ABSTRACT
A number of pre-clinical rodent models have been developed in an effort to recapitulate injury mechanisms and identify potential therapeutics for traumatic brain injury (TBI), which is a major cause of death and long-term disability in the United States. The lack of restorative treatments for TBI, however, has led to considerable criticism of current pre-clinical therapeutic development strategies-namely, the translatability of widely used rodent models to human patients. The use of large animal models, such as the pig, with more brain anatomy and physiology comparable to humans may enhance the translational capacity of current pre-clinical animal models. The objective of this study was to develop and characterize a graded piglet TBI model with quantitative pathological features at the cellular, tissue, and functional level that become more prominent with increasing TBI severity. A graded TBI was produced by controlled cortical impact (CCI) in "toddler-aged" Landrace piglets by increasing impact velocity and/or depth of depression to 2 m/sec; 6 mm; 4 m/sec; 6 mm; 4 m/sec; 12 mm; or 4 m/sec; 15 mm, producing a range of neural injury responses that corresponded to injury severity. Quantitative gait analysis was performed pre-TBI and one, three, and seven days post-TBI, and piglets were sacrificed seven days post-TBI. Increasing impact parameters correlated to increases in lesion size with piglets that sustained a 6 mm depth of depression exhibiting significantly smaller lesions than piglets that sustained a depth of depression of 12 mm or 15 mm. Similarly, the extent of neuronal loss, astrogliosis/astrocytosis, and white matter damage became more prominent as CCI parameters were increased. These cellular and tissue-level changes correlated with motor function deficits including swing/stance time, stride velocity, and two- versus three-limb support. The piglet TBI model described here could serve as a translational platform for studying TBI sequelae across injury severities and identifying novel therapeutics.
Subject(s)
Brain Injuries, Traumatic/pathology , Disease Models, Animal , Animals , SwineABSTRACT
BACKGROUND: Efforts to develop stroke treatments have met with limited success despite an intense need to produce novel treatments. The failed translation of many of these therapies in clinical trials has lead to a close examination of the therapeutic development process. One of the major factors believed to be limiting effective screening of these treatments is the absence of an animal model more predictive of human responses to treatments. The pig may potentially fill this gap with a gyrencephalic brain that is larger in size with a more similar gray-white matter composition to humans than traditional stroke animal models. In this study we develop and characterize a novel pig middle cerebral artery occlusion (MCAO) ischemic stroke model. METHODS: Eleven male pigs underwent MCAO surgery with the first 4 landrace pigs utilized to optimize stroke procedure and 7 additional Yucatan stroked pigs studied over a 90 day period. MRI analysis was done at 24 hrs and 90 days and included T2w, T2w FLAIR, T1w FLAIR and DWI sequences and associated ADC maps. Pigs were sacrificed at 90 days and underwent gross and microscopic histological evaluation. Significance in quantitative changes was determined by two-way analysis of variance and post-hoc Tukey's Pair-Wise comparisons. RESULTS: MRI analysis of animals that underwent MCAO surgery at 24 hrs had hyperintense regions in T2w and DWI images with corresponding ADC maps having hypointense regions indicating cytotoxic edema consistent with an ischemic stroke. At 90 days, region of interest analysis of T1 FLAIR and ADC maps had an average lesion size of 59.17 cc, a loss of 8% brain matter. Histological examination of pig brains showed atrophy and loss of tissue, consistent with MRI, as well as glial scar formation and macrophage infiltration. CONCLUSIONS: The MCAO procedure led to significant and consistent strokes with high survivability. These results suggest that the pig model is potentially a robust system for the study of stroke pathophysiology and potential diagnostics and therapeutics.
