Gadolinium causes M1 and M2 microglial apoptosis after intracerebral haemorrhage and exerts acute neuroprotective effects

• Published in: Journal of pharmacy and pharmacology 2020-05, Vol.72 (5), p.709-718
• Main Authors: Ohnishi, Masatoshi, Kai, Takao, Shimizu, Yuki, Yano, Yukino, Urabe, Yuui, Tasaka, Shunpei, Akagi, Marina, Yamaguchi, Yasunori, Inoue, Atsuko
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; Arginase - metabolism; Behavior, Animal - drug effects; Biomarkers - metabolism; Brain Edema - drug therapy; Cell death; Cerebral Hemorrhage - drug therapy; Cerebral Hemorrhage - metabolism; Cerebral Hemorrhage - pathology; Chemokine CCL1 - metabolism; Chemokines; Collagen; Collagenase; Edema; Gadolinium; Gadolinium - therapeutic use; Hematoma; Hemorrhage; Inflammation; intracerebral haemorrhage; M2 microglia; Male; Mice; Microglia; Microglia - drug effects; Microglia - metabolism; Microinjection; mRNA; Myelination; Neurological diseases; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Nitric oxide; Nitric Oxide Synthase Type II - metabolism; Nitric-oxide synthase; Polarization; RNA, Messenger - metabolism; Transforming Growth Factor beta - metabolism; Transforming growth factor-b
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.13235

Abstract Objectives 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. Methods 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. Key findings 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. Conclusions Gadolinium induced M1 and M2 microglial apoptosis and exerted acute neuroprotective effects after ICH.