Na+, K+-ATPase Activating Antibody Displays in vitro and in vivo Beneficial Effects in the Pilocarpine Model of Epilepsy.

Na+, K+-ATPase is an important regulator of brain excitability. Accordingly, compelling evidence indicates that impairment of Na+, K+-ATPase activity contributes to seizure activity in epileptic mice and human with epilepsy. In addition, this enzyme is crucial for plasma membrane transport of water, glucose and several chemical mediators, including glutamate, the major excitatory transmitter in the mammalian brain. Since glucose hypometabolism and increased glutamate levels occur in clinical and experimental epilepsy, we aimed the present study to investigate whether activation of Na+, K+-ATPase activity with specific antibody (DRRSAb) would improve glucose uptake and glutamate release in pilocarpine-treated mice. We found decreased uptake of the glucose fluorescent analog 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-il)amino]-2-desoxi-d-glucose (2-NBDG) in cerebral slices from pilocarpine-treated animals. Interestingly, decreased 2-NBDG uptake was not detected in DRRSAb-treated slices, suggesting a protective effect of the Na+, K+-ATPase activator. Moreover, DRRSAb prevented the increase in glutamate levels in the incubation media of slices from pilocarpine-treated mice. In addition, in vivo intrahippocampal injection of DRRSAb restored crossing activity of pilocarpine-treated mice in the open-field test. Overall, the present data further support the hypothesis that activation of the Na+, K+-ATPase is a promising therapeutic strategy for epilepsy.

Effect of atorvastatin on behavioral alterations and neuroinflammation during epileptogenesis.

Temporal lobe epilepsy (TLE) is the most frequent and medically refractory type of epilepsy in humans. In addition to seizures, patients with TLE suffer from behavioral alterations and cognitive deficits. Poststatus epilepticus model of TLE induced by pilocarpine in rodents has enhanced the understanding of the processes leading to epilepsy and thus, of potential targets for antiepileptogenic therapies. Clinical and experimental evidence suggests that inflammatory processes in the brain may critically contribute to epileptogenesis. Statins are inhibitors of cholesterol synthesis, and present pleiotropic effects that include antiinflammatory properties. We aimed the present study to test the hypothesis that atorvastatin prevents behavioral alterations and proinflammatory state in the early period after pilocarpine-induced status epilepticus. Male and female C57BL/6 mice were subjected to status epilepticus induced by pilocarpine and treated with atorvastatin (10 or 100mg/kg) for 14days. Atorvastatin slightly improved the performance of mice in the open-field and object recognition tests. In addition, atorvastatin dose-dependently decreased basal and status epilepticus-induced levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and interferon-γ (INF-γ) and increased interleukin-10 (IL-10) levels in the hippocampus and cerebral cortex. The antiinflammatory effects of atorvastatin were qualitatively identical in both sexes. Altogether, these findings extend the range of beneficial actions of atorvastatin and indicate that its antiinflammatory effects may be useful after an epileptogenic insult.