 IU/kg for 4 successive weeks to mimic an IFN-α-induced depression model had distinct inflammatory changes in the amygdala. Interestingly, 4-week 20 mg/kg or 40 mg/kg paeoniflorin pretreatments reversed the depressive-like behaviors and the abnormal inflammatory cytokine levels in the serum, mPFC, vHi and amygdala. These cytokines were not limited to the commonly reported IL-6, IL-1β and TNF-α, but also IL-9, IL-10, IL-12, and MCP-1. Besides, the increased density of microglia in IFN-α-treated mice was reversed by paeoniflorin in these three brain areas. Taken together, our data suggest that paeoniflorin can reverse the long-term, high-dose IFN-α-induced depressive-like behaviors that were associated with local distinct neuroinflammation in the mPFC, vHi and particularly the amygdala. Paeoniflorin might have a preventive therapeutic potential in IFN-α-induced depression.