Cyclooxygenase-2/PGE2 pathway facilitates pentylenetetrazol-induced seizures.
Cyclooxygenases (COXs) are rate-limiting enzymes in the metabolic pathways in which arachidonic acid is converted to prostaglandins. COX-2 is the isoform induced at injury/inflammation sites and expressed constitutively in a few tissues, such as the central nervous system, and plays a role in neurodegenerative diseases associated with increased excitatory activity. However, the role of COX-2 and its main product, prostaglandin E(2) (PGE(2)), in the convulsive states is not fully established. In this study we showed that the selective COX-2 inhibitor, celecoxib (at the dose of 2mg/kg, but not at the doses of 0.2 or 20mg/kg, p.o.), protects against the seizures induced by pentylenetetrazol (PTZ, 60 mg/kg, i.p.). The role of PGE(2) in the convulsions induced by PTZ was further investigated by administering anti-PGE(2) antibodies (4 microg/2 microl, i.c.v.), and assessing electroencephalographic changes induced by PTZ (PTZ, 60 mg/kg, i.p.). Anti-PGE(2) antibodies attenuated PTZ-induced seizures in rats. In addition, combining PGE(2) (100 ng/2 microl, i.c.v.) with a subconvulsant dose of PTZ (20mg/kg, i.p.) caused seizures, further supporting a role for this prostaglandin in the convulsions induced by PTZ. Finally, we showed that the anticonvulsant action of celecoxib (2mg/kg, p.o.) was reversed by the intracerebroventricular administration of PGE(2) (10 ng/2 microl, i.c.v.). These data constitute strong converging pharmacological evidence supporting a facilitatory role for the COX-2/PGE(2) pathway in the seizures induced by PTZ. However, whether selective COX-2 inhibitors are safer anti-inflammatory drugs for epileptic patients than nonspecific inhibitors remains to be determined.
Oliveira
Mauro Schneider
MS
Departamento de Fisiologia e Farmacologia, Centro de Ciências da Saúde, Universidade Federal de Santa Maria, 97105-900 Santa Maria, RS, Brazil.
Furian
Ana Flávia
AF
Royes
Luiz Fernando Freire
LF
Fighera
Michele Rechia
MR
Fiorenza
Natália Gindri
NG
Castelli
Marcelo
M
Machado
Pablo
P
Bohrer
Denise
D
Veiga
Marlei
M
Ferreira
Juliano
J
Cavalheiro
Esper Abraão
EA
Mello
Carlos Fernando
CF
D000704:Analysis of Variance; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000276:immunology / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004569:Electroencephalography / Q000379:methods; D008297:Male; D010433:Pentylenetetrazole; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012640:Seizures / Q000139:chemically induced / Q000503:physiopathology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology
D000906:Antibodies; D016861:Cyclooxygenase Inhibitors; D011720:Pyrazoles; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D000068579:Celecoxib; D015232:Dinoprostone; D010433:Pentylenetetrazole