Effects of the potential lithium-mimetic, ebselen, on brain neurochemistry: a magnetic resonance spectroscopy study at 7 tesla

• Published in: Psychopharmacology Vol. 233; no. 6; pp. 1097 - 1104
• Main Authors: Masaki, Charles, Sharpley, Ann L., Godlewska, Beata R., Berrington, Adam, Hashimoto, Tasuku, Singh, Nisha, Vasudevan, Sridhar R., Emir, Uzay E., Churchill, Grant C., Cowen, Philip J.
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 01.03.2016; Springer; Springer Nature B.V
• Subjects: Adult; Antioxidants; Azoles - pharmacology; Biomedical and Life Sciences; Biomedicine; Bipolar disorder; Brain; Cross-Over Studies; Double-Blind Method; Electrophysiology; Female; Glutamic Acid - metabolism; Glutamine - metabolism; Gyrus Cinguli - drug effects; Gyrus Cinguli - metabolism; Health aspects; Humans; Inositol - metabolism; Isoindoles; Lithium; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy - methods; Male; Methods; Neurochemistry; Neurosciences; Observations; Occipital Lobe - drug effects; Occipital Lobe - metabolism; Organoselenium Compounds - pharmacology; Original Investigation; Pharmacology/Toxicology; Psychiatry; Psychopharmacology; Young Adult; Magnetic resonance spectroscopy; Bipolar disorder; Inositol; Ebselen; Glutamate
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-015-4189-2

Rationale Lithium is an effective treatment for bipolar disorder, but safety issues complicate its clinical use. The antioxidant drug, ebselen, may be a possible lithium-mimetic based on its ability to inhibit inositol monophosphatase (IMPase), an action which it shares with lithium. Objectives Our primary aim was to determine whether ebselen lowered levels of inositol in the human brain. We also assessed the effect of ebselen on other brain neurometabolites, including glutathione, glutamate, glutamine, and glutamate + glutamine (Glx) Methods Twenty healthy volunteers were tested on two occasions receiving either ebselen (3600 mg over 24 h) or identical placebo in a double-blind, random-order, crossover design. Two hours after the final dose of ebselen/placebo, participants underwent proton magnetic resonance spectroscopy ( 1 H MRS) at 7 tesla (T) with voxels placed in the anterior cingulate and occipital cortex. Neurometabolite levels were calculated using an unsuppressed water signal as a reference and corrected for individual cerebrospinal fluid content in the voxel. Results Ebselen produced no effect on neurometabolite levels in the occipital cortex. In the anterior cingulate cortex, ebselen lowered concentrations of inositol ( p  = 0.028, Cohen’s d  = 0.60) as well as those of glutathione ( p  = 0.033, d  = 0.58), glutamine ( p  = 0.024, d  = 0.62), glutamate ( p  = 0.01, d  = 0.73), and Glx ( p  = 0.001, d  = 1.0). Conclusions The study suggests that ebselen produces a functional inhibition of IMPase in the human brain. The effect of ebselen to lower glutamate is consistent with its reported ability to inhibit the enzyme, glutaminase. Ebselen may have potential as a repurposed treatment for bipolar disorder.