Antiepileptogenic effects of the selective COX-2 inhibitor etoricoxib, on the development of spontaneous absence seizures in WAG/Rij rats

Fingolimod Exerts only Temporary Antiepileptogenic Effects but Longer-Lasting Positive Effects on Behavior in the WAG/Rij Rat Absence Epilepsy Model

“…It is known that glial activation and the related overexpression of proinflammatory cytokines seem to play a crucial role in epileptogenesis both in humans and in several animal models of epilepsy [58][59][60][61]; however, to date, such a relationship between neuroinflammation and absence seizure development in WAG/Rij rats remains unclear [27,28]. Indeed, neuroinflammation and related mediators worsen absence seizures in this strain [28-30, 62, 63], while cyclooxygenase inhibitors have some partial antiabsence properties [11,63,64] and etoricoxib, a selective COX-2 inhibitor, also possesses antiepileptogenic effects in this strain, which appear to be more effective than fingolimod with a reduction in the development of absence seizures of about 45% vs 30% obtained with fingolimod [11]. Overall, based on the current knowledge, neuroinflammation does not convincingly seem to take part in the epileptogenic process in WAG/Rij rats; rather, it seems to accompany and participate in seizure generation and synchronization [27] as also supported by findings in the GAERS model of absence epilepsy [65]; accordingly, these mechanism may contribute to the limited fingolimod effects in this model.…”

“…WAG/Rij rat progenitors, weighing about 60 g (4 weeks old), were originally purchased from Charles River Laboratories s.r.l. (Calco, Lecco, Italy) and the rats used in these protocols were all obtained from our breeding colony at the University of Catanzaro animal facility, as previously described [11,36]. WAG/Rij rats were housed three/four per cage and kept under stable environmental conditions, humidity (60 ± 5%) and temperature (21 ± 2 °C), in a room with 12/12 h reversed light/dark cycle (lights on at 20.00).…”

“…Increasing knowledge suggests that the immune system and inflammation are involved in the pathogenesis of epilepsy, thereby representing potentially suitable targets to develop novel disease-modifying drugs [8]. However, the clinical efficacy of anti-inflammatory and immunosuppressant drugs in epilepsy remains to be fully defined [9][10][11].…”

“…Despite in this latter model neuroinflamamtion does not seem to play a major role [28]; it has been demonstrated that drugs (e.g. etoricoxib, indomethacin and rapamycin) acting on inflammation can both reduce absence seizures and their development and accordingly, increasing neuroinflammation increases absence seizures 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 5 [11,[29][30][31]. The role of inflammatory cytokines have been previously studied by Van Luijtelaar et al [28], IL-1beta and TNF-alpha administration can both increase absence seizures in this model while their levels were found to be altered in the blood and/or the brain of WAG/Rij rats at some ages with no clear correlation with SWDs development concluding therefore that a possible modulatory effect of neuroinflammation is plausible but TNF-alpha might not have necessarily a negative impact as also suggested by some other previous articles in other models [32].…”

“…Technology INC), as previously described [11]. After surgery, all animals were allowed at least 1 week of recovery and then connected to pre-amplifiers (Pinnacle Technology's 8400-9000 video/EEG system with Sirenia Software, Kansas, USA) through a flexible recording cable and an electric swivel, attached above the cages, permitting free movements for the animals [39].…”