The specific aims of this research proposal are to determine the effects that the anticonvulsants phenytoin, carbamazepine, valproic acid, ethosuximide, acetazolamide, and diazepam have on cation and anion transport processes and intracellular pH homostasis of glial cells isolated from the cerebral cortices of 3-day old neonatal rats and maintained in isolated tissue culture. They include determination of the acute and chronic effects of each agent on: (1) the DNA and protein content of treated cultures, (2) the activity of the transport enzymes Na+/K+, Ca++/Mg++, and HCO3-ATPase, (3) the concentration of intracellular Na+, K+, and Cl, and ion flux measurements, (4) the activity of the glial specific enzyme carbonic anhydrase, (5) the membrane potential, resistance and conductance, (6) the intracellular pH, (7) the effect of specific inhibitors of cation and anion transport in the presence and absence of anticonvulsant drugs, (8) the effect of increasing extracellular K+, and (9) the effect of pentylenetetrazol alone and with each anticonvulsant agent. These studies will involve the disiplines of neuropharmacology, biochemistry, electrolyte and acid-base chemistry, eletrophysiology, cellular biology, and isolated tissue culture. The experiments are designed to test the hypothesis that changes in these parameters will enhance glial cell regulatory process thereby providing the CNS with an enhanced ability to regulate the extracellular fluid. Such experiments are important, for if a thorough understanding of the mechanisms of these drugs is to be obtained, a comprehensive examination of their effects on glial cells as well as neurons must be undertaken. When the mechanisms of these anticonvulsants are determined, new drugs exhibiting similar characteristics but with fewer side-effects can be made and tested for clinical efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS022200-02
Application #
3404321
Study Section
Neurological Sciences Subcommittee 1 (NLS)
Project Start
1985-04-01
Project End
1988-03-31
Budget Start
1986-04-01
Budget End
1987-03-31
Support Year
2
Fiscal Year
1986
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
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
Hertz, L; Bender, A S; Woodbury, D M et al. (1989) Potassium-stimulated calcium uptake in astrocytes and its potent inhibition by nimodipine. J Neurosci Res 22:209-15

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