The overall objective of this proposal is to understand factors that determine the extracellular levels of endogenous adenosine during conditions of cerebral hypoxia and/or ischemia.Adenosine acts as a potent endogenous neuroprotectant and augmentation of adenosinergic tone appears to be a reasonable basis for therapeutic intervention in cerebral ischemia. To model various states of metabolic stress, the rat hippocampal slice is exposed to conditions of hypoxia, hypoglycemia and in vitro ischemia which is combined hypoxia + hypoglycemia. We correlate electrophysiological indices of neuronal responsiveness with HPLC and isotope measurements of adenosine influx. In the last grant period, we show that a moderate elevation in levels of the inhibitory neuromodulator adenosine contributes to the early, reversible depression of synaptic transmission during hypoxia, hypoglycemia and in vitro ischemia. When exposed to extended conditions of in vitro ischemia, adenosine efflux abruptly rises four to sixfold in close temporal association with an anoxic depolarization whose occurrence is strongly correlated with the irreversible loss of synaptic transmission. The stimulus or trigger for this relatively large release of adenosine is not known. In vitro ischemia is associated with a number of events including: '1) increased intracellular Ca2+,2) excessive release of excitatory amino acids, particularly glutamate, 2) an anoxic depolarization, and 4) ATP depletion. Under normoxic conditions each of this stimuli may affect extracellular adenosine levels. Based on our work and that of others we propose the following working, hypothesis: The anoxic depolarization induces the release of glutamate which, through activation of glutamate receptors, initiates a large Ca2+ influx. The Ca2+ influx triggers, perhaps through ATP depletion, a substantial release of adenosine. The proposed studies will provide insight into the acute neuronal response to ischemic conditions and will provide an increased understanding into adenosine's role as an endogenous neuroprotectant and its potential use in therapeutic 'intervention of cerebral ischemia.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS028027-06
Application #
2266734
Study Section
Neurology A Study Section (NEUA)
Project Start
1990-02-01
Project End
1998-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
6
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Texas Tech University
Department
Physiology
Type
Schools of Medicine
DUNS #
609980727
City
Lubbock
State
TX
Country
United States
Zip Code
79430
Fowler, J C; Gervitz, L; Partridge, L D (1999) Hydroxylamine blocks pre- but not postsynaptic adenosine A(1) receptor-mediated actions in rat hippocampus. Brain Res 837:309-13
Fowler, J C; Partridge, L D; Gervitz, L (1999) Hydroxylamine blocks adenosine A1 receptor-mediated inhibition of synaptic transmission in rat hippocampus. Brain Res 815:414-8
Fowler, J C; Li, Y (1998) Contributions of Na+ flux and the anoxic depolarization to adenosine 5'-triphosphate levels in hypoxic/hypoglycemic rat hippocampal slices. Neuroscience 83:717-22
Fowler, J C (1997) Hydrogen peroxide opposes the hypoxic depression of evoked synaptic transmission in rat hippocampal slices. Brain Res 766:255-8
Fowler, J C (1995) Phorbol ester alters the electrophysiological responses to hypoxia and ischemic-like conditions in the rat hippocampal slice. Mol Chem Neuropathol 26:31-42
Liu, Z W; Fowler, J C (1995) Phorbol ester alters rat hippocampal neuronal response to hypoxia. Neuroreport 6:2069-72
Fowler, J C (1995) Choline substitution for sodium triggers glutamate and adenosine release from rat hippocampal slices. Neurosci Lett 197:97-100
Fowler, J C (1993) Changes in extracellular adenosine levels and population spike amplitude during graded hypoxia in the rat hippocampal slice. Naunyn Schmiedebergs Arch Pharmacol 347:73-8
Fowler, J C (1993) Purine release and inhibition of synaptic transmission during hypoxia and hypoglycemia in rat hippocampal slices. Neurosci Lett 157:83-6
Fowler, J C (1993) Glucose deprivation results in a lactate preventable increase in adenosine and depression of synaptic transmission in rat hippocampal slices. J Neurochem 60:572-6

Showing the most recent 10 out of 12 publications