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  3. Pretreatment with low-dose fimasartan ameliorates NLRP3 inflammasome-mediated neuroinflammation and brain injury after intracerebral hemorrhage

Pretreatment with low-dose fimasartan ameliorates NLRP3 inflammasome-mediated neuroinflammation and brain injury after intracerebral hemorrhage

  • Exp Neurol. 2018 Dec:310:22-32. doi: 10.1016/j.expneurol.2018.08.013.
Xiuli Yang 1,  Jing Sun 2,  Tae Jung Kim 3,  Young-Ju Kim 3,  Sang-Bae Ko 3,  Chi Kyung Kim 4,  Xiaofeng Jia 5,  Byung-Woo Yoon 6
Affiliations

Affiliations

  • 1 Department of Neurology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
  • 2 Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea; Department of Neurology, China-Japan Union Hospital of Jilin University, Changchun, 130000 Jilin, China.
  • 3 Department of Neurology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea.
  • 4 Department of Neurology, Korea University Guro Hospital, Seoul 08308, Republic of Korea.
  • 5 Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Anatomy Neurobiology, University of Maryland School of Medicine, Baltimore, MD 21201, USA; Department of Biomedical Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA; Department of Anesthesiology and Critical Care Medicine, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: xjia@som.umaryland.edu.
  • 6 Department of Neurology, Seoul National University Hospital, Seoul 03080, Republic of Korea; Biomedical Research Institute, Seoul National University Hospital, Seoul 03080, Republic of Korea; Neuroscience Research Institute, Seoul National University College of Medicine, Seoul 03087, Republic of Korea. Electronic address: bwyoon@snu.ac.kr.
PMID: 30171865 DOI: 10.1016/j.expneurol.2018.08.013
Abstract

Nucleotide-binding and oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome, which is composed of an NLRP3 domain, the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC) domain, and procaspase-1, plays an important role in the immune pathophysiology of the secondary damage induced by intracerebral hemorrhage (ICH). This study aims to investigate whether pre-stroke treatment with fimasartan, an angiotensin II receptor blocker, has anti-inflammatory effects on ICH by inhibiting the activation of the NLRP3 inflammasome. Sprague-Dawley rats were divided into five groups: sham, vehicle, low-dose (0.5 mg/kg) and regular-doses (1.0 and 3.0 mg/kg) fimasartan. These rats were treated for 30 days before the induction of collagenase-induced ICH and continuously 3 days after surgery. The mean blood pressure (BP) in the low-dose fimasartan group was not significantly different from that of control, and BP in the regular-dose groups was decreased in a dose-dependent manner. Pretreatment with low-dose fimasartan attenuated ICH-induced edema and improved neurological functions. Activation of the NLRP3/ASC/Caspase-1 and the NF-κB pathways after ICH was markedly reduced by low-dose fimasartan. The double immunofluorescence staining of brain cells showed a significant decrease in the co-localization of NLRP3 with Iba1 (microglia marker) positive cells by fimasartan treatment. Cultured microglia cells stimulated by hemolysate demonstrated significant activation of the inflammasome, which was reduced by fimasartan. Pretreatment with a low-dose fimasartan alleviated brain damage after acute ICH by inhibiting the NLRP3 inflammasome without lowering MBP. Our study suggests pre-stroke administration of fimasartan could potentially attenuate ICH-induced secondary brain injury by targeting the inflammasome.

Keywords

Brain injury; Intracerebral hemorrhage; NLRP3 inflammasome; Stroke.

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