Cardiorespiratory responses to hypercapnia in different rat models of epilepsy and the effect of epileptogenesis

Details

Supervisors

El Tahry, Riëm

Faculty

Faculté de pharmacie et des sciences biomédicales

Degree label

Master [120] en sciences biomédicales, à finalité approfondie

Abstract

Sudden unexpected death in epilepsy (SUDEP) is the main cause of epilepsy-related deaths and frequent tonic-clonic seizures are leading risk factors. The underlying mechanism involves autonomic abnormalities including bradycardia and central apnoea characterized with severe hypercapnia. Impaired central chemoreception, the mechanism detecting PCO2 changes in the blood and regulating breathing, accordingly, might contribute to these dysfunctions. This project aimed to first investigate central chemoreception in 2 different epilepsy models and secondly characterize it during the epileptogenesis. Three groups of rats were used for the first part: kainic acid (KA) Wistar rats (n=10) characterized with tonic-clonic seizures, Genetic Absence Epilepsy Rat from Strasbourg (GAERS) (n=8) with absence seizures and healthy Wistar rats (n=14). Frequency of breathing (fb) and heart rate (HR) responses were measured using photoplethysmography 1h before, 1h during and 1h after 10% CO2 challenge 6 months post KA injection. Epilepsy severity for KA rats was confirmed with video-electroencephalogram. In the second part, CO2 challenge was performed once a month for 4 months post KA injection in KA rats (n=14) and their cardiorespiratory responses were measured. Results from the first part suggested an increase in the fb during CO2 exposure in healthy (p < 0.001) and GAERS rats (p < 0.01), with a decrease in HR for both groups, although GAERS rats exhibited a delayed response. In contrast, KA rats showed significantly attenuated fb and HR responses to CO2 (HR: p < 0.001, fb: p < 0.05), indicating impaired chemoreceptive mechanisms in chronic KA rat model. The second part revealed gradual decrease in the fb and HR response to CO2 along epileptogenesis of KA rats. fb response dropped significantly in the 3rd and 4th months (p<0.01 and p<0.0001) and HR response increased in the 1st,3rd and 4th months (p<0.05, p<0.0001 and p<0.0001). These findings show that cardiorespiratory impairment evolves over time with the severity of epilepsy. Overall, these results indicate that KA rats with tonic-clonic seizures have impaired central chemoreceptive and cardioregulatory mechanisms that evolve over time with the severity of epilepsy. These findings not only contribute to advancing our understanding of underlying pathophysiology of central apnoea in SUDEP but also open new avenues for risk stratification in SUDEP.