RESUMO
BACKGROUND AND PURPOSE: The efficacy of retigabine (RGB), a positive allosteric modulator of K+ channels indicated for adjunct treatment of partial seizures, was studied in two adult models of kainic acid (KA)-induced status epilepticus to determine it's toleratbility. METHODS: Retigabine was administered systemiclly at high (5 mg/kg) and low (1-2 mg/kg) doses either 30 min prior to or 2 hr after KA-induced status epilepticus. High (1 µg/µL) and low (0.25 µg/µL) concentrations of RGB were also delivered by intrahippocampal microinjection in the presence of KA. RESULTS: Dose-dependent effects of RGB were observed with both models. Lower doses increased seizure behavior latency and reduced the number of single spikes and synchronized burst events in the electroencephalogram (EEG). Higher doses worsened seizure behavior, produced severe ataxia, and increased spiking activity. Animals treated with RGB that were resistant to seizures did not exhibit significant injury or loss in GluR1 expression; however if stage 5-6 seizures were reached, typical hippocampal injury and depletion of GluR1 subunit protein in vulernable pyramidal fields occurred. CONCLUSIONS: RGB was neuroprotective only if seizures were significantly attenuated. GluR1 was simultaneously suppressed in the resistant granule cell layer in presence of RGB which may weaken excitatory transmission. Biphasic effects observed herein suggest that the human dosage must be carefully scrutinized to produce the optimal clinical response.
RESUMO
In adult rats, intraperitoneal injection of kainate (KA) results in sustained status epilepticus and persistent behavioral comorbidities such as hyperexcitability, anxiety, and altered response to environmental cues. Intrahippocampal KA also results in sustained status epilepticus and continuous high frequency oscillations in the electroencephalograph (EEG), although subsequent behavioral side effects are unknown. We hypothesized that retigabine, a recently discovered anticonvulsant and potent positive modulator of Kv7 channels, may attenuate seizure-induced behavioral abnormalities. Status epilepticus was induced by administration of KA either intraperitoneally (15 mg/kg) or by single intrahippocampal injection (1.0 µg/0.5 µL). After 24 h, half of systemically KA-treated animals that reached stage 6 seizures were injected once daily with retigabine (5 mg/kg) for 14 continuous days. All groups underwent three behavioral tests--capture and handling, open field, and elevated plus maze--24 h following the last retigabine treatment and were sacrificed at 25-28 days. In the capture and handling test, systemic KA treatment resulted in frisky behavior and resistance to capture with wild attempts to escape during the 1st, 2nd, and 3rd weeks of the observation period. In contrast, these behaviors were attenuated in KA+retigabine-treated animals. In the open-field test, KA-treated animals spent more time in the center zone, but KA+retigabine-treated rats had greater overall activity compared with those having vehicle, KA, or retigabine-only treatment. In the elevated plus maze, KA+retigabine-treated animals traveled greater distances in open and closed arms (proximal and distal) compared with controls, also signifying anxiety reduction. Retigabine-only-treated rats traveled more in the open proximal arms compared with controls, indicating increased hyperlocomotion in normotensive rats. Although treatment with KA+retigabine resulted in anxiolytic-like effects in all three behavioral tasks compared with vehicle, this group did not significantly differ from systemically KA-treated rats in most measurements in open-field and elevated plus maze tasks, suggesting that retigabine may also cause hyperlocomotion unrelated to anxiety level. Despite that intrahippocampal KA-treated rats displayed comparable seizure behavior, epileptiform activity, and hippocampal injury, their behavior resembled the controls, suggesting that molecular and subsequent cellular changes are also partially responsible for anxiolytic-like effects and that these results are likely independent of the hippocampus.
