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Abstract：
Myelin loss subsequent to oligodendrocyte death has been reported in a variety of myelin-associated disorders such as multiple sclerosis (MS). Lipopolysaccharide (LPS) has been shown to elicit cellular responses in the central nervous system (CNS) and trigger immune infiltrates and glial cells to release a variety of inflammatory cytokines and mediators. LPS-induced oligodendrocytes toxicity may be chosen as an efficient model to evaluate the role of oligodendrocytes in neuroprotective activities of compounds. β-Caryophyllene (BCP) is a selective type 2 cannabinoid (CB2) receptor agonist. However, the mechanisms underlying the anti-inflammatory effects of BCP are not completely understood. On this basis, we aimed to investigate the protective effects of a wide range of BCP concentrations against LPS-induced toxicity in a proliferative oligodendrocyte cell line (OLN-93) and evaluate the possible correlation between BCP concentration and selective modulation of CB2, Nrf2, sphingomyelinase (SMase) and peroxisome proliferator-activated receptors (PPAR)-γ signaling pathways. We found that LPS significantly increases the levels of reactive oxygen species (ROS), nitric oxide (NO) metabolite and tumor necrosis factor (TNF)-α production while decreases the level of GSH. BCP could prevent LPS-induced cytotoxicity and excessive production of NO, ROS, and TNF-α. Also, we demonstrated that BCP\'s protective effects against LPS-induced oligodendrocytes toxicity were mediated via the CB2 receptor through different pathways including Nrf2/HO-1/anti-oxidant axis, and PPAR-γ, at low (0.2 and 1 µM), and high (10-50 µM) concentrations, respectively. Additionally, we observed that the addition of SMase inhibitors imipramine (IMP) and fluoxetine (FLX) synergistically increased the protective effects of BCP. Finally, BCP at low concentrations exerted promising protective effects that could be considered for the treatment of neurodegenerative disorders such as MS. However, more studies using other models of neurodegenerative diseases should be undertaken to assess different parameters such as the activity or expression of SMase.
摘要：
少突胶质细胞死亡后的髓磷脂损失已在多种髓磷脂相关疾病如多发性硬化(MS)中报道。脂多糖（LPS）已被证明在中枢神经系统（CNS）中引起细胞反应，并引发免疫浸润和神经胶质细胞释放多种炎性细胞因子和介质。可以选择LPS诱导的少突胶质细胞毒性作为评价少突胶质细胞在化合物的神经保护活性中的作用的有效模型。β-石竹烯（BCP）是一种选择性的2型大麻素（CB2）受体激动剂。然而,BCP抗炎作用的潜在机制尚不完全清楚.在此基础上,我们的目的是研究广泛浓度的BCP对LPS诱导的增殖性少突胶质细胞细胞系(OLN-93)毒性的保护作用,并评估BCP浓度与选择性调节CB2,Nrf2,鞘磷脂酶(SMase)和过氧化物酶体增殖物激活受体(PPAR)-γ信号通路之间的可能相关性.我们发现LPS显著增加活性氧（ROS）的水平，一氧化氮（NO）代谢物和肿瘤坏死因子（TNF）-α的产生同时降低了GSH的水平。BCP可以防止LPS诱导的细胞毒性和NO的过量产生，ROS,和TNF-α。此外，我们证明了BCP对LPS诱导的少突胶质细胞毒性的保护作用是通过CB2受体通过不同的途径介导的，包括Nrf2/HO-1/抗氧化轴，和PPAR-γ，在低（0.2和1µM），和高（10-50µM）浓度，分别。此外,我们观察到SMase抑制剂丙咪嗪（IMP）和氟西汀（FLX）的添加协同增加了BCP的保护作用。最后,低浓度的BCP发挥了有希望的保护作用，可以考虑用于治疗神经退行性疾病，如MS。然而,应使用其他神经退行性疾病模型进行更多研究，以评估不同的参数，例如SMase的活性或表达。
