Pennsylvania Biotechnology Center, Kannalife Sciences, Inc, 3805 Old Easton Road, Doylestown, PA, 18902, USA.
Center for Substance Abuse Research, Department of Anatomy and Cell Biology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
J Mol Neurosci. 2022 Sep;72(9):1859-1874. doi: 10.1007/s12031-022-02038-2. Epub 2022 Jul 2.
KLS-13019, a novel devised cannabinoid-like compound, was explored for anti-inflammatory actions in dorsal root ganglion cultures relevant to chemotherapy-induced peripheral neuropathy (CIPN). Time course studies with 3 µM paclitaxel indicated > 1.9-fold increases in immunoreactive (IR) area for cell body GPR55 after 30 min as determined by high content imaging. To test for reversibility of paclitaxel-induced increases in GPR55, cultures were treated for 8 h with paclitaxel alone and then a dose response to KLS-13019 added for another 16 h. This "reversal" paradigm indicated established increases in cell body GPR55 IR areas were decreased back to control levels. Because GPR55 had previously reported inflammatory actions, IL-1β and NLRP3 (inflammasome-3 marker) were also measured in the "reversal" paradigm. Significant increases in all inflammatory markers were produced after 8 h of paclitaxel treatment alone that were reversed to control levels with KLS-13019 treatment. Accompanying studies using alamar blue indicated that decreased cellular viability produced by paclitaxel treatment was reverted back to control levels by KLS-13019. Similar studies conducted with lysophosphatidylinositol (GPR55 agonist) in DRG or hippocampal cultures demonstrated significant increases in neuritic GPR55, NLRP3 and IL-1β areas that were reversed to control levels with KLS-13019 treatment. Studies with a human GPR55-β-arrestin assay in Discover X cells indicated that KLS-13019 was an antagonist without agonist activity. These studies indicated that KLS-13019 has anti-inflammatory properties mediated through GPR55 antagonist actions. Together with previous studies, KLS-13019 is a potent neuroprotective, anti-inflammatory cannabinoid with therapeutic potential for high efficacy treatment of neuropathic pain.
KLS-13019 是一种新型拟大麻素化合物，研究其在与化疗诱导性周围神经病（CIPN）相关的背根神经节培养物中的抗炎作用。用 3µM 紫杉醇进行的时间进程研究表明，高内涵成像检测到 30 分钟后细胞体 GPR55 的免疫反应性（IR）面积增加了>1.9 倍。为了测试紫杉醇诱导的 GPR55 增加的可逆性，将培养物单独用紫杉醇处理 8 小时，然后再用 KLS-13019 处理 16 小时，进行剂量反应。这种“逆转”范式表明，细胞体 GPR55 IR 面积的增加已恢复到对照水平。因为 GPR55 先前被报道具有炎症作用，所以在“逆转”范式中还测量了 IL-1β 和 NLRP3（炎症小体-3 标志物）。单独用紫杉醇处理 8 小时后，所有炎症标志物均显著增加，而用 KLS-13019 处理后，这些标志物又恢复到对照水平。用 alamar blue 进行的伴随研究表明，紫杉醇处理导致的细胞活力降低恢复到对照水平。在背根神经节或海马培养物中用溶血磷脂酰肌醇（GPR55 激动剂）进行的类似研究表明，神经突 GPR55、NLRP3 和 IL-1β 区域显著增加，而用 KLS-13019 处理后恢复到对照水平。在 Discover X 细胞中的人 GPR55-β-arrestin 测定中进行的研究表明，KLS-13019 是一种无激动剂活性的拮抗剂。这些研究表明，KLS-13019 具有通过 GPR55 拮抗剂作用介导的抗炎特性。结合以前的研究，KLS-13019 是一种有效的神经保护、抗炎大麻素，具有治疗神经性疼痛的高疗效治疗潜力。
