Glo1 inhibitors for neuropsychiatric and anti-epileptic drug development

Abstract

Many current pharmacological treatments for neuropsychiatric disorders, such as anxiety and depression, are limited by a delayed onset of therapeutic effect, adverse side effects, abuse potential or lack of efficacy in many patients. These off-target effects highlight the need to identify novel mechanisms and targets for treatment. Recently, modulation of Glo1 (glyoxalase I) activity was shown to regulate anxiety-like behaviour and seizure-susceptibility in mice. These effects are likely to be mediated through the regulation of MG (methylglyoxal) by Glo1, as MG acts as a competitive partial agonist at GABA(A) (γ-aminobutyric acid A) receptors. Thus modulation of MG by Glo1 represents a novel target for treatment. In the present article, we evaluate the therapeutic potential of indirectly modulating MG concentrations through Glo1 inhibitors for the treatment of neuropsychiatric disorders.

Figure 1. MG is an endogenous, partial agonist at neuronal GAB_AA receptors

(A) The application of 100 μM MG to hippocampal neurons evokes Cl− currents through GABA_A receptors that are ~ ⅓ the magnitude of those evoked by 100 μM GABA in the same cells. The EC50 of the currents evoked by MG was 9.5 ± 1 μM and the physiological concentration of MG in rodent brain was measured at 5 μM. MG has a similar efficacy when applied to cerebellar granule neurons. (B) MG evoked currents in hippocampal neurons are augmented by co-application of classical anxiolytics that act as positive allosteric modulators of GABA_ARs, such as the benzodiazapenes diazepam and midazolam and the imidazopyridine zolpidem. Scale bars represent 1 nA and 10 s. Adapted from Distler et al., (2012)[7].

Figure 2. A model for GLO1 Inhibition in the treatment of neuropsychiatric disorders and epilepsy

Treatment with GLO1 inhibitors will increase concentrations of methylglyoxal due to decreased clearance by GLO1. Increased methylglyoxal will result in increased activation of GABAA receptors and subsequently, a decrease in neuropsychiatric disorder phenotypes (ie. reduced anxiety, depression and seizure). Adapted from Distler and Palmer (2013)[67].

Figure 3. Systemic administration of a GLO1 inhibitor regulates MG concentration, reduces anxiety-like behavior and attenuates seizure in mice

Pharmacological inhibition of GLO1 by BrBzGCp2 (A) reduces GLO1 enzymatic activity; (B) increases concentrations of MG in whole brain of mice 2 hrs after i.p. treatment; (C) reduces anxiety-like behavior in the open field test (C57BL6/J mice) without affecting total distance traveled (D); and (E) attenuates pilocarpine-induced seizures (50 mg/kg prior to pilocarpine (250mg/kg)). Adapted from Distler et al. (2012) and (2013)[6,7].