2-amino-5-ureidopentanamide and Disease-Models--Animal

Epilepsy is considered as one of the major disabling neuropathologies. Almost one third of adult patients with temporal lobe epilepsy (TLE) do not respond to current antiepileptic drugs (AEDs). Additionally, most AEDs do not have neuroprotective effects against the inherent neurodegenerative process underlying the hippocampal sclerosis on TLE. Dysfunctions in the GABAergic neurotransmission may contribute not only to the onset of epileptic activity but also constitute an important system for therapeutic approaches. Therefore, molecules that enhance GABA inhibitory effects could open novel avenues for the understanding of epileptic plasticity and for drug development. Parawixin2, a compound isolated from

Topics: Animals; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Male; Neurons; Neuroprotective Agents; Rats, Wistar; Spider Venoms; Urea

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Topics: Animals; Anticonvulsants; Disease Models, Animal; Epilepsy, Temporal Lobe; Hippocampus; Lithium; Male; Neurons; Neuroprotective Agents; Neurotransmitter Uptake Inhibitors; Nipecotic Acids; Pilocarpine; Rats, Wistar; Spider Venoms; Tiagabine; Urea

The aims of the present study were to investigate the anticonvulsant activity and behavioral toxicity of FrPbAII using freely moving Wistar rats. Moreover, the effectiveness of this compound against chemical convulsants was compared to that of the inhibitor of the GABAergic uptake, nipecotic acid. Our results show that FrPbAII was effective against seizures induced by the i.c.v. injection of pilocarpine (ED(50) = 0.05 microg/animal), picrotoxin (ED(50) = 0.02 microg/animal), kainic acid (ED(50) = 0.2 microg/animal) and the systemic administration of PTZ (ED(50) = 0.03 microg/animal). The anticonvulsant effect of FrPbAII differed from that of nipecotic acid in potency, as the doses needed to block the seizures were more than 10 folds lower. Toxicity assays revealed that in the rotarod, the toxic dose of the FrPbAII is 1.33 microg/animal, and the therapeutic indexes were calculated for each convulsant. Furthermore, the spontaneous locomotor activity of treated animals was not altered when compared to control animals but differed from the animals treated with nipecotic acid. Still, FrPbAII did not induce changes in any of the behavioral parameters analyzed. Finally, when tested for cognitive impairments in the Morris water maze, the i.c.v. injection of FrPbAII did not alter escape latencies of treated animals. These findings indicate that the novel GABA uptake inhibitor is a potent anticonvulsant with mild side-effects when administered to Wistar rats.

Topics: Animals; Anticonvulsants; Behavior, Animal; Disease Models, Animal; Male; Maze Learning; Motor Activity; Rats; Rats, Wistar; Receptors, GABA; Seizures; Spider Venoms; Spiders; Urea

This study was aimed at determining the effects of FrPbAII (174 Da), a novel isolated component from Parawixia bistriata spider venom, in the CNS of Wistar rats. Considering that FrPbAII inhibits the high affinity GABAergic uptake in a dose-dependent manner, its anxiolytic and anticonvulsant effects were analyzed in well-established animal models. Injection of FrPbAII in the rat hippocampus induced a marked anxiolytic effect, increasing the occupancy in the open arms of the elevated plus maze (EC(50)=0.09 microg/microl) and increasing the time spent in the lit area of the light-dark apparatus (EC(50)=0.03 microg/microl). Anxiolytic effects were also observed considering the number of entries in the open arms of the EPM and in the lit compartment of the light-dark box. Interestingly, when microinjected bilaterally in the SNPr of freely moving rats, FrPbAII (0.6 microg/microl) effectively prevented seizures induced by the unilateral GABAergic blockade of Area tempestas (bicuculline, 0.75 microg/microl). This anticonvulsant effect was similar to that evoked by muscimol (0.1 microg/microl) and baclofen (0.6 microg/microl), but differed from that of the specific GAT1 inhibitor, nipecotic acid (0.7 microg/microl). This difference could be accounted either for the parallel action of FrPbAII over glycinergic transporters or to an inspecific activity on GABAergic transporters. Data from the present investigation might be pointing to a novel compound with interesting and yet unexplored pharmacological potential.

Topics: Analysis of Variance; Animals; Anticonvulsants; Anxiety; Behavior, Animal; Bicuculline; Choice Behavior; Diazepam; Disease Models, Animal; Drug Interactions; Hippocampus; Male; Maze Learning; Neuroprotective Agents; Nipecotic Acids; Pentylenetetrazole; Rats; Rats, Wistar; Seizures; Spider Venoms; Spiders; Substantia Nigra; Urea