Department of Biomedical Sciences and Department of Physiology, College of Medicine, Korea University, Seoul, Korea.
Br J Pharmacol. 2023 Dec;180(23):3059-3070. doi: 10.1111/bph.16201. Epub 2023 Aug 16.
Pruritic dermatitis is a disease with a considerable unmet need for treatment and appears to present with not only epidermal but also peripheral neuronal complications. Here, we propose a novel pharmacological modulation targeting both peripheral dorsal root ganglion (DRG) sensory neurons and skin keratinocytes. GPR35 is an orphan G-protein-coupled receptor expressed in DRG neurons and has been predicted to downregulate neuronal excitability when activated. Modulator information is currently increasing for GPR35, and pamoic acid (PA), a salt-forming agent for drugs, has been shown to be an activator solely specific for GPR35. Here, we investigated its effects on dermatitic pathology.
We confirmed GPR35 expression in peripheral neurons and tissues. The effect of PA treatment was pharmacologically evaluated in cultured cells in vitro and in in vivo animal models for acute and chronic pruritus.
Local PA application mitigated acute non-histaminergic itch and, consistently, obstructed DRG neuronal responses. Keratinocyte fragmentation under dermatitic simulation was also dampened following PA incubation. Chronic pruritus in 1-chloro-2,4-dinitrobenzene and psoriasis models were also moderately but significantly reversed by the repeated applications of PA. Dermatitic scores in the 1-chloro-2,4-dinitrobenzene and psoriatic models were also improved by its application, indicating that it is beneficial for mitigating disease pathology.
Our findings suggest that pamoic acid activation of peripheral GPR35 can contribute to the improvement of pruritus and its associated diseases.
瘙痒性皮炎是一种治疗需求尚未得到充分满足的疾病，它不仅表现为表皮并发症，还表现为周围神经元并发症。在这里，我们提出了一种针对周围背根神经节（DRG）感觉神经元和皮肤角质形成细胞的新型药理学调节方法。GPR35 是一种在 DRG 神经元中表达的孤儿 G 蛋白偶联受体，当被激活时，据预测会下调神经元兴奋性。目前，GPR35 的调节剂信息正在增加，药物的成盐剂帕莫酸（PA）已被证明是一种仅对 GPR35 具有特异性的激活剂。在这里，我们研究了它对瘙痒性皮炎病理的影响。
我们在周围神经元和组织中证实了 GPR35 的表达。在体外培养细胞和急性和慢性瘙痒动物模型中，我们对 PA 治疗的效果进行了药理学评估。
局部 PA 应用减轻了急性非组胺性瘙痒，并且一致地阻止了 DRG 神经元的反应。在模拟性皮炎的情况下，角质形成细胞的碎裂也在 PA 孵育后得到了抑制。1-氯-2,4-二硝基苯和银屑病模型中的慢性瘙痒也被 PA 的重复应用适度但显著逆转。1-氯-2,4-二硝基苯和银屑病模型中的皮炎评分也通过其应用得到改善，表明它有利于减轻疾病病理。
我们的发现表明，外周 GPR35 的帕莫酸激活可能有助于改善瘙痒及其相关疾病。
