Neuroscience
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We have previously reported that presynaptic dysfunction and cognitive decline have been found in lipoprotein lipase (LPL) deficient mice, but the mechanism remains to be elucidated. Accumulating evidence supported that α-synuclein (α-syn) and ubiquitin C-terminal hydrolase L1 (UCHL1) are required for normal synaptic and cognitive function. In this study, we found that α-syn aggregated and the expression of UCHL1 decreased in the brain of LPL deficient mice. ⋯ Reverse changes were found in cultured cells overexpressing LPL. Furthermore, deficiency of LPL increased ubiquitination of α-syn. These results indicated that aggregation of α-syn and reduction of UCHL1 expression in LPL-deficient mice may affect synaptic function.
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Neuroactive steroids, like allopregnanolone (A) and pregnanolone (P), bind to specifics sites on the GABAA receptor complex and modulate receptor function. They are capable to inhibit or stimulate the binding of GABAA receptor-specific ligands, like t-butyl-bicyclophosphorothionate, flunitrazepam and muscimol. We have previously characterized a set of oxygen-bridged synthetic steroids (SS) analogs to A or P using synaptosomes. ⋯ One of the SS, the 3α-hydroxy-6,19-epoxypregn-4-ene-20-one (compound 5), behaved similarly to the natural neuroactive steroids. However, significant differences with compound 5 were observed on the HC CA2 region, making it steroid suitable for a specific action. Those differences may be related to structural conformation of the SS and the subunits' composition present on the receptor complex.
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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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Menopause can cause cognitive decline. Hormone Replacement Therapy (HRT) is the most effective treatment for the climacteric symptoms. However, its cognitive effect has not been well clarified, especially for the progestin component. ⋯ DG combined with E2 could ameliorate cognition in adult rats with uterus protection and without breast harm. The cognitive-improve effects were more remarkable for the adult rats than the aged ones. The findings support the potential clinical application of dydrogesterone combined with estrogen in preventing cognitive decline, especially for the early iatrogenic menopausal women.
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Cellular therapy has provided hope for restoring neurological function post stroke through promoting endogenous neurogenesis, angiogenesis and synaptogenesis. The current study was based on the observation that transplantation of human umbilical cord mesenchymal stem cells (hUCMSCs) promoted the neurological function improvement in stroked mice and meanwhile enhanced angiogenesis in the stroked hemisphere. Grafted hUCMSCs secreted human vascular endothelial growth factor A (VEGF-A). ⋯ Regarding how Notch1 signaling was linked with VEGF-A secretion, we provided some clue that Notch1 effector Hes1 mRNA expression was significantly up-regulated by OGD-neuron co-culturing and down-regulated after additional treatment of DAPT. In summary, our data provided evidence that the VEGF-A secretion from hUCMSCs after being triggered by OGD neurons is Notch1 signaling associated. This might be a possible mechanism that contributes to the angiogenic effect of hUCMSC transplantation in stroked brain.