Why Is CA3 More Vulnerable Than CA1 in Experimental Models of Controlled Cortical Impact-Induced Brain Injury?

One interesting finding of controlled cortical impact (CCI) experiments is that the CA3 region of the hippocampus, which is positioned further from the impact than the CA1 region, is reported as being more injured. The current literature has suggested a positive correlation between brain tissue stretch and neuronal cell loss. However, it is counterintuitive to assume that CA3 is stretched more during CCI injury. Recent mechanical studies of the brain have reported on a level of spatial heterogeneity not previously appreciated—the finding that CA1 was significantly stiffer than all other regions tested and that CA3 was one of the most compliant. We hypothesized that mechanical heterogeneity of anatomical structures could underlie the proposed heterogeneous mechanical response and hence the pattern of cell death. As such, we developed a three-dimensional finite element (FE) rat brain model representing detailed hippocampal structures and simulated various CCI experiments. Four groups of material properties based on recent experiments were tested. In group 1, hyperelastic material properties were assigned to various hippocampal structures, with CA3 more compliant than CA1. In group 2, linear viscoelastic material properties were assigned to hippocampal structures, with CA3 more com- pliant than CA1. In group 3, the hippocampus was represented by homogenous linear viscoelastic material properties. In group 4, a homogeneous nonlinear hippocampus was adopted. Simulation results demonstrated that for CCI with a 5-mm diameter, flat shape impactor, CA3 experienced increased tensile strains over a larger area and to a greater magnitude than did CA1 for group 1, which best explained why CA3 is more sensitive to CCI injury. However, for groups 2-4, the total volume with high strain (\u3e 30%) in CA3 was smaller than that in CA1. The FE rat brain model, with detailed hippocampal structures presented here, will help to engineer desired experimental neurotrauma models by virtually characterizing brain biomechanics before testing

Intracerebroventricular administration of chondroitinase ABC reduces acute edema after traumatic brain injury in mice

Background Brain edema is a significant challenge facing clinicians managing severe traumatic brain injury (TBI) in the acute period. If edema reaches a critical point, it leads to runaway intracranial hypertension that, in turn, leads to severe morbidity or death if left untreated. Clinical data on the efficacy of standard interventions is mixed. The goal of this study was to validate a novel therapeutic strategy for reducing post-traumatic brain edema in a mouse model. Prior in vitro work reported that the brain swells due to coupled electrostatic and osmotic forces generated by large, negatively charged, immobile molecules in the matrix that comprises brain tissue. Chondroitinase ABC (ChABC) digests chondroitin sulfate proteoglycan, a molecule that contributes to this negative charge. Therefore, we administered ChABC by intracerebroventricular (ICV) injection after controlled cortical impact TBI in the mouse and measured associated changes in edema. Results Almost half of the edema induced by injury was eliminated by ChABC treatment. Conclusions ICV administration of ChABC may be a novel and effective method of treating post-traumatic brain edema in the acute period

Mechanics of cell growth

a b s t r a c t Cell growth describes an essential feature of biological tissues. This growth process may be modeled by using a set of relatively simple governing equations based on the axioms of mass and momentum balance, and using a continuum framework that describes cells and tissues as mixtures of a solid matrix, a solvent and multiple solutes. In this model the mechanics of cell growth is driven by osmotic effects, regulated by the cells' active uptake of solutes and passive uptake of solvent. By accounting for the anisotropy of the cells' cytoskeletal structures or extracellular matrix, as well as external constraints, a wide variety of growing shapes may be produced as illustrated in various examples

d Original Contribution MOLECULES OF VARIOUS PHARMACOLOGICALLY-RELEVANT SIZES CAN CROSS THE ULTRASOUND-INDUCED BLOOD-BRAIN BARRIER OPENING IN VIVO

Abstract--Focused ultrasound (FUS) is hereby shown to noninvasively and selectively deliver compounds at pharmacologically relevant molecular weights through the opened blood-brain barrier (BBB). A complete examination on the size of the FUS-induced BBB opening, the spatial distribution of the delivered agents and its dependence on the agent's molecular weight were imaged and quantified using fluorescence microscopy. BBB opening in mice (n513) was achieved in vivo after systemic administration of microbubbles and subsequent application of pulsed FUS (frequency: 1.525MHz, peak-rarefactional pressure in situ: 570 kPa) to the left murine hippocampus through the intact skin and skull. BBB-impermeant, fluorescent-tagged dextrans at three distinct molecular weights spanning over several orders of magnitude were systemically administered and acted as model therapeutic compounds. First, dextrans of 3 and 70 kDa were delivered trans-BBB while 2000 kDa dextran was not. Second, compared with 70 kDa dextran, a higher concentration of 3 kDa dextran was delivered through the opened BBB. Third, the 3 and 70 kDa dextrans were both diffusely distributed throughout the targeted brain region. However, high concentrations of 70 kDa dextran appeared more punctated throughout the targeted region. In conclusion, FUS combined with microbubbles opened the BBB sufficiently to allow passage of compounds of at least 70 kDa, but not greater than 2000 kDa into the brain parenchyma. This noninvasive and localized BBB opening technique could, thus, provide a unique means for the delivery of compounds of several magnitudes of kDa that include agents with shown therapeutic promise in vitro but whose in vivo translation has been hampered by their associated BBB impermeability

Dynamic, regional mechanical properties of the porcine brain: Indentation in the coronal plane,"

Stress relaxation tests using a custom designed microindentation device were performed on ten anatomic regions of fresh porcine brain (postmortem time <3 h). Using linear viscoelastic theory, a Prony series representation was used to describe the shear relaxation modulus for each anatomic region tested. Prony series parameters fit to load data from indentations performed to $10% strain differed significantly by anatomic region. The gray and white matter of the cerebellum along with corpus callosum and brainstem were the softest regions measured. The cortex and hippocampal CA1/CA3 were found to be the stiffest. To examine the large strain behavior of the tissue, multistep indentations were performed in the corona radiata to strains of 10%, 20%, and 30%. Reduced relaxation functions were not significantly different for each step, suggesting that quasi-linear viscoelastic theory may be appropriate for representing the nonlinear behavior of this anatomic region of porcine brain tissue. These data, for the first time, describe the dynamic and short time scale behavior of multiple anatomic regions of the porcine brain which will be useful for understanding porcine brain injury biomechanics at a finer spatial resolution than previously possible

doi:10.1016/S1359-6446(05)03502-6

A major challenge for the pharmaceutical industry is the development of relevant model systems in which knowledge gained from high-throughput, genomic and proteomic approaches can be integrated to study function. Animal models are still the main choice for such studies but over the past few years powerful new in vitro systems have begun to emerge as useful tools to study function. Organotypic cultures made from slices of explanted tissue represent a complex multi-cellular in vitro environment with the potential to assess biological function and are uniquely placed to act as an important link between high-throughput approaches and animal models

Organotypic cultures as tools for functional screening in the CNS

Screening gets more complex with organotypic culture systems.A major challenge for the pharmaceutical industry is the development of relevant model systems in which knowledge gained from high-throughput, genomic and proteomic approaches can be integrated to study function. Animal models are still the main choice for such studies but over the past few years powerful new in vitro systems have begun to emerge as useful tools to study function. Organotypic cultures made from slices of explanted tissue represent a complex multi-cellular in vitro environment with the potential to assess biological function and are uniquely placed to act as an important link between high-throughput approaches and animal models