Department of Pharmacology, School of Pharmacy, Nantong University, #19 Qixiu Road, Nantong, Jiangsu Province, China 226001.
Invasive Technology Department, Nantong First People's Hospital, The Second Affiliated Hospital of Nantong University, #6 North Road Hai'er Xiang, Nantong, 226001, Jiangsu, China.
J Nutr Biochem. 2020 Apr;78:108323. doi: 10.1016/j.jnutbio.2019.108323. Epub 2019 Dec 17.
Microglia are the innate immune cells in the nervous system. In the resting state, they display a ramified morphology, while upon disease stimulation their processes would be retracted, along with pro-inflammatory cytokine overproduction. Reversing microglial process retraction may help reduce pro-inflammatory cytokine production and restore microglia's ability to scan surrounding environments, rendering brain function regulation to be more effective. We found that diallyl disulfide (DADS), a major organosulfur compound in garlic oil, administered at different doses and time points, promoted microglial process elongation in both cultured systems and prefrontal cortexes in mice in a reversible manner. Lipopolysaccharide (LPS), a classical activator of microglia, did not affect this pro-elongation effect of DADS at conditions in vitro and in vivo. Functional studies revealed that DADS pre-treatment attenuated LPS-induced decreases in levels of tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) mRNA as well as LPS-induced increases in levels of IL-10 and CD206 mRNA in both cultured microglia and prefrontal cortexes in mice. Protein kinase B (Akt) inhibition attenuated the pro-elongation effect of DADS on microglial process and blocked the regulatory effects of DADS on LPS-induced inflammatory responses in both cultured microglia and prefrontal cortexes in mice. In an in vivo model of neuroinflammation, DADS pre-treatment prevented LPS-induced retraction of microglial process in the prefrontal cortex in mice and attenuated LPS-induced increase in immobility time in the tail suspension test and forced swim test. These results indicate that DADS induces an Akt-dependent elongation of microglia process, along with the induction of an anti-inflammatory phenotype.
小胶质细胞是神经系统中的先天免疫细胞。在静息状态下，它们呈现出分支状形态，而在疾病刺激下，它们的突起会缩回，并伴有促炎细胞因子的过度产生。逆转小胶质细胞突起回缩可能有助于减少促炎细胞因子的产生，并恢复小胶质细胞扫描周围环境的能力，从而更有效地调节大脑功能。我们发现，二烯丙基二硫（DADS），大蒜油中的一种主要有机硫化合物，以不同的剂量和时间点给药，可在体外培养系统和小鼠前额叶皮层中以可逆的方式促进小胶质细胞突起的伸长。脂多糖（LPS），一种经典的小胶质细胞激活剂，在体外和体内条件下，不影响 DADS 的这种促伸长作用。功能研究表明，DADS 预处理可减轻 LPS 诱导的 TNF-α 和 IL-1β mRNA 水平降低以及 LPS 诱导的 IL-10 和 CD206 mRNA 水平升高，无论是在体外培养的小胶质细胞还是在小鼠前额叶皮层中。蛋白激酶 B（Akt）抑制减弱了 DADS 对小胶质细胞突起的促伸长作用，并阻断了 DADS 对 LPS 诱导的体外培养的小胶质细胞和小鼠前额叶皮层中炎症反应的调节作用。在神经炎症的体内模型中，DADS 预处理可防止 LPS 诱导的小鼠前额叶皮层中小胶质细胞突起回缩，并减轻 LPS 诱导的尾部悬挂试验和强迫游泳试验中不动时间的增加。这些结果表明，DADS 诱导 Akt 依赖性小胶质细胞突起伸长，并诱导抗炎表型。
