Phthalide derivative CD21 regulates the platelet- neutrophil extracellular trap-thrombin axis and protects against ischemic brain injury in rodents

  • Int Immunopharmacol. 2022 Dec 15;114:109547. doi: 10.1016/j.intimp.2022.109547.
Mei-Ling Wu  1 ,  Xiao Zou  1 ,  Xiao-Yu Chen  1 ,  Kai-Ting Ma  1 ,  Chu Chen  1 ,  Neng-Wei Yu  2 ,  Lu Yu  3 ,  Jun-Rong Du  4
Affiliations
  • 1. Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, China.
  • 2. Department of Neurology, Sichuan Provincial People's Hospital, University of Electronic Science and Technology of China, Chengdu, China. Electronic address: [email protected].
  • 3. School of Pharmacy, Southwest Medical University, Luzhou, China.
  • 4. Department of Pharmacology, West China School of Pharmacy, Sichuan University, Chengdu, China. Electronic address: [email protected].
PMID: 36527877 DOI: 10.1016/j.intimp.2022.109547
Abstract

Prothrombotic and proinflammatory properties of neutrophil extracellular traps (NETs) contribute to brain damage after ischemic stroke. CD21 is a novel phthalide neuroprotectant against cerebral ischemia in rodents. This study investigated effects of CD21 on the platelet-NET-thrombin axis and ischemic brain injury and the underlying mechanism. CD21 exerteddose-dependent neuroprotectionin rats that were subjected to2 h middle cerebral artery occlusion,dose-dependentlyinhibited adenosine diphosphate-mediatedplatelet aggregationin rats, and dose-dependentlyexertedanti-thrombotic activityin rodents that received a collagen-epinephrine combination, ferric chloride, or an arteriovenous shunt. Equimolar CD21 doses exerted stronger efficacy than 3-N-butylphthalide (NBP, natural phthalide for the treatment of ischemic stroke). CD21 dose-dependently improved regional cerebral blood flow, neurobehavioral deficits, and infarct volume in mice that were subjected to photothrombotic stroke (PTS). CD21 (13.79 mg/kg, i.v.) significantly decreased NET components (plasma dsDNA concentrations; mRNA levels of Elastase, myeloperoxidase, and neutrophil gelatinase-associated lipocalin and protein level of citrullinated histone H3 in ischemic brain tissues), mRNA and protein levels of peptidyl-arginine deiminase 4 (PDA4, NET formation enzyme), and mRNA levels of NET-related inflammatory mediators (interleukin-1β, interleukin-17A, matrix metalloproteinase 8, and matrix metalloproteinase 9) in ischemic brain tissues, despite no effect on mRNA levels of deoxyribonuclease I (NET elimination enzyme). Pretreatment with compound C (inhibitor of adenosine monophosphate-activated protein kinase [AMPK]) significantly reversed the inhibitory effects of CD21 on NETs, PDA4, and inflammatory mediators in PTS mice. These results suggest that CD21 might regulate the platelet-NET-thrombin axis and protect against ischemic brain injury partly through the induction of AMPK activation.

Keywords
AMPK; Acute ischemic stroke; Neuroprotectant; Neutrophil extracellular traps; Platelet aggregation; Thrombosis.
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