A Highly Selective Inhibitor of Glycine Transporter-1 Elevates the Threshold for Maximal Electroshock-Induced Tonic Seizure in Mice.

Many anti-epileptic drugs (AEDs) that mainly target ion channels or post-synaptic receptors are in clinical use, but a proportion of patients are resistant to these traditional AEDs and experience repeated severe break-out seizures. Given its involvement in the etiology of epilepsy, the neurotransmitter glycine may serve as a novel target for epilepsy treatment. Increasing evidence suggests that inhibitors of glycine transporter 1 (GlyT1) exhibit anti-seizure properties in mouse models and show potential as anti-convulsions drugs. In the present study, we investigated the effect of a highly selective GlyT1 inhibitor (named M22) on glycine transport kinetics using a radioactive substrate uptake assay and investigated the anti-seizure effects of M22 on the maximal electroshock seizure threshold (MEST) test and the timed intravenous (i.v.) pentylenetetrazole (PTZ) intravenous test. Our results demonstrate that M22 was capable of elevating the seizure threshold in the MEST test but did not alter the seizure threshold in the PTZ i.v. test. Strychnine, an inhibitor of glycine receptor activity, reversed the threshold elevation at a subconvulsive dosage (0.1 mg/kg subcutaneously) in the MEST test and did not affect M22 plasma levels in mice, suggesting that the anti-seizure effect in this model may be mediated by increased glycine receptor activity. Moreover, M22 administration did not influence motor function and coordination in mice. In combination with the previously reported excellent pharmacokinetic features of M22, our present results suggested that M22 has the potential to serve as a new anti-convulsive drug or as a lead compound for the development of AEDs.

The Relationship Between Enlarged Perivascular Spaces and Cognitive Function: A Meta-Analysis of Observational Studies.

Enlarged perivascular spaces (ePVS), visible on magnetic resonance imaging (MRI), are associated with aortic pulse wave changes produced by arterial stiffening. However, the relationship between ePVS and cognition is still unclear. We aimed to benchmark current knowledge of associations between ePVS and cognitive function using a meta-analysis of all available published data. We searched three databases for studies examining ePVS and cognition, identified seven studies involving 7,816 participants, plotted multivariate-adjusted odds ratio (OR) and 95% CI and generated summary OR with a fixed effects model. EPVS were related to the risk of impaired cognition (OR = 1.387, 95% CI = 1.198-1.606, z=4.38, P<0.001) with low heterogeneity. There was publication bias, which could be corrected by trimming and supplementation (OR=1.297, 95% CI= 1.130-1.490). EPVS were associated with impaired cognition and may be a sign of cognitive impairment rather than particular diseases. More studies are required to validate ePVS as a measurable risk marker for cognition using consistent methods to determinea characteristic appearance of ePVS.