This Article Order Full text via Infotrieve Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lysko, P. G. Articles by Feuerstein, G. Search for Related Content PubMed PubMed Citation Articles by Lysko, P. G. Articles by Feuerstein, G.

Stroke, Vol 25, 2476-2482, Copyright © 1994 by American Heart Association

ARTICLES

Neuroprotective effects of tetrodotoxin as a Na+ channel modulator and glutamate release inhibitor in cultured rat cerebellar neurons and in gerbil global brain ischemia

PG Lysko, CL Webb, TL Yue, JL Gu and G Feuerstein
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pa 19406-0939.

BACKGROUND AND PURPOSE: Studies examining the role of tetrodotoxin- sensitive ion channels in hypoxic-ischemic neuronal damage have concluded that sodium influx is an important initiating event. We examined the neuroprotectant effect of tetrodotoxin on both cultured cerebellar neurons and on CA1 hippocampal neurons of gerbils exposed to brain ischemia. METHODS: We studied neuroprotective mechanisms using cultured rat cerebellar granule cells exposed to veratridine, which induced cytotoxicity, neurotransmitter release, and calcium influx. Survival of gerbil CA1 neurons was examined by direct neuron counts 7 days after 6 minutes of global ischemia with reperfusion. RESULTS: Tetrodotoxin protected cultured neurons in a dose-dependent manner from veratridine-induced toxicity (protective concentration [PC50] = 22 nmol/L). Veratridine induced [3H]aspartate efflux that was sodium dependent, only 25% calcium dependent, and was inhibited by tetrodotoxin (inhibitory concentration [IC50] = 60 nmol/L). Veratridine initiated increases in intracellular calcium that were also reversed by tetrodotoxin (IC50 = 63 nmol/L); reversal was dependent on the sodium- calcium exchanger and the sodium-potassium pump. Neuroprotection of 90% (n = 10; P = .001 versus vehicle) of gerbil CA1 hippocampal neurons was achieved by pretreatment with 2 ng of tetrodotoxin delivered three times intracerebroventricularly, without causing hypothermia. CONCLUSIONS: Sodium channel blockers like tetrodotoxin may have utility in treatment of ischemic neuronal injury by preventing excessive neuronal depolarizations, limiting excitotoxic glutamate release through reversal of the sodium-dependent glutamate transporter, preventing intracellular calcium overload, preserving cellular energy stores, and allowing recovery of ionic homeostasis through operation of the sodium-calcium exchanger.

This article has been cited by other articles:

				Y. Aoki, M. Tamura, Y. Itoh, T. Seto, K. Nonaka, H. Mukai, and Y. Ukai Effective Plasma Concentration of a Novel Na+/Ca2+ Channel Blocker NS-7 for Its Cerebroprotective Actions in Rats with a Transient Middle Cerebral Artery Occlusion J. Pharmacol. Exp. Ther., April 13, 2001; 296(2): 306 - 311. [Abstract] [Full Text]

				M. Oka, Y. Itoh, and Y. Ukai Preferential Inhibition by a Novel Na+/Ca2+ Channel Blocker NS-7 of Severe to Mild Hypoxic Injury in Rat Cerebrocortical Slices: A Possible Involvement of a Highly Voltage-Dependent Blockade of Ca2+ Channel J. Pharmacol. Exp. Ther., May 1, 2000; 293(2): 522 - 529. [Abstract] [Full Text]

				P. Lipton Ischemic Cell Death in Brain Neurons Physiol Rev, October 1, 1999; 79(4): 1431 - 1568. [Abstract] [Full Text] [PDF]

				J. D. Eskew, R. M. Vanacore, L. Sung, P. J. Morales, and A. Smith Cellular Protection Mechanisms against Extracellular Heme. HEME-HEMOPEXIN, BUT NOT FREE HEME, ACTIVATES THE N-TERMINAL c-Jun KINASE J. Biol. Chem., January 8, 1999; 274(2): 638 - 648. [Abstract] [Full Text] [PDF]

				S. K. Gupta, P. G. Lysko, K. Pillarisetti, E. Ohlstein, and J. M. Stadel Chemokine Receptors in Human Endothelial Cells. FUNCTIONAL EXPRESSION OF CXCR4 AND ITS TRANSCRIPTIONAL REGULATION BY INFLAMMATORY CYTOKINES J. Biol. Chem., February 13, 1998; 273(7): 4282 - 4287. [Abstract] [Full Text] [PDF]

				Y. D. Teng and J. R. Wrathall Local Blockade of Sodium Channels by Tetrodotoxin Ameliorates Tissue Loss and Long-Term Functional Deficits Resulting from Experimental Spinal Cord Injury J. Neurosci., June 1, 1997; 17(11): 4359 - 4366. [Abstract] [Full Text] [PDF]

				F. C. Barone, B. Arvin, R. F. White, A. Miller, C. L. Webb, R. N. Willette, P. G. Lysko, and G. Z. Feuerstein Tumor Necrosis Factor-{alpha} : A Mediator of Focal Ischemic Brain Injury Stroke, June 1, 1997; 28(6): 1233 - 1244. [Abstract] [Full Text]

				J. Hill Lucas, D. G. Emery, and L. J. Rosenberg REVIEW {blacksquare} : Physical Injury of Neurons: Important Roles for Sodium and Chloride Ions Neuroscientist, March 1, 1997; 3(2): 89 - 101. [Abstract] [PDF]