Neuroscience
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Neonatal hypoxic-ischemic encephalopathy is a major cause of mortality and disability in newborns and the only standard approach for treating this condition is therapeutic hypothermia, which shows some limitations. Thus, putative neuroprotective agents have been tested in animal models. The present study evaluated the administration of lactate, a potential energy substrate of the central nervous system (CNS) in an animal model of hypoxia-ischemia (HI), that mimics in neonatal rats the brain damage observed in human newborns. ⋯ Animals underwent behavioral assessments: negative geotaxis, righting reflex (P8 and P14), and cylinder test (P20). Lactate administration reduced the volume of brain lesion and improved behavioral parameters after HI in both sexes. Thus, lactate administration could be a neuroprotective strategy for the treatment of neonatal HI, a disorder still affecting a significant percentage of human newborns.
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Caveolin-1 (Cav-1) is an important modulator for adult neurogenesis in post stroke brain repair but its underlying mechanisms are largely unknown. In the present study, we report that endothelial Cav-1 inhibits neuronal differentiation of neural stem/progenitor cells (NSCs/NPCs) in post ischemic brain via regulating vascular endothelial growth factor (VEGF) and NeuroD1 signaling pathway. We first investigated the dynamic change of Cav-1 and its impact on neuronal differentiation in rat and mouse models of 2 h transient middle cerebral artery occlusion (MCAO) plus 1, 7, 14, 21 and 28 day of reperfusion. ⋯ The major discoveries include: (1) Cav-1 expression in the hippocampal dentate gyrus (DG) was down-regulated on day 1 after 2 h cerebral ischemia, and gradually recovered with reperfusion time, accompanied with transient increased but gradually reduced neuronal differentiation of NPCs marked by doublecortin (DCX). (2) Cav-1 knockout mice exhibited the increased DCX and VEGF at the granular cell layers of hippocampal DG in post-ischemic brains. (3) Co-cultured with BMVECs, NPCs had remarkably decreased neuronal differentiation under OGD/R. Knockdown of Cav-1 in the BMVECs increased VEGF secretion into the medium and NeuroD1+ cells, and rescued the neuronal differentiation of NPCs without affecting astroglial and oligodendroglial differentiation. (4) Cav-1 exosomes released from BMVECs inhibited neuronal differentiation of NPCs via decreasing the expression of VEGF, p44/42MAPK phosphorylation and NeuronD1 upon OGD/R insults. Taken together, endothelial Cav-1 serves as a niche regulator to inhibit neuronal differentiation via negatively modulating VEGF, p44/42MAPK phosphorylation and NeuronD1 signaling pathway.
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Alzheimer's disease (AD) is a neurodegenerative disease mainly associated with aging, oxidative stress and genetic mutations. There are two pathological proteins involved in AD; Amyloid-β peptide and microtubule-associated protein Tau (MAPT). The β- and γ-secretase enzyme cleaves the Amyloid precursor protein, which results in the formation of extracellular plaques in brain. ⋯ The P2Y receptors give 'find me' or 'eat me' signals to microglia to either migrate or phagocytose cellular debris. Further, the actin cytoskeleton helps microglia to mediate directed chemotaxis and neuronal repair during neurodegeneration. Hence, we aim to emphasize the connection between purinergic signaling and actin-driven mechanical movements of microglia for migration and inflammation in AD.