Dipartimento di Farmacia, Università di Salerno, Fisciano, Salerno, Italy.
PLoS One. 2013 May 1;8(5):e62511. doi: 10.1371/journal.pone.0062511. Print 2013.
The efficacy of cannabinoids in the treatment of multiple sclerosis is widely documented; however their use is limited by psychoactivity mainly ascribed to the activation of the cannabinoid receptor CB1. Emerging findings support as alternative strategy in the treatment of neurodegenerative disorders, the application of compounds targeting the CB2 receptor, since likely unrelated to these side effects. Recently, a novel class of compounds, 1,8-naphthyridine, pyridine and quinoline derivatives have been demonstrated to show high CB2 receptor selectivity and affinity versus the CB1 receptor. Considering that the CB2 receptor is mainly expressed in cell and organs of the immune system, in this study we assessed the potential immune-modulatory effects of these compounds in activated lymphocytes isolated from MS patients with respect to healthy controls. These compounds blocked cell proliferation through a mechanism partially ascribed to the CB2 receptor, down-regulated TNF-α production and did not induce cell death. They also down-regulated Akt, Erk and NF-kB phosphorylation. Despite comparable effects observed in patients and healthy controls, these compounds, in particular, 1,8-naphthyridine and quinoline derivatives inhibited cell activation markers in MS patient derived lymphocytes more efficiently than in healthy control derived cells. Indeed, 1,8-naphthyridin-2-one derivative reduced the levels of Cox-2 in lymphocytes from patients whereas no effect was observed in control cells. Our findings suggest potential application of these drugs in neuro-inflammation, supporting further investigations of the effects of compounds in the therapy of MS, particularly on the aspects regarding activation and inflammation.
大麻素在多发性硬化症治疗中的疗效已被广泛记录；然而，它们的使用受到精神活性的限制，主要归因于大麻素受体 CB1 的激活。新出现的研究结果支持将针对 CB2 受体的化合物作为治疗神经退行性疾病的替代策略，因为这可能与这些副作用无关。最近，一类新型化合物，1,8-萘啶、吡啶和喹啉衍生物，已被证明对 CB2 受体具有高选择性和亲和力，而对 CB1 受体的亲和力较低。鉴于 CB2 受体主要在免疫细胞和器官中表达，在这项研究中，我们评估了这些化合物在来自多发性硬化症患者的活化淋巴细胞中相对于健康对照的潜在免疫调节作用。这些化合物通过部分归因于 CB2 受体的机制阻断细胞增殖，下调 TNF-α 的产生，并且不诱导细胞死亡。它们还下调 Akt、Erk 和 NF-κB 的磷酸化。尽管在患者和健康对照组中观察到相当的效果，但这些化合物，特别是 1,8-萘啶和喹啉衍生物，在多发性硬化症患者来源的淋巴细胞中比在健康对照组来源的细胞中更有效地抑制细胞激活标志物。事实上，1,8-萘啶-2-酮衍生物降低了来自患者的淋巴细胞中 Cox-2 的水平，而对照细胞中没有观察到这种作用。我们的研究结果表明这些药物在神经炎症中的潜在应用，支持进一步研究化合物在多发性硬化症治疗中的作用，特别是在激活和炎症方面。
