SYNERGIC EFFECTS OF DOXYCYCLINE AND CELECOXIB IN A PILOCARPINE MODEL OF EXPERIMENTAL EPILEPSY IN RATS

Neuroinflammation provoked by prolonged seizures is emerging as a key factor in the epileptogenesis. We hypothesized that not only one, but multiple proinflammatory pathways are activated after initial epileptogenic event. The purpose of this study was to assess the effect of single and combined application of two anti-inflammatory drugs on pilocarpine-induced epileptogenic activity and markers of brain neuroinflammation. Male immature Wistar rats were used. The animals were allocated into 4 groups of 6 animals each (n = 6) and were subjected to pilocarpine model of neonatal epilepsy. In the first (control group), animals were given, pilocarpine hydrochloride (2% 10ml 400 mg/kg, i.p.). In the second, thirth and fourth groups animals were given for 7 days via gavage, Doxycycline (20 mg/kg, per os), Celecoxib (20 mg/kg, per os) and combination of Doxycycline (20 mg/kg, per os) plus Celecoxib (20 mg/kg, per os), respectively. On the 7-th day animals from the last 3 groups were injected i.p. pilocarpine. During the observation period of 2 h, after pilocarpine administration, the Racine's scale was used to score the degree of seizures. We also assessed the number of the so-called "wet dog shakes" (WDS). 24 h later animals were sacrificed and serum was collected to measure the level IL-1 beta by sandwich-ELISA. None of those anti-inflammatory drugs were effective in attenuating epileptogenic activity and level of IL-1 beta when administered individually. When combination of these drugs was administered, this resulted in attenuation of increased levels of proinflammatory cytokines, evaluated by ELISA, scores on Racine's scale and number of WDS. Our results indicated that administration of a drug combination targeting multiple inflammatory signalling pathways for a limited duration after an initial insult like SE, may provide an important approach to neuroprotection and antiepileptogenic therapy.