Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran; Student Research Committee, Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Biochem Pharmacol. 2019 Jan;159:154-171. doi: 10.1016/j.bcp.2018.12.001. Epub 2018 Dec 5.
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 (CB) 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 CB, 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 CB 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.
髓磷脂丢失继发于少突胶质细胞死亡已在多种髓鞘相关疾病中报道，如多发性硬化症（MS）。脂多糖（LPS）已被证明可在中枢神经系统（CNS）中引发细胞反应，并触发免疫浸润物和神经胶质细胞释放各种炎症细胞因子和介质。LPS 诱导的少突胶质细胞毒性可能被选为评估化合物在神经保护活性中少突胶质细胞作用的有效模型。β-石竹烯（BCP）是一种选择性 2 型大麻素（CB）受体激动剂。然而，BCP 抗炎作用的机制尚不完全清楚。在此基础上，我们旨在研究广泛的 BCP 浓度对 LPS 诱导的增殖性少突胶质细胞系（OLN-93）毒性的保护作用，并评估 BCP 浓度与选择性调节 CB、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。γ。我们发现 LPS 显著增加活性氧（ROS）、一氧化氮（NO）代谢物和肿瘤坏死因子（TNF）-α的产生水平，同时降低 GSH 水平。BCP 可以防止 LPS 诱导的细胞毒性和 NO、ROS 和 TNF-α的过度产生。此外，我们证明 BCP 对 LPS 诱导的少突胶质细胞毒性的保护作用是通过 CB 受体通过不同的途径介导的，包括 Nrf2/HO-1/抗氧化轴和 PPAR-γ，分别在低（0.2 和 1μM）和高（10-50μM）浓度下。此外，我们观察到添加鞘磷脂酶抑制剂丙咪嗪（IMP）和氟西汀（FLX）可协同增强 BCP 的保护作用。最后，BCP 在低浓度下表现出有希望的保护作用，可考虑用于治疗多发性硬化症等神经退行性疾病。然而，应该使用其他神经退行性疾病模型进行更多研究，以评估 SMase 的活性或表达等不同参数。
