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PPAR inhibition of spinal pain transmission

PPAR 抑制脊髓疼痛传递

基本信息

批准号：
10112962
负责人：
BRADLEY K. TAYLOR
金额：
$ 45.55万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-18 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10112962
关键词：
Adenylate Cyclase Advanced Glycosylation End Products Affect Affective 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 Intrathecal Injections Lactoylglutathione Lyase Measures Mechanics Mediating Metabolic Modeling Molecular Motivation 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 Differences Signal Transduction Spinal Spinal Cord Spine pain Stimulus Streptozocin Structure of beta Cell of islet TRPA channel Testing Traumatic Nerve Injury United States adduct adenylyl cyclase 1 chronic neuropathic pain chronic pain db/db mouse diabetic dorsal horn experience glycation inhibitor/antagonist innovation male mouse model new therapeutic target novel novel drug class overexpression pain behavior pain processing pain reduction pain relief painful neuropathy preclinical study public health relevance receptor small molecule small molecule inhibitor tissue processing transmission process

项目摘要

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.

9% 的美国人口患有糖尿病，其中约三分之一的患者患有糖尿病慢性神经性疼痛，通常称为疼痛性糖尿病神经病（PDN）。 PDN 很难镇痛治疗仅对一小部分 PDN 患者有效。的发展与糖尿病相关的疼痛镇痛药，特别是 2 型糖尿病，由于我们的不完全研究而停滞不前。了解PDN的底层机制。一个重要的新线索来自最近的发现甲基乙二醛 (MG) 是一种高反应性的糖酵解二羰基产物，会随着高血糖在 PDN 患者中尤其高。 MG 引起蛋白质的非酶糖基化。这由此产生的蛋白质加合物或晚期糖基化终产物 (MG-AGE) 具有毒性，会导致糖尿病并发症包括 PDN。我们的中心假设是 2 型糖尿病患者的 MG 升高会导致疼痛和可以通过针对 MG 本身、TRPA1、AC1、Epac 和 PPARγ 的新型药物来缓解这一问题。到检验 MG 导致 2 型糖尿病神经病理性疼痛 (PDN) 的假设，具体目标 1 将首先确定 MG 及其代谢酶 Glyoxalase-1 的升高是否发生在疼痛处理过程中 2 型遗传性 Leprdb/db (db/db) 小鼠和 Zucker 糖尿病脂肪 (ZDF) 大鼠模型中的组织糖尿病。然后我们询问一类有前途的新型 MG 清除肽是否能减轻情感疼痛和脊髓疼痛传播。我们的初步数据表明，基因缺失或药理抑制 TRPA1 是 MG 的糖化靶标，可阻断 MG 引起的疼痛。事实上，TRPA1 是开发用于慢性疼痛的新型镇痛药，但尚未在 2 型 PDN 模型中进行测试。为了填补这个差距，具体目标 2 将检验 TRPA1 拮抗剂减轻情感疼痛和脊髓疼痛的假设 db/db 小鼠和 ZDF 大鼠中的传播。 TRPA1 通道打开（例如通过 MG）后，产生的 Ca2+ 流入细胞导致 Ca2+ 敏感蛋白激活，其中包括腺苷酸环化酶 I （AC1）。我们的数据表明，用 NB001 选择性抑制 AC1 可阻断 2 型 PDN。 AC1 生成细胞内第二信使 cAMP，不仅靶向蛋白激酶 A，还靶向交换蛋白由 cAMP (Epac) 直接激活。 Specific Aim 3 将使用新型 Epac1 和 Epac2 小分子抑制剂确定哪些目标驱动 PDN。 33 篇原创研究文章、评论和一本书在上一个资助周期（以 PI 作为第一或高级作者的 22 次）发表，我们的进展包括发现吡格列酮是一种过氧化物酶体增殖物激活受体 γ (PPARγ) 激动剂，FDA- 批准用于治疗糖尿病，作用于背角神经元，抑制与皮肤相关的慢性疼痛炎症和创伤性神经损伤。我们的新数据表明对 PDN 和 MG 诱导的额外功效疼痛，对女性具有令人惊讶的强大镇痛作用。具体目标 4 建议研究 PPARγ db/db 和 ZDF 的作用机制，新的重点是脊髓伤害性传播中的性别差异。

项目成果

期刊论文数量（47）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Short-lived diabetes in the young-adult ZDF rat does not exacerbate neuronal Ca(2+) biomarkers of aging.

年轻成年 ZDF 大鼠的短期糖尿病不会加剧衰老的神经元 Ca(2) 生物标志物。

DOI：
10.1016/j.brainres.2014.10.052
发表时间：
2015
期刊：
Brain research
影响因子：
2.9
作者：
Maimaiti,Shaniya;DeMoll,Chris;Anderson,KatieL;Griggs,RyanB;Taylor,BradleyK;Porter,NadaM;Thibault,Olivier
通讯作者：
Thibault,Olivier

Endogenous analgesia, dependence, and latent pain sensitization.