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.

Environmental pollutants, found in aquatic ecosystems, have been shown to have an effect on olfactory-mediated behaviors including feeding, mate attraction, and other important social behaviors. Crayfish are polytrophic, meaning that they feed on and become prey for all levels of the aquatic food web as well as are also important for the transfer of energy between benthic and terrestrial food webs. Because crayfish are a keystone species, it is important to investigate any factors that may affect their population size. Crayfish are active at night and rely heavily on their sensory appendages (e.g., antennulues, maxillipeds, and pereopods) to localize food sources. In this experiment, we investigated the effects of atrazine (ATR) exposure on the chemosensory responses of male and female crayfish to food odors. We exposed crayfish to environmentally relevant, sublethal levels of ATR [80 ppb (µg/L)] for 72 h and then examined the behavioral responses of both ATR-treated and control crayfish to food odor delivered from one end of a test arena. We used Noldus Ethovision XT software to measure odor localization and locomotory behaviors of crayfish in response to food (fish) odor. We found that control crayfish spent more time in the proximal region of the test arena and at the odor source compared with ATR-treated crayfish. Furthermore, there were no differences in the time spent moving and not moving, total distance travelled in the tank, and walking speed (cm/s) when control and ATR-treated crayfish were compared. Overall, this indicates that acute ATR exposure alters chemosensory abilities of crayfish, whereas overall motor function remains unchanged.

The herbicide atrazine is known to impact negatively olfactory-mediated behaviors in aquatic animals. We have shown that atrazine exposure has deleterious effects on olfactory-mediated behavioral responses to food odors in crayfish; however, recovery of chemosensory abilities post-atrazine exposure has not been investigated. We examined whether crayfish (Orconectes virilis) recovered chemosensory abilities after a 96-h exposure to sublethal, environmentally relevant concentrations of 80 ppb (µg/L) atrazine. Following treatment, we analyzed the ability of the crayfish to locate a food source using a Y-maze with one arm containing fish-flavored gelatin and the other containing unflavored gelatin. We compared the time spent in the food arm of the Y-maze, near the food source, as well as moving and walking speed of control and atrazine-treated crayfish. We also compared the number of crayfish that handled the food source and the amount of food consumed. Following 24-, 48-, and 72-h recovery periods in fresh water, behavioral trials were repeated to determine if there was any observable recovery of chemosensory-mediated behaviors. Atrazine-treated crayfish spent less time in the food arm, at the odor source, and were less successful at finding the food odor source than control crayfish for all times tested. Additionally, atrazine-treated crayfish consumed less fish-flavored than control crayfish; however, treatment did not affect locomotion. Overall, we found that crayfish are not able to recover chemosensory abilities 72 h post-atrazine exposure. Because crayfish rely heavily on their chemosensory abilities to acquire food, the negative impacts of atrazine exposure could affect population size in areas where atrazine is heavily applied.

BackgroundThe glutamine synthetase inhibitor methionine sulfoximine (MSO), shown previously to prevent death caused by an inflammatory liver response in mice, was tested on in vitro production of cytokines by mouse peritoneal macrophages triggered with lipopolysaccharide (LPS).ResultsMSO significantly reduced the production of Interleukin 6 (IL-6) and Tumor Necrosis Factor Alpha (TNFα) at 4 and 6 h after LPS-treatment. This reduction did not result from decreased transcription of IL-6 and TNFα genes, and therefore appeared to result from post-transcriptional inhibition of synthesis of these cytokines. MSO treatment did not inhibit total protein synthesis and did not reduce the production of a third LPS-triggered cytokine CXCL1, so the effect was not a toxic or global downregulation of the LPS response. The anti-inflammatory effects of a glutamine synthetase inhibitor were seen even though the medium contained abundant (2 mM) glutamine, suggesting that the target for this activity was not glutamine synthetase. In agreement with this hypothesis, the L,R isomer of MSO, which does not inhibit glutamine synthetase and was previously thought to be inert, both significantly reduced IL-6 secretion in isolated macrophages and increased survival in a mouse model for inflammatory liver failure.ConclusionsOur findings provide evidence for a novel target of MSO. Future attempts to identify the additional target would therefore also provide a target for therapies to treat diseases involving damaging cytokine responses.