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

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.

Figures

Fig. 1

Voxel placement and representative spectra from the anterior cingulate cortex (ACC) and occipital cortex (OCC). Each acquired spectrum (64 averages) is overlaid with the metabolite fit from LCModel (red line) with major peaks labeled. The difference between the metabolite fit and underlying spectrum is shown below as a residual, which remains small and uniform indicating a high quality spectral fit. tCR total creatine, Ins myo-inositol, Cho choline, Glu glutamate, NAA N-acetylaspartate

Fig. 2

Anterior cingulate cortex concentrations of inositol (μmol/g) following treatment with ebselen (3600 mg over 24 h) or placebo in 16 individual subjects. Ebselen treatment resulted in a significant decrease in inositol (p = 0.028, paired t test). Black dotted line represents mean (and standard error) for group at each visit

Fig. 3

Anterior cingulate cortex concentrations of Glx (μmol/g) following treatment with ebselen (3600 mg over 24 h) or placebo in 16 individual subjects. Ebselen treatment resulted in a significant decrease in Glx (p = 0.001, paired t test). Black dotted line represents mean (and standard error) for group at each visit