1 Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. 2 CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly 80% of the NMDA-evoked current, with EC50 of approximately 5 mm. This effect was selective, reversible, use-dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. 3 CHF3381 also inhibited voltage-gated Naþ currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 mm). 4 Consistent with the mild effects on voltage-gated Naþ channels, CHF3381 (100 mm) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anticonvulsant agent and Naþ channel blocker lamotrigine (100 mm) inhibited stimulation-evoked glutamate overflow by approximately 50%. 5 CHF3381 reduced kindled seizure-induced c-fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo. 6 The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation.
Mechanisms of action of CHF3381 in the forebrain
BARBIERI, Mario;BUZZI, Andrea;ZUCCHINI, Silvia;SIMONATO, Michele
2003
Abstract
1 Aim of this study was to gain insight into the mechanism of action of CHF3381, a novel putative antiepileptic and neuroprotective drug. 2 CHF3381 blocked NMDA currents in primary cultures of cortical neurons: maximal effect was nearly 80% of the NMDA-evoked current, with EC50 of approximately 5 mm. This effect was selective, reversible, use-dependent and elicited at the concentrations reached in the rodent brain after peripheral administration of therapeutic doses. 3 CHF3381 also inhibited voltage-gated Naþ currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 mm). 4 Consistent with the mild effects on voltage-gated Naþ channels, CHF3381 (100 mm) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anticonvulsant agent and Naþ channel blocker lamotrigine (100 mm) inhibited stimulation-evoked glutamate overflow by approximately 50%. 5 CHF3381 reduced kindled seizure-induced c-fos mRNA levels within the same brain regions, and to a similar level, as the selective NMDA receptor antagonist MK801, providing circumstantial evidence to the idea that CHF3381 blocks NMDA receptors in vivo. 6 The present mechanistic studies suggest that the primary mechanism of action of CHF3381 in the forebrain is blockade of NMDA receptors. On this basis, this compound may have a potential use in other diseases caused by or associated with a pathologically high level of NMDA receptor activation.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
