Developmental Neurotoxic Effects of Percutaneous Drug Delivery: Behavior and Neurochemical Studies in C57BL/6 Mice

Abstract

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.

Experimental Social Stress: Dopaminergic Receptors, Oxidative Stress, and c-Fos Protein Are Involved in Highly Aggressive Behavior

“…Stress can be defined as the sum of external factors that affect an individual’s homeostasis ( Arora et al, 2010 ). The organism can either adapt to the stressor or promote a maladaptive response that leads to structural changes in neural networks, which results in an imbalance in individual and social behaviors such as aggressiveness ( Wooda and Bhatnagar, 2015 ; Wu et al, 2016 ; Vindas et al, 2017 ). Dopamine is one of the main neurotransmitters that modulates the stress response, and changes in its levels, receptors and mesolimbic and mesocortical pathways have already been identified in animals that exhibit aggressive behavior ( Yu et al, 2014 ; Berridge and Kringelbach, 2015 ; Gray et al, 2015 ; Yamaguchi and Lin, 2018 ; Frau et al, 2019 ).…”

Coptisine Alleviates Imiquimod-Induced Psoriasis-like Skin Lesions and Anxiety-like Behavior in Mice

“…Another possible explanation for the effects of coptisine on the central nervous systems is through the brain-skin connection, in that it may send a signal to the brain via the ascending pathway of sensory nerves in the skin or modulate the hypothalamic-pituitary-adrenal axis [72]. Previous reports have demonstrated that chronic topical administration of dermatology drugs such as hydroquinone, isotretinoin, and tacrolimus induce behavioral changes by regulating neuroendocrine systems [73]. Further studies are needed to determine the mechanisms of action of coptisine on central nervous systems.…”

Serotonin/5‐HT7 receptor provides an adaptive signal to enhance pigmentation response to environmental stressors through cAMP‐PKA‐MAPK, Rab27a/RhoA, and PI3K/AKT signaling pathways

“…The fixed tissues were embedded in paraffin and sectioned coronally into 4-μm or 14-μm slices for immunofluorescence (IF, 5-HT7R, HMB45, and TH) and hematoxylin-eosin (HE) stainings as previously reported. 27 Secondary antibodies: Mouse IgG Rhod (TRITC) conjugated (Product number CW0222S, 1:200, CWBio, Beijing, China), Rabbit IgG FITC conjugated (Product number CW0219S, 1:200, CWBio, Beijing, China). Confocal microscopy (Leica) and Image J quantified stained sections.…”