Unraveling the Interplay of Dopamine, Carbon Monoxide, and Heme Oxygenase in Neuromodulation and Cognition

Abstract

The dopaminergic system plays important roles in neuromodulation, including prominent roles in complex neurological functions such as cognition, reward, motivation, and memory. Understandably, the highly complex nature of such physiological functions means that their regulation is intertwined with other signaling pathways, as has been demonstrated by numerous studies. Contrary to its public perception of being poisonous at all concentrations, carbon monoxide (CO) is produced endogenously from heme degradation by heme oxygenase (HO) as part of the physiological process of red blood cell turnover. Physiological concentrations of CO can reach high micromolar ranges in the hemoglobin bound form. Low-dose CO has shown therapeutic effects in numerous animal models, including traumatic brain injury via engaging various hemoprotein targets. As such, the HO−CO axis has been shown to offer beneficial effects in organ protection, anti-inflammation, and neuroprotection, among many others. Further, a large number of publications have shown the interactions among CO, HO, and the dopaminergic system. In this review, we critically examine such experimental evidence in a holistic fashion and in the context of a possible dopamine−HO−CO signaling axis. We hope that this Perspective will stimulate additional investigations into the molecular connectivity related to this possible axis and open doors to the development of novel therapeutics that impact the dopaminergic system.

Carbon Monoxide as a Potential Therapeutic Agent: A Molecular Analysis of Its Safety Profiles

“…Although much more work needs to be done to determine if CO is a transmitter of a light signal, there is sufficient evidence to support an increase in free CO during light exposure. These results suggest there are potential roles for CO in many different areas where light response is key, such as the circadian rhythm and possibly cognition. , …”

“…These results suggest there are potential roles for CO in many different areas where light response is key, such as the circadian rhythm and possibly cognition. 14 , 93…”

“…Recent years have witnessed a steady increase in interest in the signaling roles and therapeutic effects of CO. , Studies in animal models have demonstrated the promise of using CO for treating inflammation of various types, sickle cell disease, cancer, and cancer metastasis . CO has also been shown to offer cytoprotection and organ protection, − play an important role in neuromodulation and cognition via a possible CO–dopamine–heme oxygenase signaling axis, and regulate the circadian clock, which is further implicated in an array of pathophysiological and pharmacological events . Despite all the success in demonstrating the pharmacological effects of CO in cell culture and in animal models, there are also many unanswered questions, including issues of sufficiency of the heme supply to allow CO a role in rapid signaling, the molecular mechanisms(s) of action, , and safety.…”