Journal of neurotrauma
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Journal of neurotrauma · Apr 2017
Repetitive Model of Mild Traumatic Brain Injury Produces Cortical Abnormalities Detectable by Magnetic Resonance Diffusion Imaging (DTI/DKI), Histopathology, and Behavior.
Noninvasive detection of mild traumatic brain injury (mTBI) is important for evaluating acute through chronic effects of head injuries, particularly after repetitive impacts. To better detect abnormalities from mTBI, we performed longitudinal studies (baseline, 3, 6, and 42 days) using magnetic resonance diffusion tensor imaging (DTI) and diffusion kurtosis imaging (DKI) in adult mice after repetitive mTBI (r-mTBI; daily × 5) or sham procedure. This r-mTBI produced righting reflex delay and was first characterized in the corpus callosum to demonstrate low levels of axon damage, astrogliosis, and microglial activation, without microhemorrhages. ⋯ Using Thy1-YFP-16 mice to fluorescently label neuronal cell bodies and processes revealed low levels of axon damage in the cortex after r-mTBI. Finally, r-mTBI produced social deficits consistent with the function of this anterior cingulate region of cortex. Overall, vulnerability of cortical regions is demonstrated after mild repetitive injury, with underlying differences of DTI and DKI, microglial activation, and behavioral deficits.
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Journal of neurotrauma · Apr 2017
SYNAPTIC MITOCHONDRIA SUSTAIN MORE DAMAGE THAN NON-SYNAPTIC MITOCHONDRIA FOLLOWING TRAUMATIC BRAIN INJURY AND ARE PROTECTED BY CYCLOSPORINE A.
Currently, there are no Food and Drug Administration (FDA)-approved pharmacotherapies for the treatment of those with traumatic brain injury (TBI). As central mediators of the secondary injury cascade, mitochondria are promising therapeutic targets for prevention of cellular death and dysfunction after TBI. One of the most promising and extensively studied mitochondrial targeted TBI therapies is inhibition of the mitochondrial permeability transition pore (mPTP) by the FDA-approved drug, cyclosporine A (CsA). ⋯ This is the first study to examine the effects of CsA on isolated synaptic and non-synaptic mitochondria after experimental TBI. We conclude that synaptic mitochondria sustain more damage than non-synaptic mitochondria 24 h after severe controlled cortical impact injury (CCI), and that intraperitoneal administration of CsA (20 mg/kg) 15 min after injury improves synaptic and non-synaptic respiration, with a significant improvement being seen in the more severely impaired synaptic population. As such, CsA remains a promising neuroprotective candidate for the treatment of those with TBI.
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Journal of neurotrauma · Apr 2017
A novel model of traumatic brain injury in adult zebrafish demonstrates response to injury and treatment comparable with mammalian models.
Traumatic brain injury (TBI) is a leading cause of death and morbidity in industrialized countries with considerable associated health care costs. The cost and time associated with pre-clinical development of TBI therapeutics is lengthy and expensive with a poor track record of successful translation to the clinic. The zebrafish is an emerging model organism in research with unique technical and genomic strengths in the study of disease and development. ⋯ Significant behavioral impairment included decreased swim distance and velocity (p < 0.05), as well as heightened anxiety and altered group social dynamics. Responses to injury were pHIFU dose-dependent and modifiable with MK-801, MDL-28170, or temperature modulation. Together, results indicate that the zebrafish exhibits responses to injury and intervention similar to mammalian TBI pathophysiology and suggest the potential for use to rapidly evaluate therapeutic compounds with high efficiency.
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Journal of neurotrauma · Apr 2017
A clinically relevant closed-head model of single and repeat concussive injury in the adult rat using a controlled cortical impact device.
Repeat concussions (RC) can result in significant long-term neurological consequences and increased risk for neurodegenerative disease compared with single concussion (SC). Mechanisms underlying this difference are poorly understood and best elucidated using an animal model. To the best of our knowledge, there is no closed-head model in the adult rat using a commercially available device. ⋯ No obvious gross pathology was observed on the cortical surface or in coronal sections. Further examination showed thinning of the cortex and corpus callosum in RC animals compared with shams and increased axonal pathology in the corpus callosum of both SC and RC animals. Our data present a model of CHI that results in clinically relevant markers of concussion and an early differentiation between SC and RC.