Autism and Alzheimer's disease (AD) are, respectively, neurodevelopmental and degenerative diseases with an increasing epidemiological burden. The AD-associated amyloid-β precursor protein-α has been shown to be elevated in severe autism, leading to the ‘anabolic hypothesis' of its etiology. Here we performed a focused microarray analysis of genes belonging to NOTCH and WNT signaling cascades, as well as genes related to AD and apoptosis pathways in cerebellar samples from autistic individuals, to provide further evidence for pathological relevance of these cascades for autism. By using the limma package from R and false discovery rate, we demonstrated that 31% (116 out of 374) of the genes belonging to these pathways displayed significant changes in expression (corrected P-values <0.05), with mitochondria-related genes being the most downregulated. We also found upregulation of GRIN1, the channel-forming subunit of NMDA glutamate receptors, and MAP3K1, known activator of the JNK and ERK pathways with anti-apoptotic effect. Expression of PSEN2 (presinilin 2) and APBB1 (or F65) were significantly lower when compared with control samples. Based on these results, we propose a model of NMDA glutamate receptor-mediated ERK activation of α-secretase activity and mitochondrial adaptation to apoptosis that may explain the early brain overgrowth and disruption of synaptic plasticity and connectome in autism. Finally, systems pharmacology analyses of the model that integrates all these genes together (NOWADA) highlighted magnesium (Mg2+) and rapamycin as most efficient drugs to target this network model in silico. Their potential therapeutic application, in the context of autism, is therefore discussed.
All anatomical elements contributing to the blood-brain barrier (BBB) play a crucial role in maintaining the permeability and CNS homeostasis under physiological/pathological conditions. These elements are endothelial cells, pericytes, astroglia, and neurons that are known as a neurovascular unit (NVU). Being the integral system, NVU contributes to the regulation of neuroplasticity, neurogenesis, intercellular communications and permeability of BBB. Brain capillary endothelial cells (BCEC) are the very important part of NVU. In this review, we discuss the critical role of BCEC ion channels in BBB structural and functional integrity. In last decades, much attention has been paid to the expression of tight junctions and adherence junctions in BCEC whereas less number of studies was focused on the expression and functioning of ion channels in BCEC, however, there is growing evidence supporting their important role in the regulation of NVU/BBB functions. In general, electrophysiological properties of BCEC depend on the expression of various ion channels whose activity, presumably, coordinates intercellular communication within the NVU. Particularly, we focus on BCEC ion channels-dependent mechanisms of NVU functioning, arteriole smooth muscle cells dynamic modulation, and changes in the regional cerebral blood flow. We put special attention on ligand-gated ion channels, store-operated calcium channels, TRP ion channels, calcium-activated, voltage-gated potassium channels in BCEC. Understanding the role of ion channel signaling in the control of cerebral blood flow will helps to reveal the potential therapeutic targets to recover the NVU/BBB functional integrity in different pathological conditions (ischemia, neuroinflammation, neurodegeneration) both in vivo and in vitro BBB models.Key words: neurovascular unit; brain endothelial cells; ion channels; blood-brain barrier.For contacts: Anton N. Shuvaev, e-mail: shuvaevanton@hotmail.com Function of Brain Endothelial Ion ChannelsNeurovascular unit in physiological/pathological conditions: the role of endothelial cells. Blood-brain barrier (BBB) plays an important role in the regulation of pivotal brain functions due to ability of brain endothelial cells to provide selective transport of metabolites, xenobiotics, neurotransmitters and hormones, to regulate water exchange, and to take part in the regulation of neurogenesis. All the above-mentioned events take place within the neurovascular unit (NVU) consisting of endothelial cells, pericytes, astroglia, and neurons [1, 2]. Close interactions between the cells of the NVU are based on the coordinated expression and activity of receptors, transporters and channels contributing to establishment and maintenance of the BBB structural and functional integrity in physiological conditions, or to its impairment in central nervous system disorders such as hypertension [3], stroke [4], Alzheimer's disease [5], diabetes mellitus [6] and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy [7].B...
ATP activity in mouse bone marrow cells was in vitro estimated by expression of phosphatidylserine on the outer membrane surface using FITC-labeled annexin. ATP induced apoptosis in bone marrow cells. Purinergic receptor antagonists PPADS and suramin modulated the apoptotic effect of ATP on hemopoietic cells. Acute and subacute administration of doxorubicin, an inductor of oxidative burst, decreased cell sensitivity to ATP and abolished its apoptotic effect.
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