The brain heme oxygenase/biliverdin reductase system as a target in drug research and development

ABSTRACT

Introduction

The heme oxygenase/biliverdin reductase (HO/BVR) system is involved in heme metabolism. The inducible isoform of HO (HO-1) and BVR both exert cytoprotective effects by enhancing cell stress response. In this context, some xenobiotics, which target HO-1, including herbal products, behave as neuroprotectants in several experimental models of neurodegeneration. Despite this, no drug having either HO-1 or BVR as a main target is currently available.

Areas covered

After a description of the brain HO/BVR system, the paper analyzes the main classes of drugs acting on the nervous system, with HO as second-level target, and their neuroprotective potential. Finally, the difficulties that exist for the development of drugs acting on HO/BVR and the possible ways to overcome these hurdles are examined.

Expert opinion

Although the limited clinical evidence has restricted the translational research on the HO/BVR system, mainly because of the dual nature of its by-products, there has been growing interest in the therapeutic potential of these enzymes. Scientists should boost the translational research on the HO/BVR system which could be supported by the significant evidence provided by preclinical studies.

KEYWORDS:

• carbon monoxide
• drug research and development
• heme oxygenase
• nervous system
• neurodegeneration

Article Highlights

• Heme oxygenase (HO) is a ubiquitous enzyme involved in the degradation of heme into biliverdin (BV), carbon monoxide (CO) and ferrous iron.

• Heme oxygenase works in association with biliverdin reductase (BVR), which transforms BV into bilirubin (BR).

• The HO/BVR system plays a key role in the cell stress response.

• The inducible HO isoform (HO-1) is a target of many drugs acting on the nervous system.

• Although several lines of preclinical research have shown the potential beneficial role of HO-1 modulation in neurodegenerative disorders and other free radical-related diseases, no drug having HO-1 as a main target is currently under investigation or marketed.

• The dual nature of the HO and BVR by-products can be a plausible reason for such a restraint in the translational research about the HO/BVR system.

This box summarizes key points contained in the article.

Declaration of interest

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer is currently an employee of Proterris, Inc. which develops inhaled CO (iCO) therapies for potential application. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose

Correction Statement

This article has been republished with minor changes. These changes do not impact the academic content of the article