Avaliação da atividade respiratória e crises convulsivas induzidas por PTZ em ratos Wistar adultos

Abstract

Epilepsy is a neurological disorder characterized by the spontaneous and recurrent occurrence of epileptic seizures. It is highly prevalent worldwide, and one-third of patients are refractory to pharmacological treatment. Among these patients, the leading cause of death is SUDEP (Sudden Unexpected Death in Epilepsy), which is attributed to respiratory arrest following a seizure event. Additionally, it has been observed that epilepsy patients exhibit a blunted ventilatory response to CO2, which may contribute to respiratory failure associated with a seizure event. In light of this, this study was divided into two parts, one involving the assessment of respiratory activity during acute seizures induced by PTZ (pentylenetetrazole) and another evaluating the ventilatory response to hypercapnia after chronically induced repeated seizures by PTZ. The first part of the study investigated respiratory activity in adult Wistar rats at different levels of behavioral seizure severity. Animals underwent surgery for electrode implantation in the cortex and diaphragm muscle, allowing simultaneous recordings of electroencephalogram (EEG) and diaphragmatic electromyogram (DIAEMG). Respiratory activity (respiratory frequency and maximum diaphragmatic amplitude) was assessed based on DIAEMG. Seizures were acutely induced by PTZ injection at different doses, and their severity was classified based on a pre-established table, with absence seizures representing the lowest score and tonic-clonic seizures as the most severe. Respiratory activity was grouped into different levels of seizure severity. During absence seizures and myoclonic jerks, respiratory frequency significantly decreased (~50% reduction) compared to pre-ictal and post-ictal periods. Pronounced changes occurred with more severe seizures (clonic and tonic), including periods of apnea, especially during tonic seizures. Apnea duration was significantly longer in tonic seizures compared to clonic seizures. Notably, during PTZ-induced tonic seizures, apnea events were marked by tonic contraction of DIAEMG (tonic phase apnea). In most animals (5 out of 7), this was a fatal event where respiratory arrest caused by the seizure preceded asystole. In conclusion, we provide the first systematic assessment of respiratory activity in acute seizures induced by PTZ and demonstrate that respiratory dysfunction is more pronounced in more severe seizures. The second part of the study investigated ventilatory response in adult Wistar rats after repeated convulsive seizures induced by PTZ. Seizures were induced (with an i.p. dose of 40 mg/kg) on alternate days, totaling 10 injections. After three consecutive high-scoring seizures and at the end of the treatment, ventilatory response to 7% CO2 was assessed. After three consecutive severe seizures, no difference in ventilation was observed compared to the control group. However, after the 10th PTZ injection, an attenuation of ventilation was observed in animals with recurrent seizures, and this decrease was due to a lower increase in respiratory frequency. Therefore, chronically induced repeated seizures by PTZ promote an attenuation of ventilatory response to hypercapnia.