Development and characterization of a pentylenetetrazol-induced convulsive seizure model in non-anaesthetized sheep

The pathophysiology of seizures is complex and could contribute to a range of morbidities including sudden unexpected death of epilepsy (SUDEP). A better understanding of seizure-induced pathophysiology can lead to the development of targeted interventions. Here, we describe the development and characterization of a novel large mammalian model of convulsive seizures in non-anesthetized sheep induced by pentylenetetrazol (PTZ), one of the most widely used proconvulsant drugs in epilepsy research. A dose of intravenous PTZ that reliably induced a reproducible and consistent level of seizure in non-anaesthetized sheep was determined. Convulsive seizures went through a relatively predictable sequence, similar to that seen in other animal models of epilepsy. A species-specific seizure severity scale system, based on the field Racine's scale that is widely used in epilepsy research, was designed to establish a user-friendly scoring system for PTZ-induced seizures in sheep. We demonstrated that convulsive seizures caused substantial increases in mean arterial pressure and heart rate. The translational value of this large animal model can be further enhanced when combined with other translational tools such as quantitative systems physiology and pharmacology, potential biomarker testing and experimental preclinical trials of potential prophylactic treatments. An advanced animal model, such as described in this study, provides a unique opportunity for comprehensive physiological monitoring of neural and systemic pathways activated by interictal and ictal activity and can contribute to the development of preventive therapies for seizures.