Ohnishi Masatoshi, Kai Takao, Shimizu Yuki, Yano Yukino, Urabe Yuui, Tasaka Shunpei, Akagi Marina, Yamaguchi Yasunori, Inoue Atsuko
Department of Pharmacotherapeutics, Graduate School of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima, Japan.
Department of Pharmacotherapeutics, Faculty of Pharmacy and Pharmaceutical Sciences, Fukuyama University, Fukuyama, Hiroshima, Japan.
J Pharm Pharmacol. 2020 May;72(5):709-718. doi: 10.1111/jphp.13235. Epub 2020 Feb 9.
Gadolinium (Gd) affects microglial polarization during remyelination. We previously reported that the suppression of proinflammatory microglia was neuroprotective in intracerebral haemorrhage (ICH). The objective of the present study was to investigate the effects of Gd on microglial polarization and neuronal injury after ICH.
Gadolinium was intraperitoneally administered to ICH mice prepared by an intrastriatal microinjection of collagenase type VII. The polarization of M1, 2a, b and c microglia was evaluated by real-time PCR using the respective markers. Changes in representative mRNAs were also confirmed by immunological methods. Neuroprotective effects were evaluated by counting NeuN-positive cells and a behavioural analysis.
One day after ICH, the mRNA levels of proinflammatory M1 microglial markers, such as inducible nitric oxide synthase (iNOS), and anti-inflammatory M2 microglial markers, such as arginase1 (M2a, c), Ym1 (M2a), and transforming growth factor-β (M2c), increased, while those of chemokine CCL1 (M2b) only increased after 3 days. Gd decreased the levels of all M1 and M2 markers. Arginase1 and iNOS protein levels also increased, and Gd reduced them due to apoptotic cell death. Gadolinium attenuated oedema, neuron loss, neurological deficits and the mortality rate without affecting haematoma sizes.
Gadolinium induced M1 and M2 microglial apoptosis and exerted acute neuroprotective effects after ICH.
钆（Gd）在髓鞘再生过程中影响小胶质细胞极化。我们之前报道过，在脑出血（ICH）中抑制促炎性小胶质细胞具有神经保护作用。本研究的目的是探讨Gd对ICH后小胶质细胞极化和神经元损伤的影响。
通过向纹状体内微量注射VII型胶原酶制备ICH小鼠，然后对其腹腔注射钆。使用各自的标志物通过实时PCR评估M1、2a、b和c小胶质细胞的极化情况。代表性mRNA的变化也通过免疫学方法得到证实。通过计数NeuN阳性细胞和进行行为分析来评估神经保护作用。
ICH后1天，促炎性M1小胶质细胞标志物如诱导型一氧化氮合酶（iNOS）的mRNA水平以及抗炎性M2小胶质细胞标志物如精氨酸酶1（M2a、c）、Ym1（M2a）和转化生长因子-β（M2c）的mRNA水平均升高，而趋化因子CCL1（M2b）的mRNA水平仅在3天后升高。Gd降低了所有M1和M2标志物的水平。精氨酸酶1和iNOS蛋白水平也升高，而Gd由于凋亡性细胞死亡使其降低。钆减轻了水肿、神经元丢失、神经功能缺损和死亡率，而不影响血肿大小。
钆诱导M1和M2小胶质细胞凋亡，并在ICH后发挥急性神经保护作用。
