2. Academic Validation
  3. Peroxynitrite-Triggered Carbon Monoxide Donor Improves Ischemic Stroke Outcome by Inhibiting Neuronal Apoptosis and Ferroptosis

Peroxynitrite-Triggered Carbon Monoxide Donor Improves Ischemic Stroke Outcome by Inhibiting Neuronal Apoptosis and Ferroptosis

  • Mol Neurobiol. 2024 May 20. doi: 10.1007/s12035-024-04238-w.
Xin-Jian Guo # 1,  Lin-Yan Huang # 1,  Shi-Tong Gong # 2,  Ming Li 1,  Wan Wang 1,  Jie Chen 1,  Yi-De Zhang 1,  Xicun Lu 3,  Xiaohua Chen 3,  Lan Luo 1,  Youjun Yang 3,  Xiao Luo 4 5,  Su-Hua Qi 6
Affiliations

Affiliations

  • 1 School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China.
  • 2 Xuzhou Central Hospital, Affiliated Xuzhou Clinical College of Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China.
  • 3 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai, 200237, China.
  • 4 State Key Laboratory of Bioreactor Engineering, Shanghai Key Laboratory of Chemical Biology, School of Pharmacy, East China University of Science and Technology, Meilong Road 130, Shanghai, 200237, China. xluo@chem.ecnu.edu.cn.
  • 5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Dongchuan Road 500, Shanghai, 200241, China. xluo@chem.ecnu.edu.cn.
  • 6 School of Medical Technology, Xuzhou Key Laboratory of Laboratory Diagnostics, Xuzhou Medical University, Xuzhou, 221004, Jiangsu, China. suhuaqi@xzhmu.edu.cn.
  • # Contributed equally.
PMID: 38767837 DOI: 10.1007/s12035-024-04238-w
Abstract

Cerebral ischemia-reperfusion injury produces excessive reactive oxygen and nitrogen species, including superoxide, nitric oxide, and peroxynitrite (ONOO-). We recently developed a new ONOO--triggered metal-free carbon monoxide donor (PCOD585), exhibiting a notable neuroprotective outcome on the rat middle cerebral artery occlusion model and rendering an exciting intervention opportunity toward ischemia-induced brain injuries. However, its therapeutic mechanism still needs to be addressed. In the pharmacological study, we found PCOD585 inhibited neuronal Bcl2/Bax/caspase-3 Apoptosis pathway in the peri-infarcted area of stroke by scavenging ONOO-. ONOO- scavenging further led to decreased Acyl-CoA synthetase long-chain family member 4 and increased Glutathione Peroxidase 4, to minimize lipoperoxidation. Additionally, the carbon monoxide release upon the ONOO- reaction with PCOD585 further inhibited the neuronal Iron-dependent Ferroptosis associated with ischemia-reperfusion. Such a synergistic neuroprotective mechanism of PCOD585 yields as potent a neuroprotective effect as Edaravone. Additionally, PCOD585 penetrates the blood-brain barrier and reduces the degradation of zonula occludens-1 by inhibiting matrix metalloproteinase-9, thereby protecting the integrity of the blood-brain barrier. Our study provides a new perspective for developing multi-functional compounds to treat ischemic stroke.

Keywords

Anti-lipid peroxidation; Carbon monoxide; Ferroptosis; Iron homeostasis; Ischemic/reperfusion injury.

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