A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy

描述（由申请人提供）：伴随慢性神经性疼痛的化疗诱导的周围神经病变（CIPN）是紫杉烷类（例如，紫杉醇），铂络合物（例如，奥沙利铂），长春花生物碱（例如，长春新碱）和蛋白酶体抑制剂（例如，1 -3因此，CIPN是减少剂量和停止本可挽救生命的治疗的最常见原因之一。2 -7通过确定可立即转化为临床的治疗靶点来解决这一重大公共卫生问题至关重要。我们已经确定 A3腺苷受体（A3 AR）激动作为治疗或逆转CIPN的新的可行治疗策略（附录1和参考文献8）。值得注意的是，选择性A3 AR激动剂IB-MECA及其2-氯类似物（Cl-IBMECA）作为抗肿瘤药物正在进行高级临床试验。9，10该提案强调了一项多学科研究计划，该计划以我们的初步数据为基础，探索A3 AR激动剂在CIPN中的适用性范围，同时研究潜在的保护作用机制。使用IB-MECA，三个特定目标将测试我们的中心假设：A3 AR激动剂是由化疗药物引起的CIPN的有效治疗剂，具有不同的抗肿瘤作用机制（紫杉醇，奥沙利铂和硼替佐米），在外周感觉传入（PSA）神经元和/或脊髓水平发挥有益作用。在目标1中，我们将测试1）IB-MECA是否阻断和逆转神经性疼痛，2）IB-MECA的作用是否对使用药理学和遗传敲除方法的A3 AR介导的机制具有特异性，3）潜在的中枢和外周作用位点是IB-MECA作用的基础，以及4）IB-MECA是否预防化疗诱发的表皮内神经纤维变性和初级传入自发放电。在目标2中，我们将研究IB-MECA通过PSA中的线粒体保护作用减轻神经性疼痛的机制。最后，在目标3中，我们将研究IB-MECA的作用是否包括减弱神经炎症和/或脊髓中谷氨酸稳态的失调，已知这是中枢致敏所必需的过程。我们将专注于NF？B和MAPK（ERK 1/2，p38）信号传导和神经胶质源性促（TNF和IL 6）/抗（IL 10）炎性细胞因子，以及对脊髓谷氨酸转运体（神经元和神经胶质）和神经胶质谷氨酰胺合成酶的表达和活性的影响。如果我们的假设成立，我们的结果预计将提供药理学原理的“概念验证”的使用 选择性A3 AR激动剂作为CIPC的新方法。从翻译的角度来看，这可能会导致CIPN的IB-MECA的“快速通道”调查。这种令人兴奋的可能性强调了我们的研究提案在这种关键和未满足的医疗环境中可能产生的直接临床影响。考虑到A3 AR激动剂影响的疾病的广度，了解其基于机制的作用具有深远的基础科学和临床意义。

DESCRIPTION (provided by applicant): Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is the major dose-limiting toxicity of widely used antitumoral agents in the taxane (e.g., paclitaxel), platinum-complex (e.g., oxaliplatin), vinca alkaloids (e.g., vincristine) & proteasome-inhibitor (e.g., bortezomib) classes.1-3 Thus, CIPN is one of most common causes of dose reduction & discontinuation of what is otherwise a life-saving therapy.2-7 Addressing this major public health issue by identifying therapeutic targets with immediate potential translation to the clinic is of paramount significance. We have identified A3 adenosine receptor (A3AR) agonism as a new viable therapeutic strategy for treating or reversing CIPN (Appendix 1 & ref8). Noteworthy, the selective A3AR agonists IB-MECA & its 2-chloro analogue (Cl-IBMECA) are in advanced clinical trials as antiinflammatory & antitumor agents.9,10 This proposal highlights a multidisciplinary research plan that builds upon our preliminary data to explore the breadth of A3AR agonist applicability in CIPN while investigating underlying protective mechanism(s) of action. Using IB-MECA, three Specific Aims will test our central hypothesis: A3AR agonists are effective therapeutics in CIPN caused by chemotherapeutics with distinct antitumor mechanisms of action (paclitaxel, oxaliplatin & bortezomib) with beneficial effects exerted at the level of the peripheral sensory afferent (PSA) neuron &/or spinal cord. In Aim 1, we will test if 1) IB-MECA blocks & reverses neuropathic pain, 2) the effects of IB-MECA are specific to an A3AR mediated mechanism using pharmacological & genetic knockout approaches, 3) potential central & peripheral site(s) of action underlie IB-MECA's action & 4) IB-MECA prevents chemotherapy-evoked degeneration of intraepidermal nerve fibers & primary afferent spontaneous discharge. In Aim 2, we will investigate the mechanism(s) whereby IB-MECA attenuates neuropathic pain through mitoprotective effects in PSA. Finally, in Aim 3, we will investigate if IB-MECA's effects include attenuating neuroinflammation &/or the dysregulation of glutamate homeostasis in the spinal cord, processes known to be essential to central sensitization. We will focus on NF¿B & MAPK (ERK1/2, p38) signaling & glial-derived pro (TNF¿, IL1¿, & IL6)/anti (IL10)-inflammatory cytokines, as well as, the effects on the expression & activities of spinal glutamate transporters (neuronal & glial) & glial glutamine synthetase. If our hypothesis holds true, the outcome of our results are anticipated to provide the pharmacological rationale for "proof-of-concept" for the use of selective A3AR agonists as a new approach in CIPN. From a translational perspective, this could conceivably lead to a "fast track" investigation of IB-MECA for CIPN. This exciting possibility underscores the immediate clinical impact that our research proposal may have in this critical & unmet medical setting. Given the breadth of disorders impacted by A3AR agonists understanding their mechanism-based effects has far-reaching basic science & clinical implications.