Department of Pharmacological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104, USA.
J Neurosci. 2012 May 2;32(18):6149-60. doi: 10.1523/JNEUROSCI.6343-11.2012.
Chemotherapy-induced peripheral neuropathy (CIPN) accompanied by chronic neuropathic pain is a major dose-limiting side effect of a large number of antitumoral agents including paclitaxel (Taxol). Thus, CIPN is one of most common causes of dose reduction and discontinuation of what is otherwise a life-saving therapy. Neuropathological changes in spinal cord are linked to CIPN, but the causative mediators and mechanisms remain poorly understood. We report that formation of peroxynitrite (PN) in response to activation of nitric oxide synthases and NADPH oxidase in spinal cord contributes to neuropathological changes through two mechanisms. The first involves modulation of neuroexcitatory and proinflammatory (TNF-α and IL-1β) and anti-inflammatory (IL-10 and IL-4) cytokines in favor of the former. The second involves post-translational nitration and modification of glia-derived proteins known to be involved in glutamatergic neurotransmission (astrocyte-restricted glutamate transporters and glutamine synthetase). Targeting PN with PN decomposition catalysts (PNDCs) not only blocked the development of paclitaxel-induced neuropathic pain without interfering with antitumor effects, but also reversed it once established. Herein, we describe our mechanistic study on the role(s) of PN and the prevention of neuropathic pain in rats using known PNDCs (FeTMPyP(5+) and MnTE-2-PyP(5+)). We also demonstrate the prevention of CIPN with our two new orally active PNDCs, SRI6 and SRI110. The improved chemical design of SRI6 and SRI110 also affords selectivity for PN over other reactive oxygen species (such as superoxide). Our findings identify PN as a critical determinant of CIPN, while providing the rationale toward development of superoxide-sparing and "PN-targeted" therapeutics.
化疗引起的周围神经病（CIPN）伴有慢性神经病理性疼痛，是包括紫杉醇（Taxol）在内的大量抗肿瘤药物的主要剂量限制副作用。因此，CIPN 是减少剂量和中断原本救命治疗的最常见原因之一。脊髓中的神经病理学变化与 CIPN 有关，但导致这种变化的介质和机制仍知之甚少。我们报告，脊髓中一氧化氮合酶和 NADPH 氧化酶的激活导致过氧亚硝酸盐（PN）的形成，通过两种机制导致神经病理学变化。第一种机制涉及神经兴奋和促炎（TNF-α 和 IL-1β）和抗炎（IL-10 和 IL-4）细胞因子的调节，有利于前者。第二种机制涉及已知参与谷氨酸能神经传递的神经胶质衍生蛋白的翻译后硝化和修饰（星形胶质细胞特异性谷氨酸转运体和谷氨酰胺合成酶）。用 PN 分解催化剂（PNDCs）靶向 PN 不仅可以阻断紫杉醇诱导的神经病理性疼痛的发展，而不干扰抗肿瘤作用，而且一旦建立也可以逆转它。在此，我们描述了我们使用已知的 PNDCs（FeTMPyP(5+)和 MnTE-2-PyP(5+)）在大鼠中对 PN 作用和预防神经病理性疼痛的机制研究。我们还展示了我们的两种新的口服活性 PNDCs（SRI6 和 SRI110）预防 CIPN 的效果。SRI6 和 SRI110 的改进化学设计还提供了对 PN 的选择性，而不是对其他活性氧物质（如超氧自由基）的选择性。我们的发现确定了 PN 是 CIPN 的关键决定因素，同时为开发超氧化物节约和“PN 靶向”治疗提供了依据。
