Department of Functional Morphology, Institute of Physiology, The Czech Academy of Sciences, Prague, Czech Republic.
J Cell Mol Med. 2020 Jul;24(14):7949-7958. doi: 10.1111/jcmm.15427. Epub 2020 Jun 2.
Paclitaxel-induced peripheral neuropathy (PIPN) is often associated with neuropathic pain and neuroinflammation in the central and peripheral nervous system. Antihypertensive drug losartan, an angiotensin II receptor type 1 (AT1R) blocker, was shown to have anti-inflammatory and neuroprotective effects in disease models, predominantly via activation of peroxisome proliferator-activated receptor gamma (PPARγ). Here, the effect of systemic losartan treatment (100 mg/kg/d) on mechanical allodynia and neuroinflammation was evaluated in rat PIPN model. The expression of pro-inflammatory markers protein and mRNA levels in dorsal root ganglia (DRGs) and spinal cord dorsal horn (SCDH) were measured with Western blot, ELISA and qPCR 10 and 21 days after PIPN induction. Losartan treatment attenuated mechanical allodynia significantly. Paclitaxel induced overexpression of C-C motif chemokine ligand 2 (CCL2), tumour necrosis alpha (TNFα) and interleukin-6 (IL-6) in DRGs, where the presence of macrophages was demonstrated. Neuroinflammatory changes in DRGs were accompanied with glial activation and pro-nociceptive modulators production in SCDH. Losartan significantly attenuated paclitaxel-induced neuroinflammatory changes and induced expression of pro-resolving markers (Arginase 1 and IL-10) indicating a possible shift in macrophage polarization. Considering the safety profile of losartan, acting also as partial PPARγ agonist, it may be considered as a novel treatment strategy for PIPN patients.
紫杉醇诱导的周围神经病变（PIPN）常伴有中枢和周围神经系统的神经病理性疼痛和神经炎症。抗高血压药物氯沙坦，血管紧张素 II 受体 1 型（AT1R）阻断剂，在疾病模型中显示出抗炎和神经保护作用，主要通过激活过氧化物酶体增殖物激活受体γ（PPARγ）。在这里，我们评估了全身氯沙坦治疗（100mg/kg/d）对大鼠 PIPN 模型机械性痛觉过敏和神经炎症的影响。用 Western blot、ELISA 和 qPCR 检测 PIPN 诱导后 10 天和 21 天背根神经节（DRG）和脊髓背角（SCDH）中促炎标志物的蛋白和 mRNA 水平。氯沙坦治疗显著减轻机械性痛觉过敏。紫杉醇诱导 DRG 中 C-C 基序趋化因子配体 2（CCL2）、肿瘤坏死因子-α（TNFα）和白细胞介素-6（IL-6）的过度表达，其中证明存在巨噬细胞。DRG 中的神经炎症变化伴随着 SCDH 中胶质细胞激活和致痛调节物产生。氯沙坦显著减轻紫杉醇诱导的神经炎症变化，并诱导抗炎标记物（精氨酸酶 1 和 IL-10）的表达，表明巨噬细胞极化可能发生转变。考虑到氯沙坦的安全性，作为部分 PPARγ 激动剂，它可能被考虑作为 PIPN 患者的一种新的治疗策略。
