Compelling Evidence: A Critical Update on the Therapeutic Potential of Carbon Monoxide.

Carbon monoxide (CO) is an endogenous signaling molecule. It is produced via heme degradation by heme oxygenase (HMOX), releasing stoichiometric amounts of CO, iron, and biliverdin (then bilirubin). The HMOX-CO axis has long been shown to offer beneficial effects by modulating inflammation, proliferation and cell death as they relate to tissue and organ protection. Recent years have seen a large number of studies examining CO pharmacology, its molecular targets, cellular mechanisms of action, pharmacokinetics, and detection methods using various delivery modalities including inhaled CO gas, CO solutions, and various types of CO donors. Unfortunately, one widely used donor type includes four commercially available carbonyl complexes with metal or borane, CORM-2 (Ru²⁺), CORM-3 (Ru²⁺), CORM-A1 (BH₃), and CORM-401 (Mn⁺), which have been shown to have minimal and/or unpredictable CO production and extensive CO-independent chemical reactivity and biological activity. As a result, not all "CO biological activities" in the literature can be attributed to CO. In this review, we summarize key findings based on CO gas and CO in solution for the certainty of the active principal and to avoid data contamination resulting from the confirmed or potential reactivities and activities of the "carrier" portion of CORMs. Along a similar line, we discuss interesting potential research areas of CO in the brain including a newly proposed CO/HMOX/dopamine axis and the role of CO in cognitive stimulation and circadian rhythm. This review is critical for the future development of the CO field by steering clear of complications caused by chemically reactive donor molecules.