Wu Huali, Feng Junyi, Lv Wenting, Huang Qiaoling, Fu Mengsi, Cai Minxuan, He Qiangqiang, Shang Jing
State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
Jiangsu Key Laboratory of TCM Evaluation and Translational Research, China Pharmaceutical University, Nanjing, China.
PLoS One. 2016 Sep 8;11(9):e0162570. doi: 10.1371/journal.pone.0162570. eCollection 2016.
Dermatosis often as a chronic disease requires effective long-term treatment; a comprehensive evaluation of mental health of dermatology drug does not receive enough attention. An interaction between dermatology and psychiatry has been increasingly described. Substantial evidence has accumulated that psychological stress can be associated with pigmentation, endocrine and immune systems in skin to create the optimal responses against pathogens and other physicochemical stressors to maintain or restore internal homeostasis. Additionally, given the common ectodermal origin shared by the brain and skin, we are interested in assessing how disruption of skin systems (pigmentary, endocrine and immune systems) may play a key role in brain functions. Thus, we selected three drugs (hydroquinone, isotretinoin, tacrolimus) with percutaneous excessive delivery to respectively intervene in these systems and then evaluate the potential neurotoxic effects. Firstly, C57BL/6 mice were administrated a dermal dose of hydroquinone cream, isotretinoin gel or tacrolimus ointment (2%, 0.05%, 0.1%, respectively, 5 times of the clinical dose). Behavioral testing was performed and levels of proteins were measured in the hippocampus. It was found that mice treated with isotretinoin or tacrolimus, presented a lower activity in open-field test and obvious depressive-like behavior in tail suspension test. Besides, they damaged cytoarchitecture, reduced the level of 5-HT-5-HT1A/1B system and increased the expression of apoptosis-related proteins in the hippocampus. To enable sensitive monitoring the dose-response characteristics of the consecutive neurobehavioral disorders, mice received gradient concentrations of hydroquinone (2%, 4%, 6%). Subsequently, hydroquinone induced behavioral disorders and hippocampal dysfunction in a dose-dependent response. When doses were high as 6% which was 3 times higher than 2% dose, then 100% of mice exhibited depressive-like behavior. Certainly, 6% hydroquinone exposure elicited the most serious impairment of hippocampal structure and survival. The fact that higher doses of hydroquinone are associated with a greater risk of depression is further indication that hydroquinone is responsible for the development of depression. These above data demonstrated that chronic administration of different dermatology drugs contributed into common mental distress. This surprising discovery of chemical stressors stimulating the hippocampal dysfunction, paves the way for exciting areas of study on the cross-talk between the skin and the brain, as well as is suggesting how to develop effective and safe usage of dermatological drugs in daily practice.
皮肤病通常作为一种慢性病需要长期有效的治疗；然而，对皮肤科药物心理健康的综合评估却未得到足够重视。皮肤病学与精神病学之间的相互作用已被越来越多地描述。大量证据表明，心理压力可能与皮肤中的色素沉着、内分泌和免疫系统相互作用，以产生针对病原体和其他物理化学应激源的最佳反应，从而维持或恢复体内稳态。此外，鉴于大脑和皮肤具有共同的外胚层起源，我们有兴趣评估皮肤系统（色素沉着、内分泌和免疫系统）的破坏如何在脑功能中发挥关键作用。因此，我们选择了三种经皮过量递送的药物（对苯二酚、异维甲酸、他克莫司）分别干预这些系统，然后评估潜在的神经毒性作用。首先，给C57BL/6小鼠皮肤涂抹对苯二酚乳膏、异维甲酸凝胶或他克莫司软膏（分别为2%、0.05%、0.1%，临床剂量的5倍）。进行行为测试并测量海马体中的蛋白质水平。结果发现，用异维甲酸或他克莫司治疗的小鼠在旷场试验中活动较低，在悬尾试验中表现出明显的抑郁样行为。此外，它们破坏了细胞结构，降低了5-羟色胺-5-羟色胺1A/1B系统的水平，并增加了海马体中凋亡相关蛋白的表达。为了能够敏感地监测连续神经行为障碍的剂量反应特征，小鼠接受了梯度浓度的对苯二酚（2%、4%、6%）。随后，对苯二酚以剂量依赖性反应诱导行为障碍和海马功能障碍。当剂量高达6%（比2%剂量高3倍）时，100%的小鼠表现出抑郁样行为。当然，6%的对苯二酚暴露引起了最严重的海马结构损伤和存活率下降。高剂量对苯二酚与更高的抑郁风险相关这一事实进一步表明对苯二酚是导致抑郁症的原因。上述数据表明，长期使用不同的皮肤科药物会导致常见的精神困扰。这一关于化学应激源刺激海马功能障碍的惊人发现，为皮肤与大脑之间的相互作用这一令人兴奋的研究领域铺平了道路，也为在日常实践中如何开发有效且安全的皮肤科药物使用方法提供了思路。
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