The six specific aims of this competing renewal are designed to determine the effects of anticonvulsant and convulsant drugs on ion-transport processes, acid-base homeostasis and electrophysiology of astrocytes in tissue culture. These studies are designed to test the hypothesis that anticonvulsants in addition to their effects on neurons and synapses also stimulate astrocytic regulatory processes, and in so doing provide the CNS with an enhanced ability to regulate electrolyte, acid-base and neurotransmitter homeostasis within the CNS, thereby limiting seizure activity. Specifically, primary cultures of mouse cerebral cortical astrocytes will be acutely and chronically exposed to therapeutic concentrations of the prototype anticonvulsants phenytoin, carbamazepine, valproate, diazepam, ethosuximide, acetazolamide, and to the calcium channel blocker flunarizine. The effects of the above treatments on; the uptake, steady-state distribution and release of 22 Na+, 42 K+, 36 Cl- and 45 Ca++; the intracellular concentration of Na+, K+, Cl- and H+; the transport enzymes Na+/K+, Ca++/Mg++ -ATPase and the glial specific enzyme carbonic anhydrase; the electrophysiology (membrane potential, resistance and conductance); and the uptake of the neurotransmitter substance glutamate will be assessed. In addition, studies to characterize the effect of the receptor specific convulsants N-methyl-d-aspartate, and entylenetetrazol on the above parameters in untreated and anticonvulsant-treated (acute and chronic) astrocytes will also be conducted. The focus of this application does not differ significantly from that of the initial grant. Such an analysis is important for if a thorough understanding of the mechanisms of these drugs is to be obtained, a comprehensive examination of their effects on astrocytes as well as neurons must be undertaken. These studies will also enhance our understanding of the seizure process. Thus, through an increased understanding of the mechanisms of the currently available anticonvulsant drugs and the processes underlying seizure disorders, drugs with greater selectively and fewer adverse effects can be developed.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022200-05
Application #
3404323
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-04-01
Project End
1991-11-30
Budget Start
1989-12-01
Budget End
1990-11-30
Support Year
5
Fiscal Year
1990
Total Cost
Indirect Cost
Name
University of Utah
Department
Type
Schools of Medicine
DUNS #
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Bender, A S; Woodbury, D M; White, H S (1997) The rapid L- and D-aspartate uptake in cultured astrocytes. Neurochem Res 22:721-6
Filloux, F M; Fitts, R C; Skeen, G A et al. (1994) The dihydropyridine nitrendipine inhibits [3H]MK 801 binding to mouse brain sections. Eur J Pharmacol 269:325-30
Bender, A S; Woodbury, D M; White, H S (1994) Ionic dependence of adenosine uptake into cultured astrocytes. Brain Res 661:1-8
Skeen, G A; Twyman, R E; White, H S (1993) The dihydropyridine nitrendipine modulates N-methyl-D-aspartate receptor channel function in mammalian neurons. Mol Pharmacol 44:443-50
White, H S; Chow, S Y; Yen-Chow, Y C et al. (1992) Effect of elevated potassium on the ion content of mouse astrocytes and neurons. Can J Physiol Pharmacol 70 Suppl:S263-8
White, H S; Skeen, G A; Edwards, J A (1992) Pharmacological regulation of astrocytic calcium channels: implications for the treatment of seizure disorders. Prog Brain Res 94:77-87
Chow, S Y; Yen-Chow, Y C; White, H S et al. (1991) Effects of potassium on the anion and cation contents of primary cultures of mouse astrocytes and neurons. Neurochem Res 16:1275-83
Chow, S Y; Yen-Chow, Y C; White, H S et al. (1991) pH regulation after acid load in primary cultures of mouse astrocytes. Brain Res Dev Brain Res 60:69-78
Bender, A S; Woodbury, D M; White, H S (1989) Beta-DL-methylene-aspartate, an inhibitor of aspartate aminotransferase, potently inhibits L-glutamate uptake into astrocytes. Neurochem Res 14:641-6
Chow, S Y; White, H S; Yen-Chow, Y C et al. (1989) Uptakes of iodide and chloride by primary cultures of mouse astrocytes and neurons. Neurochem Res 14:963-9

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