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.

In vitro modeling of the neurovascular unit: advances in the field

“…Furthermore, other prominent protein families, such as adherens junctions (AJ) and gap junctions (GJ), play significant roles in intercellular adhesion and communication, respectively, and are integral to BBB tightness [11]. In addition to the TJs, the BBB endothelium expresses a host of efflux transporters (including P-glycoprotein-Pgp [19], breast cancer resistance protein-BCRP [20], and multidrug resistance-related proteins MRPs [21] as well as cytochrome P450 (e.g., CYP3A4, NADPH-CYP P450 reductase, etc.) [22] and Phase II detoxifying enzymes (such as UGT1A4), which help protect the brain from potentially harmful substances [19].…”

Subcutaneous Administration of Angiotensin-(1-7) Improves Recovery after Traumatic Brain Injury in Mice

“…The significant BBB disruption after CCI allows access into the CNS early after injury. [54][55][56] However, in mice after CCI the BBB is reformed relatively quickly, such that by 29 dpi the BBB has predominantly healed. 55,57 Whether or not Ang-(1-7) needs to cross the BBB to influence the CNS is uncertain.…”

The Nanotheranostic Researcher’s Guide for Use of Animal Models of Traumatic Brain Injury

“…The controlled cortical impact (CCI) model is currently one of the most used and well-characterized models of TBI due to the model’s reproducibility and specificity regarding mechanical parameters [ 57 – 60 ]. CCI models use a pneumatic or electromagnetic ( Figure 6 ) impact system to deliver a rigid impactor onto the exposed dura of the animal following craniectomy [ 58 ]. Originally developed in ferrets, the CCI model has been adapted for a variety of species, including mice, rats, swine, and monkeys [ 14 , 59 ].…”