Nerve, Purkinje Fibers, Retina

Pincus, Grove, Marino and Glaser, Presented at the International Society Of Neurochemistry (1969),^{1419, 285, 293} observed that PHT (100 µM) reduced the abnormal accumulation of intracellular sodium in hypoxic nerves. In normally functioning, oxygenated nerves, PHT did not affect intracellular sodium. The authors state that PHT has been shown to have a stabilizing influence on virtually all excitable membranes. They note that these effects have been seen in a wide variety of vertebrate and invertebrate species.

285. Pincus, J. H. and Giarrnan, N. J., The effect of diphenylhydantoin on sodium-, potassium-, magnesium-stimulated adenosine triphosphatase activity of rat brain, Biochem. Pharmacol., 16: 600-603, 1967.
293. Rawson, M. D. and Pincus, J. H., The effect of diphenylhydantoin on sodium, potassium, magnesium-activated adenosine triphosphatase in rnicrosomal fractions of rat and guinea pig brain and on whole homogenates of human brain, Biochem. Pharmacol., 17: 573-579,1968.
1419. Pincus, J. H., Grove, I., Marino. B. B. and Glaser, G. E., Studies on the mechanism of action of diphenylhydantoin, Presented at the International Soc. Neurochem., September, 1969.

Bassett, Bigger and Hoffman, The Journal of Pharmacology and Experimental Therapeutics (1970),⁸⁰⁴ found that PHT protected canine Purkinje fibers during hypoxia. To determine the effect of PHT, a Purkinje fiber preparation of the isolated heart was stimulated electrically at a constant rate, and the electrical responses were measured until optimal performance was established. Then, hypoxia was induced by perfusion with a nitrogen-carbon dioxide mixture. This hypoxia caused a fall in resting and action potential amplitude, phase zero max rate of rise (V_max), and conduction velocity. PHT (.01-.1 µM) significantly delayed these hypoxia-induced effects, especially the fall in phase zero V_max. In another set of experiments, PHT, given after hypoxia-induced depression of the Purkinje fibers, transiently improved action potential amplitude, conduction velocity and V_max. The authors conclude that PHT's effectiveness in abolishing arrhythmias arising from coronary artery occlusion may be due, in part, to its ability to maintain and/or improve Purkinje fiber V_max and conduction.

804. Bassett, A. L., Bigger, J. T., and Hoffman, B. F., Protective action of DPH on canine Purkinje fibers during hypoxia, J. Pharmacol. Exp. Ther., 173: 336-343, 1970.

Honda, Podos and Becker, Investigative Ophthalmology (1973),¹¹⁶⁰ observed the protective effect of PHT (100 µM) against oxygen deprivation in the retina of rabbits as registered on one of the two major peaks of the electroretinogram.

1160, Honda, Y., Podos, S. M., and Becker, B., The effect of diphenylhydantoin on the electroretinogram of rabbits. II. Effects of hypoxia and potassium, Invest. Ophthal., 12: 573-578, 1973.

Naskar, Schuettauf, Quinto and Dreyer, Society for Neuroscience Abstracts (2000),³⁵⁹² explored whether phenytoin could protect retinal ganglion cells from the effects of partial optic nerve crush. The optic nerve of Long Evans rats was partially crushed, and the animals were administered either an intraperitoneal does of phenytoin or vehicle. A third group underwent sham optic nerve crush. A fourth group, after nerve crush, received PHT and memantine, a glutamate antagonist known to protect retinal ganglion cells in this model. Retinal ganglion cell survival was evaluated at 7 days. Phenytoin significantly reduced ganglion cell loss after partial optic nerve crush. Co-administration of memantine did not additionally increase cell survival. Phenytoin can protect against retinal ganglion cell loss following partial optic nerve crush. This effect was not addictive with a glutamate antagonist, suggesting that either agent alone is equally protective at saving the same population of ganglion cells at risk. Phenytoin is known to decrease neuronal firing and neurotransmitter release; this may underlie its ability to act as a neuroprotectant in this experimental model.

3592. Nasker, R., Schuettauf, F., Quinto, K., and Dreyer, E., Phenytoin blocks retinal ganglion cell death after partial optic nerve crush, Soc. Neurosci. Abstr. , 26(PT1): 29.15, 2000.