PPAR inhibition of spinal pain transmission

PPAR 抑制脊髓疼痛传递

• 批准号: 9333812
• 负责人: BRADLEY K. TAYLOR
• 金额: $ 52.38万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-12-18 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9333812
• 关键词: Adenylate Cyclase; Advanced Glycosylation End Products; Affect; Affective; Age; Agonist; Analgesics; Behavioral; Biological Assay; Blood; Books; Cations; Cells; Chemosensitization; Complications of Diabetes Mellitus; Conflict (Psychology); Cutaneous; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Cytotoxin; Data; Development; Diabetes Mellitus; Diabetic Neuralgia; Diamond; Drug Targeting; Enzymes; Extracellular Signal Regulated Kinases; FDA approved; Female; Funding; Genetic; Glucose; Glycolysis; Hyperalgesia; Hyperglycemia; Inflammation; Inherited; Intracellular Second Messenger; Intrathecal Injections; Lactoylglutathione Lyase; Measures; Mechanics; Mediating; Metabolic; Modeling; Molecular; Motivation; Mus; Natural History; Nerve; Neurons; Nociception; Non-Insulin-Dependent Diabetes Mellitus; PPAR alpha; PPAR gamma; Pain; Patients; Peptides; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Pioglitazone; Plasma; Population; Posterior Horn Cells; Progress Reports; Proteins; Publishing; Pyruvaldehyde; Rattus; Research; Second Messenger Systems; Sex Characteristics; Signal Transduction; Spinal; Spinal Cord; Spine pain; Stimulus; Streptozocin; Structure of beta Cell of islet; TRPA1 Channel; Testing; Traumatic Nerve Injury; United States; adduct; adenylyl cyclase 1; chronic neuropathic pain; chronic pain; diabetic; dorsal horn; experience; glycation; inhibitor/antagonist; innovation; male; mouse model; new therapeutic target; novel; novel drug class; overexpression; pain behavior; painful neuropathy; preclinical study; public health relevance; receptor; small molecule; small molecule inhibitor; tissue processing; transmission process

Diabetes affects 9% of the United States population and approximately one-third of these patients experience chronic neuropathic pain, commonly referred to as painful diabetic neuropathy (PDN). PDN is difficult to manage as analgesic treatments are only effective in a small subset of PDN patients. The development of analgesics for pain associated with diabetes, in particular type 2 diabetes, is stalled by our incomplete understanding of the underlying mechanisms of PDN. An important new clue comes from the recent finding that methylglyoxal (MG), a highly reactive dicarbonyl product of glycolysis that accumulates with hyperglycemia, is particularly high in patients with PDN. MG causes non-enzymatic glycation of proteins. The resulting protein adducts, or advanced glycation end products (MG-AGEs), are toxic and contribute to diabetic complications including PDN. Our central hypothesis is that elevated MG in type 2 diabetes causes pain and that this can be alleviated with new classes of drugs targeting MG itself, TRPA1, AC1, Epac, and PPARγ. To test the hypothesis that MG drives neuropathic pain (PDN) in type 2 diabetes, Specific Aim 1 will first determine whether elevations in MG and its metabolizing enzyme, Glyoxalase-1, occur in pain processing tissues in the hereditary Leprdb/db (db/db) mouse and Zucker Diabetic Fatty (ZDF) rat models of type 2 diabetes. We then ask whether a promising new class of MG-scavenging peptides will alleviate affective pain and spinal pain transmission. Our preliminary data indicate that genetic deletion or pharmacological inhibition of TRPA1, a glycation target of MG, blocks MG-induced pain. Indeed, TRPA1 is a leading target for the development of new analgesics for chronic pain, but has not been tested in models of type 2 PDN. To fill this gap, Specific Aim 2 will test the hypothesis that TRPA1 antagonists reduce affective pain and spinal pain transmission in db/db mice and ZDF rats. Consequent to TRPA1 channel opening (e.g. by MG), the resulting Ca2+ influx into the cell leads to the activation of Ca2+-sensitive proteins, which includes adenylyl cyclase I (AC1). Our data indicate that selective inhibition of AC1 with NB001 blocks type 2 PDN. AC1 generates the intracellular second messenger, cAMP, which targets not only protein kinase A but also exchange protein directly activated by cAMP (Epac). Specific Aim 3 will use novel Epac1 and Epac2 small molecule inhibitors to determine which of these targets drive PDN. Among the 33 original research articles, reviews, and a book published during the previous funding cycle (22 with the PI as first or senior author), our Progress includes the discovery that pioglitazone, a peroxisome proliferator-activated receptor gamma (PPARγ) agonist that is FDA- approved to treat diabetes, acts at dorsal horn neurons to inhibit the chronic pain associated with cutaneous inflammation and traumatic nerve injury. Our new data indicate additional efficacy in PDN and MG-induced pain, with surprisingly robust analgesic effects in females. Specific Aim 4 proposes to study PPARγ mechanism of action in db/db and ZDF, with a new focus on sex differences in spinal nociceptive transmission.

糖尿病影响美国9％的人口，其中约有三分之一的患者经历 慢性神经性疼痛，通常称为疼痛的糖尿病神经病（PDN）。 PDN很难 作为镇痛治疗的管理仅在一小部分PDN患者中有效。发展的发展 与糖尿病相关的疼痛的镇痛药，特别是2型糖尿病，我们的不完整停滞不前 了解PDN的基本机制。一个重要的新线索来自最近的发现 那种甲基乙醇（Mg），一种高反应性的糖溶解产物，可与 PDN患者的高血糖症，特别高。 MG引起蛋白质非酶糖基化。这 由此产生的蛋白质加合物或晚期糖基化终产物（MG-AGES）有毒，有助于糖尿病 包括PDN在内的并发症。我们的中心假设是，2型糖尿病中升高的毫克会导致疼痛和 可以通过针对MG本身，TRPA1，AC1，EPAC和PPARγ的新药物来缓解这种情况。到 测试MG在2型糖尿病中驱动神经性疼痛（PDN）的假设，具体AIM 1将首先 确定MG及其代谢酶（乙二醇酶-1）是否发生在疼痛加工中 遗传性LEPRDB/DB（DB/DB）小鼠和Zucker糖尿病脂肪（ZDF）大鼠2型的组织中的组织 糖尿病。然后，我们询问承诺的新类MG扫除宠物是否会减轻情感痛苦 和脊柱疼痛传播。我们的初步数据表明遗传缺失或药物抑制 Mg的糖基化靶标TRPA1阻塞了Mg诱导的疼痛。确实，TRPA1是 为慢性疼痛开发新的镇痛药，但尚未在2型PDN模型中进行测试。填写这个 差距，特定目标2将检验以下假设：TRPA1拮抗剂减轻情感疼痛和脊柱疼痛 DB/DB小鼠和ZDF大鼠的传播。因此，TRPA1通道打开（例如，通过mg），由此产生 Ca2+对细胞的影响会导致Ca2+敏感蛋白的激活，其中包括腺苷酸环化酶I （AC1）。我们的数据表明，使用NB001块对AC1进行选择性抑制2型PDN。 AC1生成 细胞内第二使者CAMP，它不仅针对蛋白激酶A，还针对蛋白质 特定的目标3将使用新颖的EPAC1和EPAC2小分子抑制剂 确定哪些目标驱动PDN。在33篇原始研究文章中，评论和一本书 在上一个融资周期中发表（22名与PI为第一或高级作者），我们的进度包括 发现Pioglitazone是一种过氧化物组增殖物激活的受体伽马（PPARγ）激动剂，是FDA- 批准治疗糖尿病，作用于背喇叭神经元以抑制与皮肤相关的慢性疼痛 炎症和创伤性神经损伤。我们的新数据表明PDN和MG诱导的效率 疼痛，在女性中具有令人惊讶的镇痛作用。特定目标4研究PPARγ DB/DB和ZDF中的作用机理，新的重点是脊柱伤害性传播的性别差异。