College of Basic Medical Science , Zhejiang Chinese Medical University , Hangzhou 310058 , P.R. China.
Department of Pharmacology, College of Basic Medical Sciences , Jilin University , Changchun , Jilin 130021 , P.R. China.
ACS Chem Neurosci. 2019 Mar 20;10(3):1716-1728. doi: 10.1021/acschemneuro.8b00617. Epub 2018 Dec 20.
For an affliction that debilitates an estimated 50 million adults in the United States, the current chronic pain management approaches are inadequate. The Centers for Disease Control and Prevention have called for a minimization in opioid prescription and use for chronic pain conditions, and thus, it is imperative to discover alternative non-opioid based strategies. For the realization of this call, a library of natural products was screened in search of pharmacological inhibitors of both voltage-gated calcium channels and voltage-gated sodium channels, which are excellent targets due to their well-established roles in nociceptive pathways. We discovered (-)-hardwickiic acid ((-)-HDA) and hautriwaic acid (HTA) isolated from plants, Croton californicus and Eremocarpus setigerus, respectively, inhibited tetrodotoxin-sensitive sodium, but not calcium or potassium, channels in small diameter, presumptively nociceptive, dorsal root ganglion (DRG) neurons. Failure to inhibit spontaneous postsynaptic excitatory currents indicated a preferential targeting of voltage-gated sodium channels over voltage-gated calcium channels by these extracts. Neither compound was a ligand at opioid receptors. Finally, we identified the potential of both (-)-HDA and HTA to reverse chronic pain behavior in preclinical rat models of HIV-sensory neuropathy, and for (-)-HDA specifically, in chemotherapy-induced peripheral neuropathy. Our results illustrate the therapeutic potential for (-)-HDA and HTA for chronic pain management and could represent a scaffold, that, if optimized by structure-activity relationship studies, may yield novel specific sodium channel antagonists for pain relief.
对于一种估计在美国使 5000 万成年人衰弱的疾病，目前的慢性疼痛管理方法是不够的。疾病控制与预防中心呼吁减少慢性疼痛情况下的阿片类药物处方和使用，因此，发现替代非阿片类的基于策略是当务之急。为了实现这一呼吁，对天然产物库进行了筛选，以寻找电压门控钙通道和电压门控钠通道的药理学抑制剂，由于它们在伤害性途径中作用明确，因此是极好的靶点。我们从植物 Croton californicus 和 Eremocarpus setigerus 中分别发现了（-）-硬脂酸（（-）-HDA）和 hautriwaic 酸（HTA），它们抑制河豚毒素敏感的钠通道，但不抑制钙或钾通道，在小直径、推测为伤害性的背根神经节（DRG）神经元中。未能抑制自发的突触后兴奋性电流表明，这些提取物优先靶向电压门控钠通道而不是电压门控钙通道。这两种化合物都不是阿片受体的配体。最后，我们确定了（-）-HDA 和 HTA 在 HIV 感觉神经病变的临床前大鼠模型中逆转慢性疼痛行为的潜力，并且对于（-）-HDA 特别地，在化疗引起的周围神经病变中也有潜力。我们的结果说明了（-）-HDA 和 HTA 用于慢性疼痛管理的治疗潜力，并且可能代表一种支架，如果通过构效关系研究进行优化，可能会产生用于缓解疼痛的新型特定钠通道拮抗剂。
