Abstracts

Rationale: Status epileptics (SE) can be refractory to standard anti-seizure medications in up to 20% of patients. The timely abortion of SE is key to preventing harmful consequences. Prolonged SE is molecularly characterized by acute alterations in certain ion channels including a decrease in the inhibitory properties and internalization of the γ-Aminobutyric acid type A receptors (GABARs). This increases excitability and weakens the effectiveness of many standard medications such as phenobarbital; the anticonvulsant effect of which is mediated via the modulation of such channels. We have recently shown that blockade of tropomyosin-related kinase B receptor (TrkB) with the investigational new drug, lestaurtinib (CEP-701), attenuates SE-induced hyperexcitability. Since TrkB is a regulator of GABARs (Roberts D et al., PNAS, 2005), and its blockade might potentially prevent SE-induced changes in these receptors, we hypothesized that TrkB blockade with CEP-701 will potentiate the anticonvulsant effect of phenobarbital against kainic acid (KA)-induced SE.Methods: Seizures were induced in periadolescent P35-P40 Sprague Dawley rats by injecting 0.5 μg of KA into the basolateral amygdala and SE was confirmed using epidural cortical electroencephalography (EEG). Fifteen minutes after SE onset, rats received either 25 mg/kg of CEP (KA-CEP group) or its vehicle (KA-V group) intraperitoneally (i.p.). At 6 hours after SE onset, rats were given 100 mg/kg of phenobarbital i.p., supplemented every 15 minutes with an additional 25 mg/kg until cessation of seizures was achieved.Results: All the rats that received KA developed electroclinical SE within 30 minutes to 1 hour after KA injections. The average cumulative dose of phenobarbital required to achieve seizure cessation in the KA-CEP group (107.5 ± 5.3 mg/kg, n=10) was significantly lower than in the KA-V group (132.5 ± 6.5 mg/kg, n=10, t-test, p=0.008). Moreover, recurrence of SE occurred 5-10 hours after abortive therapy in 4 of the KA-V rats, and only in 2 of the KA-CEP rats.Conclusions: Given its known clinical safety profile in children, CEP-701 is a clinically promising adjuvant drug that can be potentially used with standard anticonvulsant medications to abort SE. Ongoing experiments in our laboratory are exploring the underlying molecular mechanisms of the herein reported effect of CEP-701; specifically, its potential role in reversing SE-induced changes in GABARs.