Although epilepsy is a common neurological problem, the mechanisms involved in the initiation and termination of seizure discharges are poorly understood. The long-term goal of this research is to understand how neurons become synchronized into seizure discharges and to understand how the brain terminates the synchronization allowing the seizure to end. In this grant period the focus will be on the role of the ionic environment in neuronal synchronization. First, the role of the neuronal Na+/K+ ATPase as an uptake mechanism in the recovery of the [K+]0 from elevated levels during and after neuronal activity will be tested by measuring the ceiling level and rate of recovery of the [K+]0 in vivo in normal adult rats and in rats treated with astrocyte inhibitors during and after seizures induced by electrical stimulation, administration of chemical convulsants and during and after spreading depression. This hypothesis will be further tested in vitro in the dentate gyrus during non-synaptic field bursts and during spreading depression in control conditions and after treatments designed to alter glial and neuronal uptake mechanisms. To determine whether the abnormal regulation of the [K+]0 in the immature brain is due to developmental immaturity of the neuronal Na+/K+ ATPase, the ceiling level and rate of recovery of the [K+]0 in vivo and in vitro in adult and juvenile rats (PN 10-25) will be compared. Finally, a quantitative interpretation of activity-dependent changes in [K+]0 that have been measured to date and that are to be gathered during this grant period will be developed. A second hypothesis to be tested is that alterations of the intracellular pH of the granule cells are critical for the termination of seizure discharges in the dentate gyrus. First, the intracellular pH fluctuations in vitro and extracellular fluctuations in pH in vivo and in vitro and their correspondence with the seizure discharges and dependence on normal glial function will be determined in normal rats and in rats treated with astrocyte inhibitors. Finally, to determine whether alterations in intracellular pH underlies the termination of the seizure discharges, manipulations that alter the seizure duration and the ability of the tissue to pump hydrogen ions will be carried out in vitro while measuring intracellular pH.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS039941-03
Application #
6531118
Study Section
Special Emphasis Panel (ZRG1-BDCN-2 (01))
Program Officer
Fureman, Brandy E
Project Start
2000-04-01
Project End
2004-02-28
Budget Start
2002-03-01
Budget End
2003-02-28
Support Year
3
Fiscal Year
2002
Total Cost
$186,875
Indirect Cost
Name
Baylor College of Medicine
Department
Pharmacology
Type
Schools of Medicine
DUNS #
074615394
City
Houston
State
TX
Country
United States
Zip Code
77030
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Xu, Kaiping; Stringer, Janet L (2008) Pharmacokinetics of fructose-1,6-diphosphate after intraperitoneal and oral administration to adult rats. Pharmacol Res 57:234-8
Lian, Xiao-Yuan; Xu, Kaiping; Stringer, Janet L (2008) Oral administration of fructose-1,6-diphosphate has anticonvulsant activity. Neurosci Lett 446:75-7
Stringer, Janet L; Xu, Kaiping (2008) Possible mechanisms for the anticonvulsant activity of fructose-1,6-diphosphate. Epilepsia 49 Suppl 8:101-3
Xu, Kaiping; Stringer, Janet L (2008) Antioxidants and free radical scavengers do not consistently delay seizure onset in animal models of acute seizures. Epilepsy Behav 13:77-82
Lian, Xiao-Yuan; Khan, Firdous A; Stringer, Janet L (2007) Fructose-1,6-bisphosphate has anticonvulsant activity in models of acute seizures in adult rats. J Neurosci 27:12007-11
Stringer, Janet L; Mukherjee, Kakali; Xiang, Ting et al. (2007) Regulation of extracellular calcium in the hippocampus in vivo during epileptiform activity--role of astrocytes. Epilepsy Res 74:155-62
Lian, Xiao-Yuan; Zhang, Zhizhen; Stringer, Janet L (2005) Protective effects of ginseng components in a rodent model of neurodegeneration. Ann Neurol 57:642-8
Lian, Xiao-Yuan; Zhang, Zhi-Zhen; Stringer, Janet L (2005) Anticonvulsant activity of ginseng on seizures induced by chemical convulsants. Epilepsia 46:15-22

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