Neuroscience
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Neonatal cerebral hypoxia-ischemia (HI) is a major cause of neurological disorders and the most common cause of death and permanent disability worldwide, affecting 1-2/1000 live term births and up to 60% of preterm births. The Levine-Rice is the main experimental HI model; however, critical variables such as the age of animals, sex and hemisphere damaged still receive little attention in experimental design. We here investigated the influence of sex and hemisphere injured on the functional outcomes and tissue damage following early (hypoxia-ischemia performed at postnatal day 3 (HIP3)) and late (hypoxia-ischemia performed at postnatalday 7 (HIP7)) HI injury in rats. ⋯ Sham animals had their carotids exposed but not occluded nor submitted to the hypoxic atmosphere. Behavioral impairments were assessed in the open field arena, in the Morris water maze and in the inhibitory avoidance task; volumetric extent of tissue damage was assessed using cresyl violet staining at adult age, after completing behavioral assessment. The overall results demonstrate that: (1) HI performed at the two distinct ages cause different behavioral impairments and histological damage in adult rats (2) behavioral deficits following neonatal HIP3 and HIP7 are task-specific and dependent on sex and hemisphere injured (3) HIP7 animals presented the expected motor and cognitive deficits (4) HIP3 animals displayed discrete but significant cognitive impairments in the left hemisphere-injured females (5) HI brain injury and its consequences are determined by animal's sex and the damaged hemisphere, markedly in HIP3-injured animals.
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Estrogen receptor-related receptor-α (ERRα) is an orphan member of the nuclear receptor superfamily that interacts with peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) to stimulate vascular endothelial growth factor (VEGF) expression and angiogenesis in a hypoxia-inducible factor-1α-independent pathway. Although it is not regulated by any natural ligand, the action of ERRα can be blocked by the synthetic molecule XCT790. In the present study, Sprague-Dawley rats were randomly allocated to a sham group, injury-saline group or injury-XCT90 group. ⋯ Western blot and quantitative real-time polymerase chain reaction (qRT-PCR) analyses also indicated that XCT790 dramatically repressed the expression of ERRα, thus reducing the expression of VEGF and angiopoietin-2 (Ang-2) throughout the duration of the experiment, but the expression of PGC-1α was not affected. Immunofluorescence analyses indicated that vascular density and endothelial cell proliferation were decreased in the injury-XCT90 group compared with the injury-saline group. These results suggest that ERRα is involved in mediating angiogenesis after SCI in the rat traumatic SCI model.
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Recent studies indicate that over-activation of Cdk5 is a crucial pro-death signal and Cdk5 activity inhibition provides neuroprotection in animal stroke models. However, Cdk5 inhibitors are reported to affect physiological functions of Cdk5 and lead to serious side effects. Therefore, targeting Cdk5 or its activators without affecting physiological functions of Cdk5 is a therapeutic strategy for ischemic brain injury. ⋯ In addition, p5-TAT reduced cleaved caspase-3 level, a marker of neuronal apoptosis. We further demonstrated that p5-TAT pre-treatment reduced cerebral infarct volume; even when p5-TAT was delayed to be administered at 24h after HI injury, p5-TAT still promoted long-term functional recovery. Therefore, Cdk5 inhibition by the small peptide p5-TAT or its derivatives is a promising therapeutic strategy for the treatment of ischemic brain injury including hypoxic-ischemic encephalopathy and stroke.
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Parkinson's disease (PD) is a progressive neurological disorder and current therapies help alleviate symptoms, but are not disease modifying. In the flavonoid class of compounds, 7,8-dihydroxyflavone (7,8-DHF) has been reported to elicit tyrosine kinase receptor B (TrkB) dimerization and autophosphorylation that further stimulates signaling cascades to promote cell survival/growth, differentiation, and plasticity. In this study we investigated if 7,8-DHF could prevent further loss of dopaminergic cells and terminals if introduced at the midpoint (i.e. intervention) of our progressive mouse model of PD. ⋯ In addition, motor deficits seen in the 2- and 4-week MPTP-treated animals were restored following administration of 7,8-DHF. We are reporting here for the first time that intervention with 7,8-DHF blocks further loss of dopaminergic terminals and restores motor deficits in our progressive MPTP mouse model. Our data suggest that 7,8-DHF has the potential to be a translational therapy in PD.
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An earlier study has demonstrated that exogenous allopregnanolone (APα) can reverse the reduction of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc) of 3-month-old male triple transgenic Alzheimer's disease mouse (3xTgAD). This paper is focused on further clarifying the origin of these new-born TH-positive neurons induced by exogenous APα treatment. We performed a deeper research in another AD mouse model, 4-month-old male APPswe/PSEN1 double transgenic AD mouse (2xTgAD) by measuring APα concentration and counting immunopositive neurons using enzyme-linked immunosorbent assay (ELISA) and unbiased stereology. ⋯ Furthermore, a single 20mg/kg of exogenous APα treatment prevented the decline of total neurons, TH-positive neurons and TH/bromodeoxyuridine (BrdU) double-positive neurons in the SNpc of 2xTgAD mice although the decreased intensity of TH-positive fibers was not rescued in the striatum. It was also noted that exogenous APα administration had an apparent increase in the doublecortin (DCX)-positive neurons and DCX/BrdU double-positive neurons of subventricular zone (SVZ), as well as in the percentage of neuronal nuclear antigen (NeuN)/BrdU double-positive neurons of the SNpc in the 2xTgAD mice. These findings indicate that a lower level of endogenous APα is implicated in the loss of midbrain dopaminergic neurons in the 2xTgAD mice, and exogenous APα-induced a significant increase in the new-born dopaminergic neurons might be derived from the proliferating and differentiation of neural stem niche of SVZ.