2. Academic Validation
  3. Propagermanium, a CCR2 inhibitor, attenuates cerebral ischemia/reperfusion injury through inhibiting inflammatory response induced by microglia

Propagermanium, a CCR2 inhibitor, attenuates cerebral ischemia/reperfusion injury through inhibiting inflammatory response induced by microglia

  • Neurochem Int. 2019 May:125:99-110. doi: 10.1016/j.neuint.2019.02.010.
Shucheng He 1,  Rui Liu 1,  Binbin Li 1,  Liangliang Huang 1,  Wenxiang Fan 1,  Charmaine Ruvimbo Tembachako 1,  Xiaoya Zheng 2,  Xiaoxing Xiong 3,  Masaaki Miyata 4,  Baohui Xu 5,  Yunman Li 6,  Weirong Fang 7
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China.
  • 2 Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China.
  • 3 Renmin Hospital of Wuhan University, Wuhan, Hubei, 430006, China.
  • 4 Department of Cardiovascular Medicine, Kagoshima City Hospital, Japan.
  • 5 Department of Surgery, Stanford University School of Medicine, Stanford, CA, 94305, USA.
  • 6 State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China. Electronic address: yunmanlicpu@hotmail.com.
  • 7 State Key Laboratory of Natural Medicines, School of Basic Medical Sciences and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, 210009, China. Electronic address: weirongfang@cpu.edu.cn.
PMID: 30794846 DOI: 10.1016/j.neuint.2019.02.010
Abstract

CCR2 could recruit immune cells migrating into brain after ischemic stroke. It is unclear whether and why Propagermanium (PG, a CCR2 Inhibitor) is able to protect against ischemic injury. Middle cerebral artery occlusion (MCAO) and reperfusion injury in C57BL/6 J male mice were performed in vivo to mimic ischemic stroke. Cultured BV2 microglia exposed to oxygen and glucose deprivation (OGD)/reoxygenation injury, LPS or IL-4 incubation were served in vitro. TTC staining, neurological score, brain water content, and MRI scan were performed to evaluate stroke outcome. Real time PCR, ELISA, and immunofluorescence were used to estimate inflammatory cytokines expression and releasing. Western blot was utilized to detect pSTAT1/STAT1 expression. Compared with MCAO mice, PG treatment significantly reduced infarction size and brain edema, improved neurological behavior at 72 h after MCAO. For inflammatory response, PG treatment inhibited inflammatory cytokines releasing, such as TNF-α, IFN-γ, IL-1β, IL-6, IL-12, IL-17, and IL-23. Further studies indicated that PG treatment downregulated mRNA expression of pro-inflammatory iNOS and CD86, and inhibited CD16 expressed in microglia. In vitro, PG incubation inhibited BV2 polarized to pro-inflammatory phenotype through STAT1 downregulation, while had no obvious effect on anti-inflammatory phenotype. Our observations suggest that CCR2 Inhibitor PG downregulated pro-inflammatory microglia polarization for decreasing pro-inflammatory microglia phenotype marker, and thereafter inhibited inflammatory responses after MCAO in a STAT1-dependent manner.

Keywords

Inflammation; Ischemic stroke; Microglia; Polarization; Propagermanium.

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