A Mouse Controlled Cortical Impact Model of Traumatic Brain Injury for Studying Blood-Brain Barrier Dysfunctions

Abstract

Traumatic brain injury (TBI) is one of the leading causes of death and disability worldwide. It is a silently growing epidemic with multifaceted pathogenesis, and current standards of treatments aim to target only the symptoms of the primary injury, while there is a tremendous need to explore interventions that can halt the progression of the secondary injuries. The use of a reliable animal model to study and understand the various aspects the pathobiology of TBI is extremely important in therapeutic drug development against TBI-associated complications. The controlled cortical impact (CCI) model of TBI described here, uses a mechanical impactor to inflict a mechanical injury into the mouse brain. This method is a reliable and reproducible approach to inflict mild, moderate or severe injuries to the animal for studying TBI-associated blood-brain barrier (BBB) dysfunctions, neuronal injuries, brain edema, neurobehavioral changes, etc. The present method describes how the CCI model could be utilized for determining the BBB dysfunction and hyperpermeability associated with TBI. Blood-brain barrier disruption is a hallmark feature of the secondary injury that occur following TBI, frequently associated with leakage of fluid and proteins into the extravascular space leading to vasogenic edema and elevation of intracranial pressure. The method described here focuses on the development of a CCI-based mouse model of TBI followed by the evaluation of BBB integrity and permeability by intravital microscopy as well as Evans Blue extravasation assay.

Keywords: Blood–brain barrier; Central nervous system; Controlled cortical impact; Edema; Endothelial permeability; Evans Blue; Hyperpermeability; Intracranial pressure; Intravital microscopy; Traumatic brain injury.