Laboratorio de Nocicepción y Dolor Neuropático, Instituto de Biología y Medicina Experimental - CONICET, Buenos Aires, Argentina.
Instituto de Investigaciones en Medicina Traslacional, Universidad Austral - CONICET, Buenos Aires, Argentina.
J Peripher Nerv Syst. 2019 Mar;24(1):100-110. doi: 10.1111/jns.12307. Epub 2019 Feb 25.
Chemotherapy-induced peripheral neuropathy is a disabling condition induced by several frequently used chemotherapeutic drugs including the front-line agent oxaliplatin (OXA). Symptoms are predominantly sensory with the development of neuropathic pain. Alternative dosing protocols and treatment discontinuation are the only available therapeutic strategies. The aim of our work was to evaluate the potential of a synthetic derivative of progesterone, 17α-hydroxyprogesterone caproate (HPGC), in the prevention and treatment of OXA-evoked painful neuropathy. We also evaluated glial activation at the dorsal root ganglia (DRG) and spinal cord levels as a possible target mechanism underlying HPGC actions. Male rats were injected with OXA and HPGC following a prophylactic (HPGCp) or therapeutic (HPGCt) scheme (starting either before or after chemotherapy). The development of hypersensitivity and allodynic pain and the expression of neuronal and glial activation markers were evaluated. When compared to control animals, those receiving OXA showed a significant decrease in paw mechanical and thermal thresholds, with the development of allodynia. Animals treated with HPGCp showed patterns of response similar to those detected in control animals, while those treated with HPGCt showed a suppression of both hypersensitivities after HPGC administration. We also observed a significant increase in the mRNA levels of activating transcription factor 3, the transcription factor (c-fos), glial fibrillary acidic protein, ionized calcium binding adaptor protein 1, interleukin 1 beta (IL-1β) and tumor necrosis factor alpha (TNFα) in DRG and spinal cord of OXA-injected animals, and significantly lower levels in rats receiving OXA and HPGC. These results show that HPGC administration reduces neuronal and glial activation markers and is able to both prevent and suppress OXA-induced allodynia, suggesting a promising therapeutic strategy.
化疗引起的周围神经病变是由几种常用化疗药物引起的一种致残性疾病，包括一线药物奥沙利铂（OXA）。症状主要是感觉性的，伴有神经性疼痛的发展。替代剂量方案和治疗中断是唯一可用的治疗策略。我们的工作目的是评估孕激素的合成衍生物 17α-羟孕酮己酸酯（HPGC）在预防和治疗 OXA 诱发的痛性神经病中的潜力。我们还评估了背根神经节（DRG）和脊髓水平的神经胶质激活作为 HPGC 作用的可能靶点机制。雄性大鼠在接受 OXA 和 HPGC 注射后，按照预防（HPGCp）或治疗（HPGCt）方案（在化疗前或化疗后开始）。评估了超敏反应和痛觉过敏的发展以及神经元和神经胶质激活标志物的表达。与对照动物相比，接受 OXA 治疗的动物表现出明显的爪机械和热阈值降低，并出现痛觉过敏。接受 HPGCp 治疗的动物表现出与对照动物相似的反应模式，而接受 HPGCt 治疗的动物在 HPGC 给药后抑制了两种超敏反应。我们还观察到在 OXA 注射动物的 DRG 和脊髓中，激活转录因子 3、转录因子（c-fos）、神经胶质纤维酸性蛋白、离子钙结合衔接蛋白 1、白细胞介素 1β（IL-1β）和肿瘤坏死因子α（TNFα）的 mRNA 水平显著增加，而接受 OXA 和 HPGC 治疗的大鼠的水平显著降低。这些结果表明，HPGC 给药降低了神经元和神经胶质激活标志物，既能预防又能抑制 OXA 诱导的痛觉过敏，提示一种有前途的治疗策略。
