dizocilpine-maleate and carbamylhydrazine

Planarians, the non-parasitic flatworms, display dose-dependent, distinct (C-like and corkscrew-like) hyperkinesias upon exposure to 0.001-10 mM aqueous solutions of glutamatergic agonists (L-glutamate and N-methyl-D-aspartate (NMDA)) and 0.001-5 mM concentrations of the glutamate decarboxylase (GAD) inhibitor (semicarbazide). In the planarian seizure-like activity (PSLA) experiments the three chemoconvulsants displayed the following order of potency (EC50): L-glutamate (0.6mM)>NMDA (1.4 mM)>semicarbazide (4.5mM). Planarian hyperkinesias behavior counting experiments also revealed that riluzole (0.001 to 1mM), an anti-convulsive agent, displayed no significant behavioral activity by itself, but attenuated hyperkinesias elicited by the three chemoconvulsants targeting either glutamatergic or GABAergic neurotransmission with the following order of potency (IC50): NMDA (44.7 µM)>semicarbazide (88.3 µM)>L-glutamate (160 µM). Further, (+)-MK-801, a specific NMDA antagonist, alleviated 3mM NMDA (47%) or 3mM L-glutamate (27%) induced planarian hyperkinesias. The results provide pharmacological evidence for the presence of glutamatergic receptor-like and semicarbazide sensitive functional GAD enzyme-like proteins in planaria in addition to demonstrating, for the first time, the anti-convulsive effects of riluzole in an invertebrate model. High performance liquid chromatography coupled with fluorescence detection (HPLC-F) analysis performed on planarian extracts post no drug treatment (control) or treatment with 3mM semicarbazide, combination of 3mM semicarbazide and 0.1 mM riluzole, or 0.1 mM riluzole revealed that 3 mM semicarbazide induced 35% decrease in the GABA levels and a combination of 3mM semicarbazide and 0.1 mM riluzole induced 42% decrease in glutamate levels with respect to the control group.

Topics: Animals; Behavior, Animal; Convulsants; Dizocilpine Maleate; Excitatory Amino Acid Agonists; gamma-Aminobutyric Acid; Glutamic Acid; Hyperkinesis; N-Methylaspartate; Planarians; Receptors, Glutamate; Riluzole; Semicarbazides; Synaptic Transmission

To investigate the antiepileptic effect of dizocilpine (MK-801) on amygdala kindling models in rats and the effects of its combination with general antiepileptic drugs.. To establish amygdala kindling models in rats and observe the effect of dizocilpine on kindling models and its combination with general antiepileptic drugs (phenobarbital, valproate and nicardipine) at ineffective dose. The influence of dizocilpine on convulsions induced by semicarbazide (SCZ) in mice were also observed.. Dizocilpine (0.1-0.25 mg.kg-1, i.p.) was shown to dose-dependently inhibit amygdala kindled seizure, shorten the after discharge duration (ADD) and reduce the Racine's stage (P < 0.01). The combination of dizocilpine with phenobarbital, valproate, nicardipine at ineffective dose shortened ADD or reduced Racine's stages (P < 0.01). Dizocilpine (0.1-0.25 mg.kg-1, i.p.) significantly prolonged the latency and reduced the rate of convulsions and death in mice.. Dizocilpine inhibits the seizure of the amygdala kindling and improve the antiepileptic activity of phenobarbital, valproate and nicardipine, indicating that these combination may provide a new approach for treating epilepsy.

Topics: Amygdala; Animals; Anticonvulsants; Dizocilpine Maleate; Electric Stimulation; Epilepsy; Female; Kindling, Neurologic; Male; Mice; Nicardipine; Phenobarbital; Random Allocation; Rats; Rats, Wistar; Semicarbazides; Valproic Acid