Cellular swelling and oxidative stress drive pathological glutamate release and brain damage in stroke

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Abstracts
CELLULAR SWELLING AND OXIDATIVE STRESS DRIVE PATHOLOGICAL GLUTAMATE RELEASE AND BRAIN DAMAGE IN STROKE
Mongin, A.A.
Center for Neuropharmacology and Neuroscience, Albany Medical College, Albany, New York, USA
A number of neurological disorders, including stroke, hyponatremia, epilepsy, and hepatic encephalopathy, are linked to pronounced cellular swelling. Such swelling is largely restricted to glial cells (astrocytes) and the postsyn-aptic neuronal processes (dendrites). Recent work strongly suggests that cell swelling is a major determinant of brain damage. In brain tissue, increases in cell volume trigger release of the toxic excitatory amino acids, glutamate and as-partate, via the volume-sensitive permeability pathway termed volume-regulated anion channel (VRAC). VRAC blockers strongly reduce ischemic brain damage and alleviate neurological deficits in animal stroke models. Our in vitro and in vivo studies demonstrated that VRAC is syner-gistically regulated by swelling and reactive oxygen species (ROS). ROS alone do not cause VRAC opening, but potently stimulate VRAC when combined with even moderate swelling. Given that stroke pathology involves oxidative stress, we tested the hypothesis that antioxidants prevent
pathological glutamate release and reduce brain infarction in rodent stroke. With this purpose we explored the neuroprotective properties of two antioxidants, Tempol and edaravone, and tested their effects on pathological amino acid release using a microdialysis approach. Tempol but not edaravone reduced extracellular levels of glutamate and as-partate during a two-hour transient focal ischemia. Consistent with latter data, Tempol but not edaravone decreased brain infarction volumes and improved neurological outcomes. Cellular and biochemical analyses established that the superior protective properties of Tempol are related to its potency in scavenging the ROS superoxide anion. Overall, our work provides new mechanistic insight into the complex relationship between oxidative stress, glutamate release and brain damage in stroke, and creates a novel basis for design and rational selection of novel therapeutic compounds.
Supported by NIHgrant NS061953.
HIGH SALT (NACL) AFFECTS TH17 POLARIZATION Muller, D.N.
Experimental and Clinical Research Center, Berlin, Germany
Current teaching suggests that the & quot-milieu interieur& quot- bathing all cells is controlled by isosmotic passive equilibration with plasma. Recent evidence has shown this idea needs to be revised. We have the first evidence that a regulatory network between immune cells and the local environment exists in mice and humans. Therefore, we hypothesize that the immune system is influenced by
the local electrolyte environment and vice versa. We found that hypertonicity induced by high salt (NaCl) affected cytokine-induced Th17 polarization by a p38MAP kinase, TonEBP, SGK1-dependent mechanism, and that such a salt-driven polarization into a chronic inflammatory state worsens autoimmune disease.
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Бюллетень сибирской медицины, 2013, том 12, № 4, с. 24−68

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