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TRPA1 modulation by Sigma-1 receptor prevents oxaliplatin-induced painful peripheral neuropathy
Brain ( IF 10.6 ) Pub Date : 2022-07-24 , DOI: 10.1093/brain/awac273
Aida Marcotti 1 , Jorge Fernández-Trillo 1 , Alejandro González 1 , Marta Vizcaíno-Escoto 1 , Pablo Ros-Arlanzón 1 , Luz Romero 2 , José Miguel Vela 2 , Ana Gomis 1 , Félix Viana 1 , Elvira de la Peña 1, 3
Affiliation  

Chemotherapy induced peripheral neuropathy (CIPN) is a frequent, disabling side effect of anticancer drugs. Oxaliplatin, a platinum compound used in the treatment of advanced colorectal cancer, often leads to a form of CIPN characterized by mechanical and cold hypersensitivity. Current therapies for CIPN are ineffective, often leading to the cessation of treatment. Transient receptor potential ankyrin 1 (TRPA1) is a polymodal, non-selective cation-permeable channel expressed in nociceptors, activated by physical stimuli and cellular stress products. TRPA1 has been linked to the establishment of CIPN and other painful neuropathic conditions. Sigma-1 receptor is an endoplasmic reticulum chaperone known to modulate the function of many ion channels and receptors. S1RA, a highly selective antagonist of Sigma-1 receptor has shown effectiveness in a phase II clinical trial for oxaliplatin CIPN. However, the mechanisms involved in the beneficial effects of S1RA are little understood. We combined biochemical and biophysical (i.e. intermolecular FRET) techniques to demonstrate the interaction between Sigma-1 receptor and human TRPA1. Pharmacological antagonism of Sigma-1R impaired the formation of this molecular complex and the trafficking of functional TRPA1 to the plasma membrane. Using patch-clamp electrophysiological recordings we found that antagonists of Sigma-1 receptor, including S1RA, exert a marked inhibition on plasma membrane expression and function of human TRPA1 channels. In TRPA1-expressing mouse sensory neurons, S1RA reduced inward currents and the firing of actions potentials in response to TRPA1 agonists. Finally, in a mouse experimental model of oxaliplatin neuropathy, systemic treatment with a S1RA prevented the development of painful symptoms by a mechanism involving TRPA1. In summary, the modulation of TRPA1 channels by Sigma-1 receptor antagonists suggests a new strategy for the prevention and treatment of CIPN and could inform the development of novel therapeutics for neuropathic pain.

中文翻译:


Sigma-1 受体调节 TRPA1 可预防奥沙利铂引起的疼痛性周围神经病



化疗引起的周围神经病变 (CIPN) 是抗癌药物常见的致残副作用。奥沙利铂是一种用于治疗晚期结直肠癌的铂化合物,通常会导致一种以机械和冷过敏为特征的 CIPN。目前的 CIPN 疗法无效,常常导致治疗停止。瞬时受体电位锚蛋白 1 (TRPA1) 是一种多模式、非选择性阳离子渗透通道,在伤害感受器中表达,由物理刺激和细胞应激产物激活。 TRPA1 与 CIPN 和其他疼痛性神经病的发生有关。 Sigma-1 受体是一种内质网伴侣,已知可调节许多离子通道和受体的功能。 S1RA 是一种 Sigma-1 受体的高选择性拮抗剂,已在奥沙利铂 CIPN 的 II 期临床试验中显示出有效性。然而,人们对 S1RA 有益作用的机制知之甚少。我们结合生物化学和生物物理(即分子间FRET)技术来证明Sigma-1受体和人TRPA1之间的相互作用。 Sigma-1R 的药理学拮抗作用损害了该分子复合物的形成以及功能性 TRPA1 向质膜的运输。使用膜片钳电生理记录,我们发现 Sigma-1 受体拮抗剂(包括 S1RA)对人 TRPA1 通道的质膜表达和功能具有显着抑制作用。在表达 TRPA1 的小鼠感觉神经元中,S1RA 减少了对 TRPA1 激动剂的内向电流和动作电位的发射。 最后,在奥沙利铂神经病小鼠实验模型中,S1RA 的全身治疗通过涉及 TRPA1 的机制阻止了疼痛症状的发展。总之,Sigma-1 受体拮抗剂对 TRPA1 通道的调节提出了预防和治疗 CIPN 的新策略,并可为神经性疼痛新疗法的开发提供信息。
更新日期:2022-07-24
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