Department of Anesthesiology & Critical Care Medicine, MSC10 6000, 2211 Lomas Blvd. NE, University of New Mexico Health Sciences Center, Albuquerque, NM 87131, USA.
USA Elixiria Biotech Inc, 200 High Point Drive, Hartsdale, NY 10530, USA.
Molecules. 2020 Mar 3;25(5):1120. doi: 10.3390/molecules25051120.
Effective, non-addictive therapeutics for chronic pain remain a critical need. While there are several potential therapeutics that stimulate anti-inflammatory mechanisms to restore homeostasis in the spinal dorsal horn microenvironment, the effectiveness of drugs for neuropathic pain are still inadequate. The convergence of increasing knowledge about the multi-factorial mechanisms underlying neuropathic pain and the mechanisms of drug action from preclinical studies are providing the ability to create pharmaceuticals with better clinical effectiveness. By targeting and activating the peroxisome proliferator-activated receptor gamma subunit (PPARγ), numerous preclinical studies report pleiotropic effects of thiazolidinediones (TDZ) beyond their intended use of increasing insulin, including their anti-inflammatory, renal, cardioprotective, and oncopreventative effects. Several studies find TDZs reduce pain-related behavioral symptoms, including ongoing secondary hypersensitivity driven by central sensitization. Previous studies find increased PPARγ in the spinal cord and brain regions innervated by incoming afferent nerve endings after the induction of neuropathic pain models. PPARγ agonist treatment provides an effective reduction in pain-related behaviors, including anxiety. Data further suggest that improved brain mitochondrial bioenergetics after PPARγ agonist treatment is a key mechanism for reducing hypersensitivity. This review emphasizes two points relevant for the development of better chronic pain therapies. First, employing neuropathic pain models with chronic duration is critical since they can encompass the continuum of molecular and brain circuitry alterations arising over time when pain persists, providing greater relevance to clinical pain syndromes. Assisting in that effort are preclinical models of chronic trigeminal pain syndromes. Secondly, considering the access to nerve and brain neurons and glia across the blood-brain barrier is important. While many therapies have low brain penetrance, a PPARγ agonist with better brain penetrance, ELB00824, has been developed. Purposeful design and recent comparative testing indicate that ELB00824 is extraordinarily efficient and efficacious. ELB00824 provides greatly improved attenuation of pain-related behaviors, including mechanical hypersensitivity, anxiety, and depression in our chronic trigeminal nerve injury models. Physiochemical properties allowing significant brain access and toxicity testing are discussed.
对于慢性疼痛，仍然需要有效的、非成瘾性的治疗方法。虽然有几种潜在的治疗方法可以刺激抗炎机制，以恢复脊髓背角微环境的内稳态，但治疗神经病理性疼痛的药物效果仍然不足。随着对神经病理性疼痛潜在多因素机制和临床前研究中药物作用机制的认识不断增加，正在为创造具有更好临床疗效的药物提供能力。通过靶向和激活过氧化物酶体增殖物激活受体 γ 亚单位（PPARγ），许多临床前研究报告了噻唑烷二酮（TDZ）除了增加胰岛素以外的多种多效性作用，包括其抗炎、肾保护、心脏保护和抗肿瘤预防作用。几项研究发现 TDZ 可减轻与疼痛相关的行为症状，包括由中枢敏化引起的持续继发性超敏反应。先前的研究发现，在诱导神经病理性疼痛模型后，脊髓和受传入神经末梢支配的脑区中 PPARγ 增加。PPARγ 激动剂治疗可有效减轻与疼痛相关的行为，包括焦虑。数据进一步表明，PPARγ 激动剂治疗后大脑线粒体生物能的改善是减轻超敏反应的关键机制。本文强调了与开发更好的慢性疼痛治疗方法相关的两点。首先，使用具有慢性持续时间的神经病理性疼痛模型至关重要，因为它们可以涵盖随着时间推移持续存在的疼痛时出现的分子和大脑电路改变的连续体，从而为临床疼痛综合征提供更大的相关性。慢性三叉神经痛综合征的临床前模型有助于实现这一目标。其次，考虑到神经和大脑神经元和神经胶质的血脑屏障通透性很重要。虽然许多疗法的大脑通透性较低，但已经开发出一种具有更好大脑通透性的 PPARγ 激动剂，ELB00824。有目的的设计和最近的比较测试表明，ELB00824 非常高效和有效。ELB00824 极大地改善了我们的慢性三叉神经损伤模型中与疼痛相关的行为，包括机械超敏反应、焦虑和抑郁的减轻。还讨论了允许大脑大量进入和毒性测试的物理化学特性。
