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

• Published in: Molecular neurobiology 2024-12, Vol.61 (12), p.10629-10644
• Main Authors: Guo, Xin-Jian, Huang, Lin-Yan, Gong, Shi-Tong, Li, Ming, Wang, Wan, Chen, Jie, Zhang, Yi-De, Lu, Xicun, Chen, Xiaohua, Luo, Lan, Yang, Youjun, Luo, Xiao, Qi, Su-Hua
• Format: Article
• Language: English
• Subjects: Animals; Apoptosis; Apoptosis - drug effects; BAX protein; Bcl-2 protein; Biomedical and Life Sciences; Biomedicine; Blood-brain barrier; Blood-Brain Barrier - drug effects; Blood-Brain Barrier - metabolism; Blood-Brain Barrier - pathology; Brain injury; Carbon monoxide; Carbon Monoxide - metabolism; Carbon Monoxide - pharmacology; Caspase-3; Cell Biology; Cerebral blood flow; Ferroptosis; Ferroptosis - drug effects; Glutathione peroxidase; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - pathology; Ischemia; Ischemic Stroke - drug therapy; Ischemic Stroke - metabolism; Ischemic Stroke - pathology; Male; Matrix metalloproteinase; Metalloproteinase; Neurobiology; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Neurosciences; Nitric oxide; Original Article; Peroxynitrite; Peroxynitrous Acid - metabolism; Rats; Rats, Sprague-Dawley; Reactive nitrogen species; Reactive oxygen species; Reperfusion; Stroke; Treatment Outcome; Zonula occludens-1 protein
• ISSN: 0893-7648; 1559-1182; 1559-1182
• DOI: 10.1007/s12035-024-04238-w

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.