A synthetic bioisoster of trimethadione and phenytoin elicits anticonvulsant effect, protects the brain oxidative damage produced by seizures and exerts antidepressant action in mice.
Epilepsy is recognized as one of the most common and serious neurological disorder affecting 1-2% of the world׳s population. The present study demonstrates that systemic administration of 3-butyl-5,5-dimethyl-1,2,3-oxathiazolidine-4-one-2,2-dioxide (DIOXIDE), a synthetic compound bioisoster of trimethadione and phenytoin (classical anticonvulsants), elicits a dose dependent anticonvulsant response in mice submitted to the subcutaneous pentylenetetrazole seizure test (scPTZ). Among various factors supposed to play role in epilepsy, oxidative stress and reactive species have strongly emerged. The protection exerted by DIOXIDE over the extent of brain oxidative damage produced by PTZ was determined, by measuring the levels of lipid peroxidation and reduced glutathione and the activity of Na(+)/K(+)-ATPase. Psychiatric disorders represent frequent comorbidities in persons with epilepsy. In this report, the potential anxiolytic and antidepressant activities of DIOXIDE were evaluated in several widely used models for assessing anxiolytic and antidepressant activities in rodents. Although DIOXIDE did not evidence anxiolytic activity at the doses tested, it revealed a significant antidepressant-like effect. Preliminary studies of its mechanism of action, by means of its capacity to act via the GABAA receptor (using the [(3)H]flunitrazepam binding assay in vitro and the picrotoxin test in vivo) and the Na(+) channel (using the alkaloid veratrine, a voltage-Na(+) channel agonist) demonstrated that the anticonvulsant effect is not likely related to the GABAergic pathway and the antidepressant-like effect could be due to its Na(+) channel blocking properties. The results for DIOXIDE suggested it as a new anticonvulsant-antioxidant and antidepressant compound that deserves further development.
Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini", Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), Buenos Aires, Argentina. Electronic address: vpastore@qb.ffyb.uba.ar.
Valentina
V
Pastore
Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini", Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), Buenos Aires, Argentina. Electronic address: criswasowski@qb.ffyb.uba.ar.
Cristina
C
Wasowski
Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini", Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), Buenos Aires, Argentina. Electronic address: jhiggs@qb.ffyb.uba.ar.
Josefina
J
Higgs
Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini", Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), Buenos Aires, Argentina. Electronic address: irenem@qb.ffyb.uba.ar.
Irene C
IC
Mangialavori
Química Medicinal, Departamento de Ciencias Biológicas, UNLP, calle 47 y 115 (B1900BJW), La Plata, Argentina. Electronic address: lbb@biol.unlp.edu.ar.
Luis E
LE
Bruno-Blanch
Instituto de Química y Fisicoquímica Biológicas "Prof. Alejandro C. Paladini", Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Junín 956 (C1113AAD), Buenos Aires, Argentina. Electronic address: mmarder@qb.ffyb.uba.ar.
Mariel
M
Marder
D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D000928:Antidepressive Agents / Q000627:therapeutic use*; D001930:Brain Injuries / Q000378:metabolism / Q000517:prevention & control*; D004195:Disease Models, Animal; D005445:Flunitrazepam / Q000493:pharmacokinetics; D005978:Glutathione / Q000378:metabolism; D019417:Hindlimb Suspension / Q000523:psychology; D015227:Lipid Peroxidation / Q000187:drug effects; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010433:Pentylenetetrazole / Q000633:toxicity; D010672:Phenytoin / Q000737:chemistry / Q000627:therapeutic use*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013997:Time Factors; D014293:Trimethadione / Q000737:chemistry / Q000627:therapeutic use*; D014702:Veratrine / Q000494:pharmacology
D000927:Anticonvulsants; D000928:Antidepressive Agents; D010672:Phenytoin; D005445:Flunitrazepam; D000254:Sodium-Potassium-Exchanging ATPase; D014702:Veratrine; D005978:Glutathione; D014293:Trimethadione; D010433:Pentylenetetrazole
3-butyl-5,5-dimethyl-1,2,3-oxathiazolidine-4-one-2,2-dioxide; Anticonvulsant; Antidepressant; Oxidative damage; Veratrine