Therapeutic effects of methionine sulfoximine in multiple diseases include and extend beyond inhibition of glutamine synthetase

ABSTRACT

Introduction: Methionine sulfoximine (MSO), a well-characterized inhibitor of glutamine synthetase, displays significant therapeutic benefits in animal models for several human diseases. This amino acid might therefore be a viable candidate for drug development to treat diseases for which there are few effective therapies.

Areas covered: We describe the effects of MSO on brain swelling occurring in overt hepatic encephalopathy resulting from liver failure, the effects of MSO on excitotoxic damage involved in amyotrophic lateral sclerosis (ALS) or resulting from stroke, and the effects of MSO on a model for an inflammatory immune response involved in a range of diseases. We conclude that these results imply the existence of another therapeutic target for MSO in addition to glutamine synthetase.

Expert opinion: We summarize the various diseases for which MSO treatment might be a candidate for drug development. We discuss why MSO has limited enthusiasm in the scientific and medical communities for use in humans, with a rebuttal to those negative opinions. And we conclude that MSO should be considered a candidate drug to treat brain swelling involved in overt hepatic encephalopathy and diseases involving an inflammatory immune response.

KEYWORDS:

• Glutamine synthetase
• methionine sulfoximine
• hepatic encephalopathy
• ALS
• inflammation

Article highlights

• Hyperammonemic brain swelling can be treated with methionine sulfoximine, an inhibitor of glutamine synthetase

• Inhibiting glutamine synthetase with methionine sulfoximine might be an effective treatment for glutamate excitotoxicity

• Methionine sulfoximine reduces an inflammatory immune response

• Methionine sulfoximine might have a therapeutic target besides, or in addition to, glutamine synthetase

This box summarizes key points contained in the article.

Acknowledgment

The authors wish to thank Dr Saul W. Brusilow for his comments and contributions to the manuscript.

Declaration of interest

W. S. A. Brusilow is a part-owner of patents for the use of MSO to treat hepatic encephalopathy and diseases involving an inflammatory immune response.  He is also part-owner of Burtch Pharma, a company formed to develop MSO for use in humans. The authors have no other 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 apart from those disclosed.

Additional information

Funding

This paper was not funded.