Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58 Rinku-Ourai Kita, Izumisano, Osaka, 598-8531, Japan.
Department of Regenerative Science, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan.
Neurochem Res. 2018 Sep;43(9):1723-1735. doi: 10.1007/s11064-018-2587-7. Epub 2018 Jun 26.
In several neurodegenerative diseases such as Alzheimer's disease (AD), microglia are hyperactivated and release nitric oxide (NO) and proinflammatory cytokines, resulting its neuropathology. Mounting evidence indicates that dietary supplementation with coconut oil (CNO) reduces the cognitive deficits associated with AD; however, the precise mechanism(s) underlying the beneficial effect of CNO are unknown. In the present study, we examined the effects of lauric acid (LA), a major constituent of CNO, on microglia activated experimentally by lipopolysaccharide (LPS), using primary cultured rat microglia and the mouse microglial cell line, BV-2. LA attenuated LPS-stimulated NO production and the expression of inducible NO synthase protein without affecting cell viability. In addition, LA suppressed LPS-induced reactive oxygen species and proinflammatory cytokine production, as well as phosphorylation of p38-mitogen activated protein kinase and c-Jun N-terminal kinase. LA-induced suppression of NO production was partially but significantly reversed in the presence of GW1100, an antagonist of G protein-coupled receptor (GPR) 40, which is an LA receptor on the plasma membrane. LA also decreased LPS-induced phagocytosis, which was completely reversed by co-treatment with GW1100. Moreover, LA alleviated amyloid-β-induced enhancement of phagocytosis. These results suggest that attenuation of microglial activation by LA may occur via the GPR40-dependent pathway. Such effects of LA may reduce glial activation and the subsequent neuronal damage in AD patients who consume CNO.
在几种神经退行性疾病中，如阿尔茨海默病 (AD)，小胶质细胞被过度激活并释放一氧化氮 (NO) 和促炎细胞因子，导致其神经病理学发生。越来越多的证据表明，椰子油 (CNO) 的饮食补充可以减轻与 AD 相关的认知缺陷；然而，CNO 有益作用的确切机制尚不清楚。在本研究中，我们使用原代培养的大鼠小胶质细胞和小鼠小胶质细胞系 BV-2 研究了月桂酸 (LA)，CNO 的主要成分之一，对实验性脂多糖 (LPS) 激活的小胶质细胞的影响。LA 减弱了 LPS 刺激的 NO 产生和诱导型一氧化氮合酶蛋白的表达，而不影响细胞活力。此外，LA 抑制了 LPS 诱导的活性氧和促炎细胞因子的产生，以及 p38-丝裂原活化蛋白激酶和 c-Jun N-末端激酶的磷酸化。在存在 GW1100（G 蛋白偶联受体 (GPR) 40 的拮抗剂）的情况下，LA 诱导的 NO 产生抑制部分但显著逆转，GPR40 是质膜上的 LA 受体。LA 还降低了 LPS 诱导的吞噬作用，GW1100 共同处理完全逆转了这一作用。此外，LA 减轻了淀粉样蛋白-β诱导的吞噬作用增强。这些结果表明，LA 通过 GPR40 依赖性途径抑制小胶质细胞激活。LA 的这种作用可能会减少 AD 患者消耗 CNO 时胶质细胞的激活和随后的神经元损伤。
