Journal of Neurophysiology, Vol 67, Issue 1 236-240, Copyright © 1992 by APS

ARTICLES

Tertiary and quaternary local anesthetics protect CNS white matter from anoxic injury at concentrations that do not block excitability

P. K. Stys, B. R. Ransom and S. G. Waxman
Department of Neurology, Yale University School of Medicine, New Haven, Connecticut.

1. Anoxic injury in CNS white matter was studied using the in vitro rat optic nerve preparation. Optic nerves were subjected to 60 min of anoxia, and functional recovery was assessed using the area under the compound action potential (CAP). In normal cerebrospinal fluid, CAP area recovered to 33.5 +/- 9.3% (SD) of control. 2. Lidocaine and procaine (0.1 or 1.0 mM), applied beginning 1 h before anoxia, significantly improved postanoxic recovery of CAP area. However, both agents also depressed the preanoxic CAP. Procaine generally allowed greater recovery with less depression compared with lidocaine. 3. The quaternary derivatives QX-314 (0.1-1.0 mM) and QX-222 (0.3-3.0 mM) resulted in more complete recovery of the CAP area from anoxia, with less depression of preanoxic excitability, compared with the tertiary compounds. At 0.3 mM, QX-314 reduced the preanoxic CAP very little (to 94.4 +/- 14% of control CAP area), yet allowed the postanoxic CAP area to recover to 99.6 +/- 19%. 4. We conclude that quaternary local anesthetics are more effective at protecting CNS white matter tracts from anoxia than tertiary compounds and that these agents can result in markedly improved recovery even at concentrations that do not block conduction. Moreover, given the relative specificity of QX-314 for noninactivating Na+ channels, we hypothesize that this channel subtype plays an important role in mediating anoxic injury in central myelinated axons.

This article has been cited by other articles:

				B. C. Hains and S. G. Waxman Neuroprotection by Sodium Channel Blockade with Phenytoin in an Experimental Model of Glaucoma Invest. Ophthalmol. Vis. Sci., November 1, 2005; 46(11): 4164 - 4169. [Abstract] [Full Text] [PDF]

				S. G. Waxman Sodium channel blockers and axonal protection in neuroinflammatory disease Brain, January 1, 2005; 128(1): 5 - 6. [Full Text] [PDF]

				M. J. Craner, J. Newcombe, J. A. Black, C. Hartle, M. L. Cuzner, and S. G. Waxman Molecular changes in neurons in multiple sclerosis: Altered axonal expression of Nav1.2 and Nav1.6 sodium channels and Na+/Ca2+ exchanger PNAS, May 25, 2004; 101(21): 8168 - 8173. [Abstract] [Full Text] [PDF]

				M. J. Craner, B. C. Hains, A. C. Lo, J. A. Black, and S. G. Waxman Co-localization of sodium channel Nav1.6 and the sodium-calcium exchanger at sites of axonal injury in the spinal cord in EAE Brain, February 1, 2004; 127(2): 294 - 303. [Abstract] [Full Text] [PDF]

				A. C. Lo, C. Y. Saab, J. A. Black, and S. G. Waxman Phenytoin Protects Spinal Cord Axons and Preserves Axonal Conduction and Neurological Function in a Model of Neuroinflammation In Vivo J Neurophysiol, November 1, 2003; 90(5): 3566 - 3571. [Abstract] [Full Text] [PDF]

				S. B. Tekkok and M. P. Goldberg AMPA/Kainate Receptor Activation Mediates Hypoxic Oligodendrocyte Death and Axonal Injury in Cerebral White Matter J. Neurosci., June 15, 2001; 21(12): 4237 - 4248. [Abstract] [Full Text] [PDF]

				S. G. Waxman Multiple Sclerosis as a Neuronal Disease Arch Neurol, January 1, 2000; 57(1): 22 - 24. [Full Text] [PDF]

				F. M. Follis, K. S. Blisard, P. S. Varvitsiotis, S. B. Pett Jr, R. T. Temes, and J. A. Wernly Selective protection of gray and white matter during spinal cord ischemic injury Ann. Thorac. Surg., May 1, 1999; 67(5): 1362 - 1369. [Abstract] [Full Text] [PDF]

				L. Leppanen and P. K. Stys Ion Transport and Membrane Potential in CNS Myelinated Axons II. Effects of Metabolic Inhibition J Neurophysiol, October 1, 1997; 78(4): 2095 - 2107. [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]

				T. R. Cummins and S. G. Waxman Downregulation of Tetrodotoxin-Resistant Sodium Currents and Upregulation of a Rapidly Repriming Tetrodotoxin-Sensitive Sodium Current in Small Spinal Sensory Neurons after Nerve Injury J. Neurosci., May 15, 1997; 17(10): 3503 - 3514. [Abstract] [Full Text] [PDF]