A3AR agonists to prevent chemotherapy-induced painful peripheral neuropathy

A3AR 激动剂可预防化疗引起的疼痛性周围神经病变

• 批准号: 8501971
• 负责人: DANIELA SALVEMINI
• 金额: $ 31.22万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8501971
• 关键词: Address; Adenosine A3 Receptor; Adverse effects; Afferent Neurons; Agonist; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Attenuated; Basic Science; Bortezomib; Chronic; Clinic; Clinical; Clinical Research; Clinical Trials; Complex; Data; Development; Disease; Dose; Dose-Limiting; Equilibrium; Foundations; Genetic; Glutamate Transporter; Glutamate-Ammonia Ligase; Glutamates; Homeostasis; Hyperalgesia; IL6 gene; Inflammatory; Interdisciplinary Study; Interleukin-1; Interleukin-10; Investigation; Knock-out; Lead; Life; Link; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MAPK11 gene; MAPK14 gene; MAPK3 gene; Mediating; Medical; Mitochondria; Modification; Nerve Fibers; Neurons; Neuropathy; Outcome; Paclitaxel; Pain; Patients; Peripheral; Peripheral Nervous System Diseases; Peroxonitrite; Platinum; Process; Production; Proteasome Inhibitor; Proteins; Public Health; Purinergic P1 Receptors; Quality of life; Research Proposals; Sensory; Signal Transduction; Site; Spinal; Spinal Cord; Stress; Synapses; TNF gene; Taxane Compound; Testing; Therapeutic; Time; Toxic effect; Translations; Vinca Alkaloids; Vincristine; allodynia; analog; attenuation; base; bench to bedside; central sensitization; chemotherapy; chronic neuropathic pain; cytokine; drug efficacy; mitochondrial dysfunction; neoplastic; neuroinflammation; neurotransmission; new therapeutic target; nitration; novel strategies; novel therapeutics; oxaliplatin; painful neuropathy; prevent; public health relevance; taxane; therapeutic target

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.

DESCRIPTION (provided by applicable): 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) &蛋白酶体抑制剂（例如硼替佐米）类别。1-3，CIPN是降低剂量降低和停止挽救生命疗法的最常见原因之一。2-7通过识别具有直接潜在转化为临床诊所具有重要意义的治疗目标来解决这一重大公共卫生问题。我们已经确定了 A3腺苷受体（A3AR）激动剂是治疗或逆转CIPN的一种新的可行治疗策略（附录1＆Ref8）。值得注意的是，有选择性的A3AR激动剂IB-MECA及其2-氯类似物（Cl-ibmeca）在高级临床试验中作为抗炎和抗肿瘤剂。9,10，这一提议强调了一项多学科研究计划，该计划是基于我们的预定性数据来探索Applysival of Applyage of Applyage a3ar agonist of Agonist agonists of Agonist of Agonists of Agonist of Agonists of agonists int of agonist of agonists的构建的计划。 行动。使用IB-MECA，三个具体目的将测试我们的中心假设：A3AR激动剂是由具有独特的抗肿瘤作用机制（紫杉醇，oxaliplatin＆bortezomib）的化学治疗药物引起的有效治疗，具有具有有益效应的有益效应，在外围感觉亲和（PSA）neuron＆/spinal（PSA）neuron＆或spinal＆或spinal＆/或spinal＆spinal＆spinal＆spinal＆spinal＆spinal＆spinal＆spinal＆或spinal＆spinal＆或spinal＆或spinal＆/或spinal。 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 pharmaceutical & 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和初级传入的赞助。在AIM 2中，我们将研究IB-MECA通过PSA中的电肌保护作用减轻神经性疼痛的机制。最后，在AIM 3中，我们将研究IB-MECA的效果是否包括衰减神经炎症和/或脊髓中谷氨酸稳态失调，这对于中枢灵敏度至关重要。 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.如果我们的假设是正确的，则预计结果的结果将为“概念证明”提供使用的药物原理。 选择性A3AR激动剂是CIPN的新方法。从翻译的角度来看，这可以想象可能导致对CIPN IB-MECA的“快速轨道”调查。这种令人兴奋的可能性强调了我们的研究建议在这种关键且未经满足的医疗环境中可能产生的直接临床影响。考虑到受A3AR激动剂影响的疾病的广度，了解其基于机制的效果具有深远的基础科学和临床意义。