Abstract

Epileptogenesis is a progressive process which culminates with spontaneous, recurrent and unpredictable epileptic seizures due to enhanced neuronal excitability. Well-characterized animal models of this process are needed to clarify its underlying molecular mechanisms, in which the role of nitric oxide has been a controversial component. We have used kindling with a sub-convulsive dose of pentylenetetrazole to objectively characterize early electroencephalographic changes during epileptogenesis. We used electroencephalographic recordings both during pentylenetetrazole (20 mg/kg) kindling for 20 days and then, 24 days later to quantify the number, duration and spectral power of epileptic discharges. The levels of nitric oxide were modulated locally in the cerebral cortex by pharmacological agents. The number of epileptiform discharges increased during the kindling protocol as well as 24 days later, revealing the induction of a self-sustaining epileptogenic process. Epileptic discharges were characterized by theta frequencies (4-10 Hz) that were associated with absence-like seizures. However, during kindling, the spectral power of the theta band progressively decreased, while the power of higher frequencies, in the beta band, increased. Nitric oxide in the cerebral cortex inhibited the number and amplitude of epileptic discharges. The electroencephalographic characterization of this kindling protocol provides a valuable tool to detect consequences of therapeutic interventions undertaken at initial phases of epileptogenesis, especially those targeted towards stopping this process. Increases of nitric oxide in the cerebral cortex could be a useful intervention to negatively modulate neuronal excitability, epileptic discharges and the progression of epileptogenesis.