Doyle Timothy M, Janes Kali, Xiao Wen Hua, Kolar Grant R, Luecke Hans F, Gratton Michael Anne, Tosh Dilip K, Jacobson Kenneth A, Bennett Gary J, Salvemini Daniela
Department of Pharmacology and Physiology, Saint Louis University School of Medicine, Saint Louis, Missouri 63104.
Institute for Translational Neuroscience, Saint Louis University, Saint Louis, Missouri 63104.
J Neurosci. 2025 Jan 15;45(3):e1268242024. doi: 10.1523/JNEUROSCI.1268-24.2024.
Alterations in mitochondrial function are the linchpin in numerous disease states including in the development of chemotherapy-induced neuropathic pain (CIPN), a major dose-limiting toxicity of widely used chemotherapeutic cytotoxins. In CIPN, mitochondrial dysfunction is characterized by deficits in mitochondrial bioenergetics (e.g., decreased ATP production) that are thought to drive the degeneration of the peripheral nerve sensory axon terminal sensory arbors in the skin (the intraepidermal nerve fibers; IENFs) and induce abnormal spontaneous discharge in peripheral nerve sensory axons. Preserving mitochondrial function is anticipated to prevent CIPN. We have now discovered that the G-protein-coupled receptor, A adenosine receptor subtype (AAR), is expressed on the mitochondrial outer membrane. Ex vivo application of a highly selective AAR agonist, MRS5980, to saphenous nerve microfilaments harvested from male oxaliplatin-treated rats reversed the loss in ATP production underscoring mitoprotective effects resulting from AAR activation on mitochondria. Moreover, in vivo administration of AAR agonists to rats during oxaliplatin treatment was associated with reduced IENF loss and a lower incidence of spontaneous discharge in peripheral afferent axons. These effects are accompanied by improved mitochondrial ATP production in primary afferent sensory axons and overall inhibition of the development of neuropathic pain. These data identify for the first time mitochondrial AAR and indicate that activation of AAR protects mitochondrial function in primary afferent sensory axons against chemotherapy-induced neurotoxicity. Repurposing AAR agonists that are already in clinical trials as anticancer agents as adjunct to chemotherapeutics will address a major unmet medical need for which there are no FDA-approved drugs.
线粒体功能改变是众多疾病状态的关键因素，包括化疗诱导的神经性疼痛（CIPN）的发生，CIPN是广泛使用的化疗细胞毒素的主要剂量限制性毒性。在CIPN中，线粒体功能障碍的特征是线粒体生物能量学缺陷（例如，ATP生成减少），这被认为会导致皮肤中周围神经感觉轴突终末感觉分支（表皮内神经纤维；IENFs）的退化，并诱导周围神经感觉轴突出现异常自发放电。维持线粒体功能有望预防CIPN。我们现在发现，G蛋白偶联受体A1腺苷受体亚型（A1AR）在线粒体外膜上表达。将高选择性A1AR激动剂MRS5980离体应用于从接受奥沙利铂治疗的雄性大鼠采集的隐神经微丝，可逆转ATP生成的损失，突出了A1AR激活对线粒体的线粒体保护作用。此外，在奥沙利铂治疗期间给大鼠体内注射A1AR激动剂，可减少IENF损失，并降低周围传入轴突自发放电的发生率。这些作用伴随着初级传入感觉轴突中线粒体ATP生成的改善以及神经性疼痛发展的总体抑制。这些数据首次确定了线粒体A1AR，并表明A1AR的激活可保护初级传入感觉轴突中的线粒体功能免受化疗诱导的神经毒性。将已在临床试验中作为抗癌药物的A1AR激动剂重新用作化疗辅助药物，将满足一项主要的未满足医疗需求，目前尚无FDA批准的药物用于此。
