Effect of SSR504734, a Selective Glycine Transporter Type 1 Inhibitor, on Seizure Thresholds, Neurotransmitter Levels, and Inflammatory Markers in Mice.

Abstract

Studies have revealed that inhibition of glycine transporter type 1 (GlyT1) may provide a balanced regulation between excitation and inhibition in some brain structures and, thereby, modulate seizure activity. Data on the role of GlyT1 in epilepsy are, however, very limited. Here, we examined the effect of SSR504734, a highly selective and reversible GlyT1 inhibitor, on three acute seizure tests in mice. We also evaluated its impact on neurotransmitter levels in the relevant brain structures following seizures, possible adverse effects, and changes in the levels of inflammatory mediators in the serum and liver. In addition, in vivo pharmacokinetic profile and in vitro ADME-Tox properties of SSR504734 were investigated. The results show that SSR504734 significantly increased the threshold for tonic hindlimb extension in the MEST test after acute and repeated treatment but had no influence on seizure thresholds in the 6 Hz and i.v. PTZ seizure tests. SSR504734 did not affect the levels of glutamate, GABA, glycine, or adenosine in brain structures of mice with MES-induced seizures. However, after acute treatment, the concentration of glutamate and adenosine in the brainstem of control animals (i.e., without seizures) decreased. Moreover, SSR504734 increased the levels of inflammatory markers (TNF-α, Il-1β, IL-6, IL-10, and TLR4) in serum. In vivo pharmacokinetic profiling and in vitro ADME-Tox data confirmed suitable drug-like properties of SSR504734, including its notable penetration into brain tissue. However, possible hepatotoxicity at higher doses should be taken into account. Further studies should be considered to better characterize the SSR504734-mediated effects as well as to validate GlyT1 as a potential new molecular target in epilepsy treatment.