Background & Aims
Pruritic dermatitis, a challenging condition with limited treatment options, presents complications involving both the epidermis and peripheral neurons. We propose a novel pharmacological strategy targeting sensory neurons in the peripheral dorsal root ganglion (DRG) and skin keratinocytes (Lee, Cho et al. 2018, Jurcakova, Ru et al. 2019). GPR35, an orphan G-protein-coupled receptor expressed in DRG neurons, is thought to reduce neuronal excitability upon activation (Zhao, Lane et al. 2014, Hu, Deng et al. 2017, Zeisel, Hochgerner et al. 2018). With increasing knowledge of GPR35 modulators, pamoic acid (PA), a drug salt-forming agent, stands out as a specific activator for GPR35 (Zhao, Sharir et al. 2010). Our investigation aims to comprehend the impact of PA on dermatotic pathology, addressing the significant treatment gap in pruritic dermatitis.
Methods
1. Dermatitis Modeling
DNCB was applied to the shaved nape one day before injection, followed by intradermal administration of either vehicles or PA on the nape skin of BALB/c mice. Scratching bouts were monitored for an hour every other day during the experimental period.
2. Acute Itch Tests and Cheek-Assays
For acute itch, we pretreated PA or vehicle in their napes, followed by intradermal injections of Hist, CQ, 5-HT, or BAM8-22. Cheek-assays involved injecting these substances into mouse cheek skin using established protocols (Kardon, Polgar et al. 2014, Lu, Wang et al. 2018). Scratching or wiping bouts were counted for 30?min post-injection.
3. Fluorescence Ca2+ Imaging
Following previously described (Yoo, Choi et al. 2017, Cho, Lee et al. 2021), cells were loaded with Fura-2, pluronic F127, and Opti-MEM for 40?min. Cells were perfused in an imaging buffer with or without test drugs. Fluorescence intensity ratios at 340 and 380?nm were then documented using SlideBook 6.0.
Results
The study investigated GPR35 expression in mouse skin, detected in TRPV1-positive nerve terminals and to a lesser extent in epidermal regions. PA, a GPR35 agonist, reduced non-histaminergic acute scratches, reversed by GPR35 antagonist CID 2745687, confirming GPR35 dependence. PA also decreased Ca2+ responses in DRG neurons to non-histaminergic irritants, implicating GPR35 in sensory neuron activity. GPR35 in HaCat keratinocytes was confirmed, and PA mitigated interleukin-induced dissociation, suggesting relief in non-histaminergic pruritic responses and keratinocyte integrity maintenance. In DNCB-induced dermatitis, on-site PA injections dose-dependently reduced spontaneous scratching. Similar results in psoriatic dermatitis showed PA efficacy in chronic pruritus. PA treatment improved dermatitis scores, especially erythema, hemorrhage, and scaling. These findings suggest that PA, through peripheral GPR35, selectively modulates acute and chronic pruritus.
Conclusions
Our research demonstrates that the activation of peripheral GPR35 using PA contributes to the improvement of pruritus and related diseases. Localized application of PA not only relieves acute non-histaminergic itch and hinders DRG neuronal responses but also reduces keratinocyte fragmentation in dermatitis-like conditions. Repeated PA applications result in a moderate yet significant reversal of chronic pruritus in both DNCB-induced dermatitis models and IMQ-induced psoriatic dermatitis models. Furthermore, dermatitis scores in these models are improved, indicating the beneficial impact of PA in alleviating disease pathology. These findings suggest the potential of peripheral GPR35 activation through PA for relieving pruritus and associated dermatological conditions.
References
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Presenting Author
Miri Kim
Poster Authors
Miri Kim
BS
Korea University
Lead Author
Ji Yeon Lim
PhD
Korea University College of Medicine, Seoul 02841, Republic of Korea
Lead Author
Minseok Kim
PhD
Korea University College of Medicine, Seoul 02841, Republic of Korea
Lead Author
Haiyan Zheng
PhD
Lead Author
Chaeeun Kim
Korea University
Lead Author
Yerin Kim
MS
Lead Author
Topics
- Specific Pain Conditions/Pain in Specific Populations: Itch