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

Publisher: Humana Press Country of Publication: United States NLM ID: 8900963 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1559-1182 (Electronic) Linking ISSN: 08937648 NLM ISO Abbreviation: Mol Neurobiol Subsets: MEDLINE

Original Publication: Clifton, NJ : Humana Press, c1987-

Peroxynitrous Acid*/metabolism ; Ischemic Stroke*/drug therapy ; Ischemic Stroke*/metabolism ; Ischemic Stroke*/pathology ; Apoptosis*/drug effects ; Ferroptosis*/drug effects ; Neurons*/drug effects ; Neurons*/metabolism ; Neurons*/pathology ; Carbon Monoxide*/pharmacology ; Carbon Monoxide*/metabolism ; Rats, Sprague-Dawley*; Animals ; Male ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Blood-Brain Barrier/drug effects ; Blood-Brain Barrier/metabolism ; Blood-Brain Barrier/pathology ; Treatment Outcome ; Rats ; Infarction, Middle Cerebral Artery/pathology ; Infarction, Middle Cerebral Artery/drug therapy

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.
Competing Interests: Declarations. Ethics Approval: The animal experiment was conducted by the national and institutional guidelines on ethics and biosafety, and the protocol was approved by the Institutional Animal Care and Use Committee of Xuzhou Medical University (License ID: 201907W079). Consent to Participate: Not applicable. Consent for Publication: Not applicable. Competing Interests: The authors declare no competing interests.
(© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

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No. BK20211348 Natural Science Foundation of Jiangsu Province; KC21030 Xuzhou Basic Research Program; JBGS202203 Leadership program through open competition in Xuzhou Medical University; No. KYCX21_2722 Postgraduate Research & Practice Innovation Program of Jiangsu Province

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

14691-52-2 (Peroxynitrous Acid)
7U1EE4V452 (Carbon Monoxide)
0 (Neuroprotective Agents)

Date Created: 20240520 Date Completed: 20241122 Latest Revision: 20241122

20241123

10.1007/s12035-024-04238-w

38767837