Malignant infarction of the middle cerebral artery in a porcine model. A pilot study

Abstract

Animal models; Central nervous system; InfarctionModels animals; Sistema nerviós central; InfartModelos animales; Sistema nervioso central; InfartoBackground and purpose Interspecies variability and poor clinical translation from rodent studies indicate that large gyrencephalic animal stroke models are urgently needed. We present a proof-of-principle study describing an alternative animal model of malignant infarction of the middle cerebral artery (MCA) in the common pig and illustrate some of its potential applications. We report on metabolic patterns, ionic profile, brain partial pressure of oxygen (PtiO2), expression of sulfonylurea receptor 1 (SUR1), and the transient receptor potential melastatin 4 (TRPM4). Methods A 5-hour ischemic infarct of the MCA territory was performed in 5 2.5-to-3-month-old female hybrid pigs (Large White x Landrace) using a frontotemporal approach. The core and penumbra areas were intraoperatively monitored to determine the metabolic and ionic profiles. To determine the infarct volume, 2,3,5-triphenyltetrazolium chloride staining and immunohistochemistry analysis was performed to determine SUR1 and TRPM4 expression. Results PtiO2 monitoring showed an abrupt reduction in values close to 0 mmHg after MCA occlusion in the core area. Hourly cerebral microdialysis showed that the infarcted tissue was characterized by reduced concentrations of glucose (0.03 mM) and pyruvate (0.003 mM) and increases in lactate levels (8.87mM), lactate-pyruvate ratio (4202), glycerol levels (588 μM), and potassium concentration (27.9 mmol/L). Immunohistochemical analysis showed increased expression of SUR1-TRPM4 channels. Conclusions The aim of the present proof-of-principle study was to document the feasibility of a large animal model of malignant MCA infarction by performing transcranial occlusion of the MCA in the common pig, as an alternative to lisencephalic animals. This model may be useful for detailed studies of cerebral ischemia mechanisms and the development of neuroprotective strategies.The Neurotraumatology and Neurosurgery Research Unit is supported by a grant from the Departament d'Universitats, Recerca i Societat de la Informació de la Generalitat de Catalunya (SGR 2014-844). This work has been supported in part by the Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) with grant FIS PI11/00700, which was co-financed by the European Regional Development Fund (ERDF) and awarded to Dr. J. Sahuquillo. A. Sánchez-Guerrero is the recipient of a personal pre-doctoral grant from the Instituto de Salud Carlos III (grant number grant number FI12/00074)