The aim of this proposal is to continue our work on volume regulation in astrocytes. We will examine the causes, regulation and consequences of astrocytic swelling, a feature common to many pathological states. As a model system we use a well- characterized in vitro model of astrocytes; primary astrocyte cultures prepared from neonatal rat brain, and we swell them using hypotonic medium or addition of putative endogenous effectors. In this manner we can isolate the swelling and volume regulation processes and examine the direct effects of activators or inhibitors without the problems and limitations associated with in situ studies. We will use tracer methods or an extracellular electrical impedance system to study the magnitude, and high voltage electron microscopy to study as [3H] taurine, [3H] glutamate and [3H] D-aspartate of high pressure liquid chromatography to study the authentic processes will be done. Electrophysiology, specifically membrane potential and whole cell voltage clamp will also be performed. Fluorescent probe methods will be used to study intracellular Ca2 and pH during swelling and immunocytochemistry and protein chemistry to study any possible cytoskeletal changes. Finally, effects of hypotonic medium on efflux of glutamate and taurine from brain slices will also be done. The overall hypothesis to be tested is that astrocytic swelling in pathological states is deleterious and by preventing such swelling we can prevent neurological deficit or death in conditions such as trauma, ischemia and hypoxia in which astroglial swelling is known to occur. One mechanism we wish to test is that astrocytic swelling leads to the release of potential neurotoxic compounds such as L-glutamate present in astrocytes in relatively high amounts and that a class of inhibitors, already shown by us and others to be effective, in improving or preventing death from experimental head trauma or a model of Reye's syndrome, acts by preventing massive efflux of glutamate from swollen astrocytes.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Project (R01)
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Neurological Sciences Subcommittee 1 (NLS)
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Albany Medical College
Schools of Medicine
United States
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Kimelberg, Harold K (2004) Volume activated anion channel and astrocytic cellular edema in traumatic brain injury and stroke. Adv Exp Med Biol 559:157-67
Vitarella, D; Conklin, D R; Kimelberg, H K et al. (1996) Metallothionein induction protects swollen rat primary astrocyte cultures from methylmercury-induced inhibition of regulatory volume decrease. Brain Res 738:213-21
Vitarella, D; Kimelberg, H K; Aschner, M (1996) Inhibition of regulatory volume decrease in swollen rat primary astrocyte cultures by methylmercury is due to increased amiloride-sensitive Na+ uptake. Brain Res 732:169-78
Rutledge, E M; Kimelberg, H K (1996) Release of [3H]-D-aspartate from primary astrocyte cultures in response to raised external potassium. J Neurosci 16:7803-11
Rising, L; Vitarella, D; Kimelberg, H K et al. (1995) Metallothionein induction in neonatal rat primary astrocyte cultures protects against methylmercury cytotoxicity. J Neurochem 65:1562-8
Kimelberg, H K; Rutledge, E; Goderie, S et al. (1995) Astrocytic swelling due to hypotonic or high K+ medium causes inhibition of glutamate and aspartate uptake and increases their release. J Cereb Blood Flow Metab 15:409-16
Olson, J E; Kimelberg, H K (1995) Hypoosmotic volume regulation and osmolyte transport in astrocytes is blocked by an anion transport inhibitor, L-644,711. Brain Res 682:197-202
Vitarella, D; DiRisio, D J; Kimelberg, H K et al. (1994) Potassium and taurine release are highly correlated with regulatory volume decrease in neonatal primary rat astrocyte cultures. J Neurochem 63:1143-9
Dave, V; Mullaney, K J; Goderie, S et al. (1994) Astrocytes as mediators of methylmercury neurotoxicity: effects on D-aspartate and serotonin uptake. Dev Neurosci 16:222-31
Aschner, M; Mullaney, K J; Wagoner, D et al. (1994) Intracellular glutathione (GSH) levels modulate mercuric chloride (MC)- and methylmercuric chloride (MeHgCl)-induced amino acid release from neonatal rat primary astrocytes cultures. Brain Res 664:133-40

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