Elizabeth beauchesne’s scientific contributions childcare resource and research unit, toronto and other places anoxi

• given the leading role of astrocytic glia in the functioning of the glymphatic system and the supposed concept of primary astrogliopathy in the pathogenesis of HE, it is to be assumed that the violation of the processes of penetration and drainage of water, as well as the neurotoxic substances dissolved therein, may be of primary importance in the mechanisms of the development of hepatic encephalopathy, and many other toxic damage and may be metabolic disorders of the brain. Number of experimental studies, as well as the study of the autopsy material of patients with ALF demonstrated violation of the expression of several key astrocytic proteins: aqp-4, GFAP (glial fibrillar acidic protein) [47], glutamine transporter SNAT5, glutamate transporters (GLT-1 (SLC1A2-solute carrier family 1 member 2; EAAT2-excitatory amino acid transporter-2)), glycine transporters (GLYT-1), glucose transporters (GLUT-1), peripheral type benzodiazepine receptors [48].Anoxi

thus, K. K. Thumburu et al. In the study of the cerebral cortex of 8 patients died in ALF showed an increase in the level of aqp-4 mrna and aqp-4 IHC expression in the region of astrocyte microvascular perivascular end-feet, as well as marked decrease in mrna level and intermediate filament protein GFAP expression on the background of the brain tissue cytotoxic edema pattern.

[show abstract] [hide abstract] ABSTRACT: the problem of acute and chronic forms of hepatic encephalopathy (HE) is not clearly identified among modern problems of hepatology and neuroscience in ukraine. Despite the significant contribution to the development of lethal complications in patients with liver pathology and long history of the study of this issue, there is still no unified opinion on the links of HE pathogenesis.Anoxi

HE is a complex of potentially reversible neurocognitive disorders in patients with chronic or acute hepatic failure (ALF). HE is more often a complication of liver cirrhosis and is the second most frequent after ascites cause of hospitalization of such patients. When decompensating liver failure in acute or chronic hepatic pathology in patients develop severe forms of HE, accompanied by a progressive increase in intracranial pressure and the development of coma, which often ends lethal due to poor corrigibility of intracranial hypertension while maintaining hepatogenic neurointoxication. HE is considered as the end result of the accumulation of a number of neurotoxic substances in the brain, among which are ammonia, mercaptans, short chain fatty acids, false neurotransmitters, gamma-aminobutyric acid, manganese.Anoxi the most popular among the reasons for the development of HE is the neurotoxic theory of ammonia. Ammonia is subjected to detoxification in the liver, turning into urea, a smaller fraction with the participation of glutamine synthetase is used in the synthesis of glutamine in muscles, liver and astrocytes of brain. In the case of hepatic dysfunction and/or portosystemic shunting, the concentration of ammonia in the blood increases to 10 times and the main load for its detoxification is shifted to myocytes and astroglia. In ALF glutamine overload of astrocytes occurs with a change in intracellular osmolarity and subsequent edema of astroglia, which is accompanied by the development of cytotoxic edema of the brain.Anoxi in this case, in astrocytes will be damaging of mitochondrial respiratory chain and mitochondrial insufficiency develops, as well as processes of nitrosative-oxidative stress and oxidation of astrocytic and neuronal RNA, disruption of gene expression, synthesis of neuro- and gliotransmitters and synaptic plasticity. The increased influx of aromatic amino acids into brain leads to the synthesis of false neurotransmitters, which worsens serotoninergic, GABA-ergic, dopaminergic and glutamatergic neurotransmission. Damage to the components of the blood-brain barrier leads to aggravation of the water imbalance, penetration of hematogenous cytokines, endotoxins and other products of systemic inflammatory reaction into the cerebral parenchyma and development of neuroinflammation, which makes an important contribution to the further progression of cerebral edema.Anoxi

Conclusions: despite a comprehensive study of the problem, many open questions remain in the pathogenesis of HE. Special attention should be paid to more detailed study of the mechanisms of formation and elimination of edematous changes in brain tissue on the background of hepatogenic intoxication and the development of a systemic inflammatory reaction, the role of astroglia and its water channels in these processes, as well as the mechanisms of damage to the blood-brain barrier.

[show abstract] [hide abstract] ABSTRACT: cerebral edema from the disruption of the blood-brain barrier (BBB) after cerebral ischemia is a major cause of morbidity and mortality as well as a common event in patients with stroke.Anoxi caveolins (cavs) are thought to regulate BBB functions. Here, we report for the first time that cav-1 overexpression (OE) decreased brain edema from BBB disruption following ischemic insult. Edema volumes and cav-1 expression levels were measured following photothrombosis and middle cerebral artery occlusion (MCAO). Endothelial cells that were transduced with a cav-1 lentiviral expression vector were transplanted into rats. BBB permeability was quantified with evans blue extravasation. Edema volume was determined from measures of the extravasation area, brain water content, and average fluorescence intensity after cy5.5 injections. Tight junction (TJ) protein expression was measured with immunoblotting.Anoxi cav-1 expression levels and vasogenic brain edema correlated strongly after ischemic insult. Cav-1 expression and BBB disruption peaked 3 d after the MCAO. In addition, intravenous administration of endothelial cells expressing cav-1 effectively increased the cav-1 levels 3 d after the MCAO ischemic insult. Importantly, cav-1 OE ameliorated the vasogenic edema by inhibiting the degradation of TJ protein expression in the acute phase of ischemic stroke. These results suggested that cav-1 OE protected the integrity of the BBB mainly by preventing the degradation of TJ proteins in rats. These findings need to be confirmed in a clinical setting in human subjects.

[show abstract] [hide abstract] ABSTRACT: thiamine is an essential enzyme cofactor required for proper metabolic function and maintenance of metabolism and energy production in the brain.Anoxi in developed countries, thiamine deficiency (TD) is most often manifested following chronic alcohol consumption leading to impaired mitochondrial function, oxidative stress, inflammation and excitotoxicity. These biochemical lesions result in apoptotic cell death in both neurons and astrocytes. Comparable histological injuries in patients with hypoxia/ischemia and TD have been described in the thalamus and mammillary bodies, suggesting a congruency between the cellular responses to these stresses. Consistent with hypoxia/ischemia, TD stabilizes and activates hypoxia inducible factor-1α (HIF-1α) under physiological oxygen levels. However, the role of TD-induced HIF-1α in neurological injury is currently unknown.Anoxi using western blot analysis and RT-PCR, we have demonstrated that TD induces HIF-1α expression and activity in primary mouse astrocytes. We observed a time-dependent increase in mrna and protein expression of the pro-apoptotic and pro-inflammatory HIF-1α target genes MCP1, BNIP3, nix and noxa during TD. We also observed apoptotic cell death in TD as demonstrated by PI/annexin V staining, TUNEL assay, and cell death ELISA. Pharmacological inhibition of HIF-1α activity using YC1 and thiamine repletion both reduced expression of pro-apoptotic HIF-1α target genes and apoptotic cell death in TD. These results demonstrate that induction of HIF-1α mediated transcriptional up-regulation of pro-apoptotic/inflammatory signaling contributes to astrocyte cell death during thiamine deficiency.Anoxi

[show abstract] [hide abstract] ABSTRACT: numerous studies have shown that the venom of phoneutria nigriventer (PNV) armed-spider causes excitotoxic signals and blood-brain barrier breakdown (bbbb) in rats. Nitric oxide (NO) is a signaling molecule which has a role in endothelium homeostasis and vascular health. The present study investigated the relevance of endothelial NO synthase (enos) uncoupling to clinical neurotoxic evolution induced by PNV. ENOS immunoblotting of cerebellum lysates processed through low-temperature SDS-PAGE revealed significant increased monomerization of the enzyme at critical periods of severe envenoming (1-2 hours), whereas enos dimerization reversal paralleled to amelioration of animals condition (5-72 hours).Anoxi moreover, enos uncoupling was accompanied by increased expression in calcium-sensing calmodulin protein and calcium-binding calbindin-D28 protein in cerebellar neurons. It is known that greater enos monomers than dimers implies the inability of enos to produce NO leading to superoxide production and endothelial/vascular barrier dysfunction. We suggest that transient enos deactivation and disturbances in calcium handling reduce NO production and enhance production of free radicals thus contributing to endothelial dysfunction in the cerebellum of envenomed rats. In addition, enos uncoupling compromises the enzyme capacity to respond to shear stress contributing to perivascular edema and it is one of the mechanisms involved in the bbbb promoted by PNV.Anoxi

Copyright © 2015. Published by elsevier ltd.

• models of injury by toxins involve the injection of hepatotoxic drugs, such as galactosamine and azoxymethane ( belanger butterworth, 2005;rahman hodgson, 2000 showed that azoxymethane increased brain levels of IL-6, enhanced microglial activation, and increased oxidative stress in mice ( chastre et al., 2012). Several studies reported that animal models of ALF induced by galactosamine and devascularization increased the permeability of the blood-brain barrier ( chastre et al., 2012;chen et al., 2013) and promoted cerebral edema ( traber, dalcanto, ganger, blei, 1989;traber, dalcanto, ganger, blei, 1987 in ALF, an increase in systemic levels of ammonia can act synergistically with pro-inflammatory cytokines, leading to hepatic encephalopathy ( aldridge, tranah, shawcross, 2015;jiang, desjardins, butterworth, 2009).Anoxi confirming this, an interesting correlation between circulating levels of TNF-a and ammonia in patients who developed encephalopathy following ALF was described ( odeh, 2007).

[show abstract] [hide abstract] ABSTRACT: the term “neuroinflammation” has been widely used to describe a series of acute or chronic conditions that cause inflammation in the central nervous system (CNS). Neurological damage can be a consequence of direct local injury or, secondary, of systemic or even distant inflammatory processes. In this respect, animal models have been developed to better understand the pathophysiology and, possibly, to evaluate more effective methods of treatment for these disorders. Animal models that promote alterations in blood–brain barrier permeability—the activation of microglia or astrocytes, modifications in neuropeptide expression, oxidative stress, increased apoptosis, release of inflammatory mediators, leukocyte infiltration, and brain edema—are likely to involve neuroinflammation and therefore can serve as useful models for human inflammatory CNS injury.Anoxi this review describes the major animal models of neuroinflammation triggered by systemic or distant inflammatory processes. We will focus on animal models of acute neurologic damage; experimental models that lead to chronic neuroinflammation will not be addressed here.