Department of Neurosurgery, CHA Bundang Medical Center, School of Medicine, CHA University, 59 Yaptap-ro, Bundang-gu, Seongnam-si, Gyeonggi-do, 13496, Republic of Korea.
Department of Neurosurgery, Kyung Hee University, Dongdaemun-gu, Seoul, 02447, Republic of Korea.
Mol Neurobiol. 2019 Aug;56(8):5539-5554. doi: 10.1007/s12035-019-1468-7. Epub 2019 Jan 12.
Neuropathic pain is a devastating chronic condition and effective treatments are still lacking. Carbon monoxide-releasing molecule-2 (CORM-2) as a carbon monoxide (CO) carrier, exerts potent anti-neuropathic pain effects; however, its poor water solubility and short half-life hinder its clinical utility. Therefore, the aim of this study was to investigate whether CORM-2-loaded solid lipid nanoparticles (CORM-2-SLNs) enhance the anti-allodynic and anti-hyperalgesic effects of CORM-2 in a rat chronic constriction injury (CCI) model. CORM-2-SLNs were prepared using a nanotemplate engineering technique with slight modifications. The physiochemical properties of CORM-2-SLNs were characterized and CO release from CORM-2-SLNs was assessed using a myoglobin assay. CO was slowly released from CORM-2-SLNs, was observed, and the half-life of CO release was 50 times longer than that of CORM-2. In vivo results demonstrate that intraperitoneal administration of CORM-2-SLNs (5 and 10 mg/kg/day, ip) once daily for seven consecutive days significantly reduced the mechanical allodynia and mechanical hyperalgesia compared with CORM-2 (10 mg/kg/day, ip). RT-PCR and Western blot analyses on days 7 and 14, revealed that treatment with CORM-2-SLNs resulted in greater reductions in the CCI-elevated levels of heme-oxygenase-2 (HO-2); inducible nitric oxide synthase (iNOS); neuronal NOS (nNOS); and inflammatory mediators (TNF-α, IBA-1, and GFAP) in the spinal cord and dorsal root ganglions compared with treatment with CORM-2. In contrast, HO-1 and IL-10 were significantly increased in the CORM-2-SLN-treated group compared with the group treated with CORM-2. These data indicate that CORM-2-SLNs are superior to CORM-2-S in alleviating mechanical allodynia and mechanical hyperalgesia.
神经病理性疼痛是一种破坏性的慢性疾病，目前仍缺乏有效的治疗方法。一氧化碳释放分子-2（CORM-2）作为一氧化碳（CO）载体，具有很强的抗神经病理性疼痛作用；然而，其水溶性差和半衰期短限制了其临床应用。因此，本研究旨在探讨 CORM-2 负载固体脂质纳米粒（CORM-2-SLNs）是否能增强 CORM-2 在大鼠慢性缩窄性损伤（CCI）模型中的抗痛觉过敏和抗痛觉过高作用。CORM-2-SLNs 采用稍加改良的纳米模板工程技术制备。对 CORM-2-SLNs 的理化性质进行了表征，并通过肌红蛋白测定法评估了 CORM-2-SLNs 中 CO 的释放情况。结果表明，CORM-2-SLNs 缓慢释放 CO，其半衰期是 CORM-2 的 50 倍。体内实验结果表明，连续 7 天每天腹腔注射 CORM-2-SLNs（5 和 10mg/kg/天，ip）一次，可明显减轻机械性痛觉过敏和机械性痛觉过高，优于 CORM-2（10mg/kg/天，ip）。第 7 和 14 天的 RT-PCR 和 Western blot 分析显示，与 CORM-2 治疗组相比，CORM-2-SLNs 治疗组可使 CCI 引起的脊髓和背根神经节中血红素加氧酶-2（HO-2）、诱导型一氧化氮合酶（iNOS）、神经元型一氧化氮合酶（nNOS）和炎症介质（TNF-α、IBA-1 和 GFAP）的升高水平显著降低，而 CORM-2-SLN 治疗组 HO-1 和 IL-10 的升高水平显著高于 CORM-2 治疗组。这些数据表明，CORM-2-SLNs 在缓解机械性痛觉过敏和机械性痛觉过高方面优于 CORM-2。
