ABSTRACT
The objective of this project was to test whether a drug-induced model of temporal lobe seizures, namely seizures induced by a gamma aminobutyric acid (GABAB) receptor antagonist, CGP35348, result in long-term disruption of hippocampal memory function. Seizures were induced in experimental rats by intracerebroventricular (i.c.v.) injection of CGP35348 (0.64⯵mol in 3⯵L) for three consecutive days; control rats received no injection. Rats were first trained to criterion on an open radial arm maze (RAM) with 4 of the 8 arms baited, then received seizure and control treatment, and tested again on the RAM during the first week (days 1-5) and fourth week (days 22-29) after the last injection. An initial i.c.v. CGP35348 injection induced a mean of 4.4 seizures in the hippocampus, often accompanied with stages 3-5 convulsions, and sometimes with jumping; three daily CGP35348 injections induced 10.4⯱â¯1.8 (nâ¯=â¯7 rats) seizures in total. In two separate experiments, seizure-treated rats performed worse than control rats in working memory (WM) during both the 1st and 4th weeks after seizures. Reference memory (RM) deficit during the 1st week after seizures was observed in only one experiment in which RM was acquired >2â¯weeks ago. The memory deficits were not accompanied by gross neuronal loss in the hippocampus. In conclusion, i.c.v. injection of a GABAB receptor antagonist in adult rats induced brief, multiple, focal hippocampal seizures that induced deficits in spatial memory for up to 4â¯weeks.
Subject(s)
GABA-B Receptor Antagonists/toxicity , Seizures/chemically induced , Seizures/physiopathology , Spatial Memory/drug effects , Spatial Memory/physiology , Animals , Hippocampus/drug effects , Hippocampus/physiopathology , Male , Maze Learning/drug effects , Maze Learning/physiology , Memory Disorders/chemically induced , Memory Disorders/physiopathology , Organophosphorus Compounds/toxicity , Rats , Rats, Long-Evans , Time Factors , gamma-Aminobutyric Acid/adverse effectsABSTRACT
BACKGROUND: Benzofurans are heterocyclic compounds with neurotropic activity. Some have been developed for the treatment of acute and degenerative neuronal injuries. OBJECTIVE: The study aimed to evaluate the in silico binding of some promising benzofurans on the GABA receptors, and the in vivo neurotropic activity of benzofuran analogues (BZF 6-10) of gamma-aminobutyric acid (GABA) on a seizure model. METHODS: The ligands with the best physicochemical attributes were docked on two GABA receptors (the alpha-1 subunit of GABAA-R and GBR1 subunit of GABAB-R). Selected benzofuran derivatives were synthesized by a multistep procedure and characterized. To examine the neurotropic effects, mice were pretreated with different concentrations of the compounds prior to PTZ- or 4- AP-induced seizures. We assessed acute toxicity, motor behavior, and the effects on seizures. RESULTS: The tested ligands that complied with Lipinski's rule of five were tested in silico with GABAA-R (ΔG = -5.51 to -5.84 kcal/mol) at the allosteric site for benzodiazepines. They bound to a similar cluster of residues as the reference compound (gaboxadol, ΔG = -5.51 kcal/mol). Synthesis was achieved with good overall yields (42-9.7%). Two compounds were selected for biological tests (BZF-7 and rac-BZF-10) on a mouse model of seizures, induced by pentylenetetrazol (PTZ) or 4-aminopyridine (4-AP). PTZ-induced seizures are associated with GABA receptors, and those 4-AP-induced with the blockage of the delayed rectifier-type potassium channel, which promotes the release of the NMDA-sensitive glutamatergic ionotropic receptor and other neurotransmitters. The biological assays demonstrated that BZF-7 and rac-BZF-10 do not protect against seizures. Indeed, BZF-7 increased the number of PTZ-induced seizures and decreased latency time. The 4-AP model apparently showed a potentiation of seizure effects after administration of the BZF-analogues, evidenced by the incidence and severity of the seizures and reduced latency time. CONCLUSION: The results suggest that the test compounds are GABAergic antagonists with stimulatory activity on the CNS.
Subject(s)
Benzofurans/pharmacology , Central Nervous System Stimulants/pharmacology , GABA-A Receptor Antagonists/pharmacology , GABA-B Receptor Antagonists/pharmacology , Animals , Benzofurans/chemical synthesis , Benzofurans/chemistry , Benzofurans/toxicity , Central Nervous System Stimulants/chemical synthesis , Central Nervous System Stimulants/chemistry , Central Nervous System Stimulants/toxicity , GABA-A Receptor Antagonists/chemical synthesis , GABA-A Receptor Antagonists/chemistry , GABA-A Receptor Antagonists/toxicity , GABA-B Receptor Antagonists/chemical synthesis , GABA-B Receptor Antagonists/chemistry , GABA-B Receptor Antagonists/toxicity , Humans , Ligands , Male , Mice , Molecular Docking Simulation , Receptors, GABA-A/chemistry , Receptors, GABA-B/chemistryABSTRACT
Cortical epileptic foci elicited by local application of bicuculline methiodide represent a model of interictal epileptic activity with a transition into ictal phases. We studied a role of GABA-B receptors in this model using GABA-B receptor antagonist CGP35348 in adult rats with implanted cortical electrodes and cannula. CGP35348 (100 or 200 mg/kg i.p.) did not affect interictal discharges but it augmented ictal activity. Latency to the first ictal episode was decreased by the lower dose of CGP35348, duration of episodes was increased by the higher dose. GABA-B receptor antagonist did not influence purely cortical epileptic phenomenon but it is proconvulsant in ictal activity generated with participation of subcortical structures.
