Journal of neurotrauma
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Journal of neurotrauma · Nov 2012
Exploring temporospatial changes in glucose metabolic disorder, learning, and memory dysfunction in a rat model of diffuse axonal injury.
Diffuse axonal injury (DAI) is the predominant effect of severe traumatic brain injury and contributes significantly to cognitive deficits. The mechanisms underlying these cognitive deficits are often associated with complex metabolic alterations. However, the relationships between temporospatial alterations in cerebral glucose metabolism and the pathophysiology of DAI-related learning and memory dysfunction are not yet completely understood. ⋯ These effects persisted for 3 months. SUVs in the hippocampus at the acute stage were significantly correlated with MWM performance during the recovery stage of DAI. These results demonstrate that microstructural injury-induced hypometabolism in the hippocampus at the acute stage are all significantly correlated with learning and memory dysfunctions during the recovery stage of DAI.
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Journal of neurotrauma · Nov 2012
A relatively brief exposure to environmental enrichment after experimental traumatic brain injury confers long-term cognitive benefits.
It is well established that a relatively brief exposure to environmental enrichment (EE) enhances motor and cognitive performance after experimental traumatic brain injury (TBI), but it is not known whether the benefits can be sustained after EE is discontinued. To address this important rehabilitation-relevant concern, anesthetized rats received a controlled cortical impact (CCI) or sham injury, and for phase 1 of the experiment were randomly assigned to either 3 weeks of EE or standard (STD) housing. Neurobehavioral outcome was assessed by established motor and cognitive tests on postoperative days 1-5 and 14-18, respectively. ⋯ The TBI + EE and TBI + EE + STD groups performed markedly better in the water maze than the TBI + STD group (p<0.0001), and did not differ from one another (p=0.53). These data replicate those of several studies from our laboratory showing that EE enhances recovery after CCI injury, and extend those findings by demonstrating that the cognitive benefits are maintained for at least 6 months post-rehabilitation. The persistent benefits shown with this paradigm provide further support for EE as a pre-clinical model of rehabilitation that can be further explored, either alone or in combination with pharmacotherapies, for optimal neurorehabilitation after TBI.
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Journal of neurotrauma · Nov 2012
Treatment of traumatic brain injury using zinc-finger protein gene therapy targeting VEGF-A.
Vascular endothelial growth factor (VEGF) plays a role in angiogenesis and has been shown to be neuroprotective following central nervous system trauma. In the present study we evaluated the pro-angiogenic and neuroprotective effects of an engineered zinc-finger protein transcription factor transactivator targeting the vascular endothelial growth factor A (VEGF-ZFP). We used two virus delivery systems, adeno-virus and adeno-associated virus, to examine the effects of early and delayed VEGF-A upregulation after brain trauma, respectively. ⋯ Adv-VEGF-ZFP treatment significantly improved fEPSP values (p=0.007) in the CA1 region relative to injury alone. Treatment with AAV2-VEGF-ZFP resulted in improved post-injury microvascular diameter and improved functional recovery on the balance beam and rotarod task at 30 days post-injury. Collectively, the results provide supportive evidence for the concept of acute and delayed treatment following TBI using VEGF-ZFP to induce angiogenesis, reduce cell death, and enhance functional recovery.
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Journal of neurotrauma · Nov 2012
GABA(A) receptor regulation after experimental traumatic brain injury.
The gamma-aminobutyric acid (GABA) type A receptor (GABA(A)R) is responsible for most fast synaptic inhibition in the adult brain. The GABA(A)R protein is composed of multiple subunits that determine the distribution, properties, and dynamics of the receptor. Several studies have shown that the Janus kinase/signal transducer and activator of transcription (JaK/STAT) and early growth response 3 (Egr3) signaling pathways can alter GABA(A)R subunit expression after status epilepticus (SE). ⋯ Our results demonstrated changes in the expression of several GABA(A)R subunit levels after injury, including GABA(A)R α1 and α4 subunits. This change appears to be transcriptional, and there is an associated increase in the phosphorylation of STAT3, and an increase in the expression of Egr3 and inducible cAMP element repressor (ICER) after FPI. These findings suggest that the activation of the JaK/STAT and Egr3 pathways after TBI may regulate injury-related changes in GABA(A)R subunit expression.
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Journal of neurotrauma · Nov 2012
Neuroprotective effects of sulforaphane after contusive spinal cord injury.
Traumatic spinal cord injury (SCI) leads to oxidative stress, calcium mobilization, glutamate toxicity, the release of proinflammatory factors, and depletion of reduced glutathione (GSH) at the site of injury. Induction of the Keap1/Nrf2/ARE pathway can alleviate neurotoxicity by protecting against GSH depletion, oxidation, intracellular calcium overload, mitochondrial dysfunction, and excitotoxicity. Sulforaphane (SF), an isothiocyanate derived from broccoli, is a potent naturally-occurring inducer of the Keap1/Nrf2/ARE pathway, leading to upregulation of genes encoding cytoprotective proteins such as NAD(P)H: quinone oxidoreductase 1, and GSH-regulatory enzymes. ⋯ Two doses of SF (10 or 50 mg/kg) were administered at 10 min and 72 h after contusion SCI. SF (50 mg/kg) treatment resulted in both acute and long-term beneficial effects, including upregulation of the phase 2 antioxidant response at the injury site, decreased mRNA levels of inflammatory cytokines (i.e., MMP-9) in the injured spinal cord, inactivation of urinary MIF tautomerase activity, enhanced hindlimb locomotor function, and an increased number of serotonergic axons caudal to the lesion site. These findings demonstrate that SF provides neuroprotective effects in the spinal cord after injury, and could be a candidate for therapy of SCI.