Neuroscience
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Cerebral ischemic injury involves death of multiple cell types at the ischemic sites. As a key regulator of cell death, the p53 gene has been implicated in the regulation of cell loss in stroke. Less focal damage is found in stroke animals pre-treated with a p53 inhibitor or in traditional p53 knockout (ko) mice. ⋯ Deletion of the p53 gene in forebrain neurons results in a decreased infarction area in ko mice. Locomotor behavior, measured in automated activity chambers, showed that CamcreTRP53(loxP/loxP) ko mice have less locomotor deficits compared to wt mice after middle cerebral artery occlusion (MCAo). We conclude that manipulation of p53 expression in neurons may lead to unique therapeutic development in stroke.
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Following intracerebral hemorrhage (ICH), high-mobility group box 1 protein (HMGB1) may promote vascular remodeling. Whether HMGB1 supports angiogenesis after ICH is unclear, as are the receptors and downstream signaling pathway(s) involved. We used the rat model of collagenase-induced ICH to determine whether HMGB1 acts via the receptor for advanced glycation end-products (RAGE) to upregulate vascular endothelial growth factor (VEGF), a potent mitogen of endothelial cells and key regulator of normal and abnormal angiogenesis in the late phase of injury. ⋯ Administering FPS-ZM1 after ICH blocked much of the stroke-induced increases in vessel density and VEGF expression. Our results suggest that after ICH, HMGB1 may upregulate VEGF in the ipsilateral striatum predominantly via RAGE. Hence, targeting the HMGB1/RAGE signaling pathway may help reduce inappropriate angiogenesis after ICH.
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Randomized Controlled Trial
No role of beta receptors in cognitive flexibility: Evidence from a task-switching paradigm in a randomized controlled trial.
There is evidence that noradrenergic coeruleo-cortical projections are involved in different forms of cognitive flexibility. So far, no studies in humans have investigated the involvement of beta receptors on task-switching performance, a well-established measure of cognitive flexibility. ⋯ The acute administration of propranolol did not affect the size of switching costs compared to the intake of the neutral placebo. Our results, corroborated by Bayesian inference, suggest that beta receptors do not modulate cognitive flexibility as measured by task-switching performance.
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Exercise reduces the risk of developing a number of neurological disorders and increases the efficiency of cellular energy production. However, overly strenuous exercise produces oxidative stress. Proper oxygenation is crucial for the health of all tissues, and tight regulation of cellular oxygen is critical to balance O2 levels and redox homeostasis in the brain. ⋯ Loss of HIF1α also abolishes exercise-induced neuroprotection. In mice lacking Hif2α in postnatal neurons, the number of TH+ DA neurons in the adult SNpc is diminished, but 3months of exercise rescues this loss. We conclude that HIF1α is necessary for exercise-induced neuroprotection and both HIF1α and HIF2α are necessary for the survival and function of adult SNpc DA neurons.
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Parkinson's disease (PD) is the most common neurodegenerative motor disorder in the world. The main causes of neurodegeneration in PD are mitochondrial impairment and oxidative stress promoted by dopamine (DA) metabolism in the cytosol. Protein l-isoaspartyl (d-aspartyl) methyltransferase (PIMT) is a protein repair enzyme with anti-apoptotic properties. ⋯ In addition, cells overexpressing wild-type PIMT produced significantly less reactive oxygen species despite DA treatment compared to cells that do not overexpress PIMT. Together, these data indicate that DA-associated PIMT downregulation is an important event contributing to neuronal cell death. More importantly, the PIMT anti-apoptotic capacity seems to be dependent on its involvement in the cellular antioxidant machinery.