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Psychopharmacology (Berl). 2016 Mar;233(6):1097-104. doi: 10.1007/s00213-015-4189-2. Epub 2016 Jan 12.

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

Author information

1
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK.
2
The Oxford Centre for Functional MRI of the Brain, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, OX3 9DU, UK.
3
Department of Pharmacology, University of Oxford, Mansfield Road, Oxford, OX1 3QT, UK.
4
Current Address: Centre for Neuroimaging Studies, PO 089, De Crespigny Park, London, SE5 8AF, UK.
5
Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, OX3 7JX, UK. phil.cowen@psych.ox.ac.uk.

Abstract

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.

KEYWORDS:

Bipolar disorder; Ebselen; Glutamate; Inositol; Magnetic resonance spectroscopy

PMID:
26758281
PMCID:
PMC4759215
DOI:
10.1007/s00213-015-4189-2
[Indexed for MEDLINE]
Free PMC Article

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