A large animal model for focal stroke: Photothrombotic lesion in the cortex of Danish Landrace pigs.

Abstract

Background: Preclinical rodent models have been crucial for studying stroke pathophysiology. However, the limited success of translating these ischemic stroke models to human trials highlights their shortcomings. To address this, we developed a large animal porcine stroke model using Rose Bengal (RB) for photothrombotic ischemic lesioning.

New method: Four Danish Landrace pigs (4-6 months old, 36-40kg) were used in this proof-of-concept study. RB (20mg/kg) was infused via a central venous catheter, and lesion sites in the motor and visual cortices were targeted using MRI, a stereotactic frame, and fiducial markers. Surgical access was achieved through burr holes, followed by green light exposure through the dura onto the neocortex for 30minutes. After recovery, the pigs underwent motor behavior assessment, euthanasia, and histological and MRI analyses.

Results: Post-stroke, significant motor deficits were observed. Three pigs were hemiparetic and immobile, while one showed reduced exploratory behavior (42% post-stroke vs. 81% pre-stroke) and peripheral sniffing (~0% vs. 9%). Histological analysis revealed ischemic changes, including nuclear shrinkage, pyknosis, and infarct zones with blood clots. Lesion size ranged from 1mm² to 18mm². Ex vivo diffusion MRI showed increased mean kurtosis in three pigs, confirming microstructural changes.

Comparison with existing methods and conclusions: The model produced behavioral and histological characteristics in pigs, which have gyrencephalic brains, large intracranial vessel diameters, and a high white-to-gray matter ratio, similar to those observed in other animals and traditional models. This model can produce a reproducible isolated cortical lesion using stereotactic coordinates and/or 3D imaging.