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.

描述（由申请人提供）：化疗引起的周围神经病变（CIPN）伴慢性神经性疼痛是紫杉醇（如紫杉醇）、铂复合物（如奥沙利铂）、长春花生物碱（如长春新碱）和蛋白酶体抑制剂（如硼替佐米）等广泛使用的抗肿瘤药物的主要剂量限制性毒性。因此，CIPN是减少剂量和停止治疗的最常见原因之一，否则这是一种挽救生命的治疗。2-7通过确定具有立即转化为临床潜力的治疗靶点来解决这一重大公共卫生问题具有至关重要的意义。我们已经确定