Journal of neurotrauma
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Journal of neurotrauma · Apr 2017
PHENELZINE PROTECTS BRAIN MITOCHONDRIAL FUNCTION In vitro and In vivo FOLLOWING TRAUMATIC BRAIN INJURY BY SCAVENGING THE REACTIVE CARBONYLS 4-HYDROXYNONENAL AND ACROLEIN LEADING TO CORTICAL HISTOLOGICAL NEUROPROTECTION.
Lipid peroxidation (LP) is a key contributor to the pathophysiology of traumatic brain injury (TBI). Traditional antioxidant therapies are intended to scavenge the free radicals responsible for either initiation or propagation of LP. A more recently explored approach involves scavenging the terminal LP breakdown products that are highly reactive and neurotoxic carbonyl compounds, 4-hydroxynonenal (4-HNE) and acrolein (ACR), to prevent their covalent modification and rendering of cellular proteins nonfunctional leading to loss of ionic homeostasis, mitochondrial failure, and subsequent neuronal death. ⋯ This effect was not shared by a structurally similar MAO-I, pargyline, which lacks the hydrazine group, confirming that the mitochondrial protective effects of PZ were related to its carbonyl scavenging and not to MAO inhibition. In subsequent in vivo studies, we documented that PZ treatment begun at 15 min after controlled cortical impact TBI significantly attenuated 72-h post-injury mitochondrial respiratory dysfunction. The cortical mitochondrial respiratory protection occurred together with a significant increase in cortical tissue sparing.
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Journal of neurotrauma · Apr 2017
Generalized Seizures after Experimental Traumatic Brain Injury Occur at the Transition from Slow-Wave to Rapid-Eye-Movement Sleep.
Sleep disturbances commonly occur after traumatic brain injury (TBI) and may predispose patients to epileptic seizures. We hypothesized that unprovoked seizure occurrence post-TBI depends on the sleep-wake cycle, and that the electrographic characteristics of a given sleep stage provide biomarkers for post-traumatic epilepsy (PTE). We show, in a rat lateral fluid percussion model, that 92% of spontaneous generalized seizures occur during the transition from stage III to rapid eye movement sleep. Moreover, a reduction in spindle duration and dominant frequency during the transition stage present as specific and sensitive noninvasive biomarkers for experimentally induced PTE with generalized electrographic seizures.
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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.