dizocilpine-maleate and indantadol

(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 EC(50) of approximately 5 micro M. 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 Na(+) currents in an apparently voltage-dependent manner. However, this effect could be obtained only at relatively high concentrations (100 micro M). (4) Consistent with the mild effects on voltage-gated Na(+) channels, CHF3381 (100 micro M) failed to affect electrical stimulation-evoked glutamate overflow in hippocampal slices. In contrast, the anti-convulsant agent and Na(+) channel blocker lamotrigine (100 micro M) 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.

Topics: Animals; Anticonvulsants; Dizocilpine Maleate; Dose-Response Relationship, Drug; Electrophysiology; gamma-Aminobutyric Acid; Glutamic Acid; Glycine; Hippocampus; Indans; Injections, Intraperitoneal; Ion Channel Gating; Male; N-Methylaspartate; Neurons; Prosencephalon; Proto-Oncogene Proteins c-fos; Rats; Rats, Sprague-Dawley; Receptors, GABA-A; Receptors, Glutamate; Receptors, N-Methyl-D-Aspartate; Signal Transduction; Sodium Channels

The aim of this study was to evaluate the neuroprotective effect of CHF3381, a novel putative NMDA antagonist characterized by a good therapeutic index. We have compared the effects of CHF3381 on kainate seizure-induced neurodegeneration with those produced by the non competitive NMDA receptor antagonist MK-801 and by the Na channel blocker lamotrigine. All compounds have been employed at doses incapable of preventing or attenuating seizures. The fluorescent marker Fluoro-Jade B has been used to identify degenerating cells. Animals pretreated with lamotrigine presented the same degree of cell damage as the controls. As for the controls, a clear correlation was also observed between seizure severity and neurodegeneration. In contrast, MK-801 and CHF3381 completely prevented cell damage. These data indicate that CHF3381 may be successfully utilized in neurological disorders characterized by or associated with neurodegenerative excitotoxicity.

Topics: Animals; Anticonvulsants; Cell Death; Dizocilpine Maleate; Excitatory Amino Acid Antagonists; Glycine; Hippocampus; Histological Techniques; Indans; Kainic Acid; Lamotrigine; Male; Mice; Neuroprotective Agents; Receptors, N-Methyl-D-Aspartate; Seizures; Triazines

CHF3381 [n-(2-indanyl)-glycinamide hydrochloride] has been selected on the basis of a screening program as the compound displaying the highest anticonvulsant activity in the maximal electroshock seizure (MES) test and the best therapeutic index with reference to the rotarod test in mice and rats. In this study, the antiepileptic activity and the behavioural toxicity of CHF3381 were characterised in multiple model systems. CHF3381 effectively prevented MES-induced convulsions when administered i.p. (ED50, 24 mg/kg and 7.5 mg/kg) or p.o. (ED50, 21 mg/kg and 21 mg/kg) in both mice and rats, respectively. The time course of oral anti-MES activity in the rat was related to the brain concentration profile of unchanged CHF3381. Interestingly, the brain drug levels were about 4-5 times higher than in plasma. CHF3381 was very effective in mice against picrotoxin-, and i.c.v. N-methyl-D-aspartate (NMDA)-induced hind limb tonic extension (ED50 Approximately/=10 mg/kg), but was a weaker antagonist of 4-amynopyridine- and bicuculline-induced tonic seizures (ED50 approximately/=100 mg/kg), and ineffective against pentylentetrazole- and picrotoxin-induced clonic seizures. CHF3381 antagonised the behavioural effects and lethality of i.p. administered NMDA (ED50 = 57 mg/kg p.o.), indicating that the compound may act as a functional NMDA antagonist. In keeping with this idea, CHF3381 weakly displaced [(3)H]-TCP from binding to NMDA receptor channels (Ki, 8.8 microM). In the rat amygdala kindling model, CHF3381 was more efficient against kindling development than against kindled seizures (minimally active dose = 80 vs. 120 mg/kg i.p). Furthermore, it significantly increased the seizure threshold in kindled rats at relatively low doses (40 mg/kg i.p.). In contrast with MK-801-induced hyperactivity, CHF3381 moderately reduced the spontaneous locomotor activity in mice at anticonvulsant doses. Toxic effects on motor performance (rotarod test) were found at high doses only (TD50 approximately/= 300 mg/kg p.o., congruent with 100 mg/kg i.p. in both mice and rats). Furthermore, CHF3381 did not impair passive avoidance and Morris water maze responding in the therapeutic range of doses. Finally, the development of tolerance after repeated doses was negligible. These data indicate that CHF3381 exerts anticonvulsant and antiepileptogenic effects in various seizure models and possesses good therapeutic window, with scarce propensity to cause neurological side-effects.

Topics: Animals; Anticonvulsants; Dizocilpine Maleate; Drug Evaluation, Preclinical; Epilepsy; Excitatory Amino Acid Antagonists; Glycine; Indans; Kindling, Neurologic; Lamotrigine; Male; Mice; Motor Activity; Rats; Rats, Sprague-Dawley; Receptors, N-Methyl-D-Aspartate; Triazines