The neuroprotective agent MS-153 stimulates glutamate uptake

We investigated the effect of(R)-(-)-5-methyl-1-nicotinoyl-2-pyrazoline (MS -153), a novel neuroprotective agent, on L-[H-3]glutamate uptake through GL T-1, a Na+/K+-dependent glial glutamate transporter, expressed in COS-7 cel ls. MS-153 (1-100 mu M) accelerated the L-[H-3]glutamate uptake through GLT -1 in a concentration-dependent and time-dependent manner. Eadie-Hofstee an alysis revealed that MS-153 significantly decreased the K-m of the glutamat e uptake by COS-7 cells expressing GLT-1. In contrast, [H-3]gamma-aminobuty ric acid (GABA) uptake through a glial GABA transporter was not affected. I n addition, MS-153 increased Na+ currents through GLT-1 expressed in Xenopu s oocytes. We also investigated the effect of MS-153 on amino acid efflux f rom rat hippocampal slices. The increase in glutamate efflux induced by 50 mM KCl was significantly attenuated by the treatment with MS-153 at 10 mu M , while MS-153 had no significant effect on the K+-evoked efflux of GABA. F urthermore, the increase in glutamate efflux by ischemia (hypoxia/aglycemia ) was partially, but significantly inhibited by MS-153. These results sugge st that the cerebroprotective effect of MS-153 in this ischemic model in vi vo is due to the specific reduction of the glutamate concentration in the e xtracellular space, which can probably be attributed to the acceleration of glutamate uptake by the indirect modulation of the glutamate transporter a ctivity. (C) 1999 Elsevier Science B.V. All rights reserved.