• 2018-07
  • 2018-10
  • 2018-11
  • 2019-04
  • 2019-05
  • 2019-06
  • 2019-07
  • 2019-08
  • br Materials and methods br Results br Discussion Inflammato


    Materials and methods
    Discussion Inflammatory signalling and in particular the arachidonic 795 cascade have been suggested as targets for disease modification, optimization of the therapeutic response, and even restoration of pharmacosensitivity (Potschka, 2010). Recently, we demonstrated that targeting of EP1 receptors using SC-51089 prevents seizure-associated up-regulation of the multidrug transporter P-glycoprotein (Pekcec et al., 2009). Based on the potential of P-glycoprotein to limit brain penetration of antiepileptic drugs (AED), we hypothesized that EP1 receptor antagonism should improve antiepileptic drug efficacy. Evidence was obtained that sub-chronic pretreatment with SC-51089 enhances the anticonvulsant effect of phenobarbital (Pekcec et al., 2009). Further translational development of the approach of course requires careful tolerability testing. The present data rather indicate that EP1 receptor antagonism exerts no relevant proconvulsant effects. In view of the excellent predictive validity of the amygdala kindling model for human temporal lobe epilepsy (Loscher, 2002, McIntyre and Gilby, 2009), these data suggest that EP1 receptor antagonist add-on treatment will not negatively affect seizure control. The only concern suggested by the present data for EP1 receptor antagonist add-on treatment is related to the delayed cessation of seizure activity in response to SC-51089, which was evident at the highest dose tested. However, it needs to be considered that lower dosages of SC-51089 exerted relevant and significant CNS effects in previous studies (Abe et al., 2009, McCullough et al., 2004, Kawano et al., 2006) so that a limitation of the dosing might prevent negative effects on duration of seizures. The effect on seizure duration might be related to an interference of EP1 receptor associated signalling with endogenous mechanisms of seizure termination. This hypothesis is strongly supported by the observation that the prostaglandin E2 derivative and EP1 receptor agonist misoprostol exerts the opposite effect with a reduction in seizure duration. Future studies are necessary to reveal the mechanisms by which EP1 receptor signalling might directly or indirectly interfere with termination of seizure activitity. COX enzymes have repeatedly been suggested as targets for adjunctive therapies in epilepsies (Kulkarni and Dhir, 2009, Takemiya et al., 2007, Potschka, 2010). We recently demonstrated that COX-2 inhibition can control P-glycoprotein expression, improve antiepileptic drug brain penetration, and restore pharmacosensitivity (Zibell et al., 2009, van Vliet et al., 2010) (Schlichtiger et al., 2010). Moreover, evidence exist that COX-2 inhibition or genetic deficiency can reduce excitotoxic brain damage in the epileptic brain (Kunz et al., 2005, Takemiya et al., 2006, Kim and Jang, 2006). Earlier studies revealed contrasting effects of COX-2 inhibition on ictogenesis in different rodent seizure models (for review see Kulkarni and Dhir, 2009). Our present data did not suggest any pro- or anticonvulsant effects of two COX-2 inhibitors with different degrees of selectivity on the generation, spread, and termination of fully kindled seizures elicited by amygdala stimulation in mice. Considering the predictive validity of the amygdala kindling model as a chronic model of temporal lobe epilepsy, these data suggest that COX-2 inhibitor add-on therapy should not exert detrimental effects on seizure frequency or severity in patients with temporal lobe epilepsy. Considering earlier reports testing COX-2 inhibitors in rodent seizure and epilepsy models, the vast majority of these studies described that non-selective COX inhibition, selective COX-2 inhibition, or genetic COX-2 deficiency can exert beneficial effects in rodent seizure models or were without impact on seizure activity and its consequences (for review see Kulkarni and Dhir, 2009). However, a small number of studies got evidence that inhibition of COX enzymes can also cause detrimental effects (Baik et al., 1999, Kim et al., 2001, Kim et al., 2008, Toscano et al., 2008, Akarsu et al., 2006). It needs to be considered that all of these data describing proconvulsant effects as well as all of the data describing anticonvulsant effects were obtained in acute seizure models eliciting seizure activity in naïve animals. This aspect might also explain the discrepancy to our data, which were obtained in fully kindled mice exhibiting numerous cellular and molecular alterations reflecting the hyperexcitable kindled network with many parallels to the pathophysiology of human temporal lobe epilepsy (McIntyre and Gilby, 2009, Loscher, 2002). To our knowledge testing of COX inhibitors in kindling models was so far limited to an evaluation of the impact of different compounds administered during the kindling process using PTZ kindling or rapid kindling paradigms, thereby describing an attenuation of kindling progression (Dhir et al., 2006, Dhir et al., 2007, Tu and Bazan, 2003, Takemiya et al., 2003). Considering other chronic models the lack of any anti- or proconvulsant effect is in line with the data reported by Holtman et al. (2009), who did not observe an impact of the COX-2 inhibitor SC-58236 on the frequency and duration of spontaneous seizures in the chronic phase of a post-status epilepticus model.