Beijing Key Laboratory for Separation and Analysis in Biomedicine and Pharmaceutical, Beijing Institute of Technology (BIT), Beijing, People's Republic of China.
Department of Pharmacology, Riphah Institute of Pharmaceutical Sciences, Riphah International University, Islamabad, Pakistan.
Clin Exp Pharmacol Physiol. 2024 Nov;51(11):e13922. doi: 10.1111/1440-1681.13922.
Neuropathic pain arises from impairments or malfunctions within the nervous system, resulting in atypical transmission and interpretation of pain signals. In the present study, we examined the neuroprotective effects of agomelatine (AGM) and agomelatine-loaded nanostructured lipid carriers (AGM-NLCs) in neuropathic animal models induced by chronic constriction injury (CCI) of the sciatic nerve. Male Sprague Dawley rats were divided into seven experimental groups to compare the effects of AGM and AGM-NLCs, which were administered at 20 mg/kg for 14 consecutive days after CCI. Our finding demonstrated that CCI triggered the onset of analgesia in these animals, corroborated by mechanical allodynia and thermal hyperalgesia. Furthermore, CCI induced an elevation in inflammatory mediators such as interleukin (IL)-1β and inducible nitric oxide synthase (iNOS), and downregulated heme oxygenase-1 (HO-1) and nuclear factor E2-related factor (Nrf2). Treatment with AGM and AGM-NLCs reversed inflammatory cascades and elevated antioxidant enzyme levels, leading to a reduction in paw withdrawal latency and threshold in rats. To further investigate the effect of AGM and AGM-NLCs, all-trans retinoic acid (ATRA) was administered, which antagonizes Nrf2. ATRA substantially downregulated Nrf2 expression and exacerbated thermal hyperalgesia, whereas Nrf2 and HO-1 expressions were significantly upregulated after AGM-NLCs administration. Overall, the results demonstrated that AGM-NLCs offer promising antinociceptive and anti-inflammatory properties in alleviating neuropathic pain symptoms, which can be attributed to improved drug delivery and therapeutic outcomes compared with AGM alone.
神经病理性疼痛源于神经系统的损伤或功能障碍，导致疼痛信号的异常传递和解释。在本研究中，我们研究了褪黑素激动剂（AGM）和载 AGM 的纳米结构脂质载体（AGM-NLC）在坐骨神经慢性缩窄性损伤（CCI）诱导的神经病理性动物模型中的神经保护作用。雄性 Sprague Dawley 大鼠分为 7 个实验组，以比较 AGM 和 AGM-NLC 的效果，CCI 后连续 14 天每天给予 20mg/kg。我们的研究结果表明，CCI 引发了这些动物的镇痛作用，机械性痛觉过敏和热痛觉过敏得到了证实。此外，CCI 诱导了炎症介质（如白细胞介素 1β和诱导型一氧化氮合酶）的升高，并下调了血红素加氧酶 1（HO-1）和核因子 E2 相关因子（Nrf2）。AGM 和 AGM-NLC 的治疗逆转了炎症级联反应，提高了抗氧化酶水平，导致大鼠的足底撤回潜伏期和阈值降低。为了进一步研究 AGM 和 AGM-NLC 的作用，给予了全反式视黄酸（ATRA），其拮抗 Nrf2。ATRA 显著下调了 Nrf2 的表达并加重了热痛觉过敏，而 AGM-NLC 给药后 Nrf2 和 HO-1 的表达明显上调。总的来说，结果表明，AGM-NLC 在缓解神经病理性疼痛症状方面具有有前景的镇痛和抗炎特性，这归因于与单独使用 AGM 相比，改善了药物递送和治疗效果。
