Browsing by Subject "neuroprotection"

Now showing 1 - 4 of 4
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    Bisperoxovanadium Mediates Neuronal Protection through Inhibition of PTEN and Activation of PI3K/AKT-mTOR Signaling after Traumatic Spinal Injuries
    (Mary Ann Liebert, Inc., publishers, 2019-08-30) Walker, Chandler L.; Wu, Xiangbing; Liu, Nai-Kui; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
    Although mechanisms involved in progression of cell death in spinal cord injury (SCI) have been studied extensively, few are clear targets for translation to clinical application. One of the best-understood mechanisms of cell survival in SCI is phosphatidylinositol-3-kinase (PI3K)/Akt and associated downstream signaling. Clear therapeutic efficacy of a phosphatase and tensin homologue (PTEN) inhibitor called bisperoxovanadium (bpV) has been shown in SCI, traumatic brain injury, stroke, and other neurological disease models in both neuroprotection and functional recovery. The present study aimed to elucidate mechanistic influences of bpV activity in neuronal survival in in vitro and in vivo models of SCI. Treatment with 100 nM bpV(pic) reduced cell death in a primary spinal neuron injury model (p < 0.05) in vitro, and upregulated both Akt and ribosomal protein S6 (pS6) activity (p < 0.05) compared with non-treated injured neurons. Pre-treatment of spinal neurons with a PI3K inhibitor, LY294002 or mammalian target of rapamycin (mTOR) inhibitor, rapamycin blocked bpV activation of Akt and ribosomal protein S6 activity, respectively. Treatment with bpV increased extracellular signal-related kinase (Erk) activity after scratch injury in vitro, and rapamycin reduced influence by bpV on Erk phosphorylation. After a cervical hemicontusive SCI, Akt phosphorylation decreased in total tissue via Western blot analysis (p < 0.01) as well as in penumbral ventral horn motor neurons throughout the first week post-injury (p < 0.05). Conversely, PTEN activity appeared to increase over this period. As observed in vitro, bpV also increased Erk activity post-SCI (p < 0.05). Our results suggest that PI3K/Akt signaling is the likely primary mechanism of bpV action in mediating neuroprotection in injured spinal neurons.
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    Effects of Statin Treatment on Outcomes after Traumatic Brain Injury
    (Liebert, 2018) Whyte, John; Ketchum, Jessica M.; Bogner, Jenny; Brunner, Robert C.; Hammond, Flora M.; Zafonte, Ross; Whiteneck, Gale G.; Weintraub, Alan; Physical Medicine and Rehabilitation, School of Medicine
    Neuroprotective treatments that have shown promise in reducing secondary injury and improving recovery in animal models of traumatic brain injury (TBI) have not been found effective to date in humans. One reason may be the delay after injury in initiating treatment. Statin medications are among the promising neuroprotective agents in animal models, and their presence in the bloodstream of many individuals at the time of injury might optimize their clinical impact. This observational study conducted by a subset of centers participating in the National Institute on Disability, Independent Living, and Rehabilitation Research (NIDILRR)-funded TBI Model System program sought to examine the effects of taking statin medication at the time injury on functional outcomes. Participants >50 years of age were prospectively enrolled during patient rehabilitation. Demographic data, cardiovascular history, and brain injury history were obtained through chart abstraction and interview. Prescription medication use in the year prior to enrollment was determined from a national pharmacy search service. Propensity scoring was used to create 49 pairs of participants who were well matched on demographic and clinical attributes but discordant for statin use. The treated and untreated participants did not differ on initial Glasgow Coma Score, time until commands were followed, duration of post-traumatic amnesia, or Functional Independence Measure (FIM) scores at rehabilitation admission, discharge, or 1 year post-injury, or on acute or rehabilitation hospital lengths of stay. Evidence of greater and lesser statin compliance was not associated with outcome. This study did not provide support for a clinically important benefit of statin use at the time of moderate to severe TBI.
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    History of Glial Cell Line-Derived Neurotrophic Factor (GDNF) and Its Use for Spinal Cord Injury Repair
    (MDPI, 2018-06-13) Walker, Melissa J.; Xu, Xiao-Ming; Neurological Surgery, School of Medicine
    Following an initial mechanical insult, traumatic spinal cord injury (SCI) induces a secondary wave of injury, resulting in a toxic lesion environment inhibitory to axonal regeneration. This review focuses on the glial cell line-derived neurotrophic factor (GDNF) and its application, in combination with other factors and cell transplantations, for repairing the injured spinal cord. As studies of recent decades strongly suggest that combinational treatment approaches hold the greatest therapeutic potential for the central nervous system (CNS) trauma, future directions of combinational therapies will also be discussed.
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    Inhibition of cPLA2 has neuroprotective effects on motoneuron and muscle atrophy following spinal cord injury
    (Liebert, 2014) Liu, Nai-Kui; Byers, James S.; Lam, Tom; Lu, Qing-Bo; Sengelaub, Dale R.; Xu, Xiao-Ming; Department of Neurological Surgery, School of Medicine
    Surviving motoneurons undergo dendritic atrophy after spinal cord injury (SCI), suggesting an important therapeutic target for neuroprotective strategies to improve recovery of function after SCI. Our previous studies showed that phospholipase A2 (PLA2) may play an important role in the pathogenesis of SCI. In the present study, we investigated whether blocking cPLA2 pharmacologically with arachidonyl trifluoromethyl ketone (ATK) or genetically using cPLA2 knockout (KO) mice attenuates motoneuron atrophy following SCI. C57BL/6 mice received either sham or contusive SCI at the T10 level. At 30 min after SCI, mice were treated with ATK or vehicle. Four weeks later, motoneurons innervating the vastus lateralis muscle of the quadriceps were labeled with cholera toxin-conjugated horseradish peroxidase, and dendritic arbors were reconstructed in three dimensions. Soma volume, motoneuron number, lesion volume, and tissue sparing were also assessed, as were muscle weight, fiber cross-sectional area, and motor endplate size and density. ATK administration reduced percent lesion volume and increased percent volume of spared white matter compared to the vehicle-treated control animals. SCI with or without ATK treatment had no effect on the number or soma volume of quadriceps motoneurons. However, SCI resulted in a decrease in dendritic length of quadriceps motoneurons in untreated animals, and this decrease was completely prevented by treatment with ATK. Similarly, the vastus lateralis muscle weights of untreated SCI animals were smaller than those of sham-surgery controls, and these reductions were prevented by ATK treatment. No effects on fiber cross-sectional areas, motor endplate area or density were observed across treatment groups. Remarkably, genetically deleting cPLA2 in cPLA2 KO mice attenuated dendritic atrophy after SCI. These findings suggest that after SCI, cord tissue damage and regressive changes in motoneuron and muscle morphology can be reduced by inhibition of cPLA2, further supporting a role for cPLA2 as a neurotherapeutic target for SCI treatment.