Phenytoin: its potential as neuroprotective and retinoprotective drug
Year: 2017
Type: article
Abstract: The concept of neuroprotection can be found in the literature from the 1940s onwards. It was initially linked to protection against convulsions due to anticonvulsants, barbiturates and phenytoin, and was therefore based on a clinical endpoint. Neuroprotection and retinoprotection as definitions were related to effects on physiological and functional parameters, at the level of the cells, tissues and organs, and at the clinical level. As there was consistent evidence for neuroprotection in both groups of outcome parameters, it was recommended that the focus should be on structural endpoints as primary surrogate endpoints. Moreover, the sensitivity of clinical endpoints is generally much lower than that of structural endpoints, and we might lose valuable retinoprotective drugs if we focus only on clinical endpoints. Phenytoin is a selective sodium-channel inhibitor, used as an anticonvulsant in the treatment of epilepsy and is neuroprotective at therapeutic concentrations in experimental models 1. It has been documented in animal experiments that phenytoin can reduce mortality due to anoxia or hypoxia, and the major endpoint pointing to ‘protection’ was ‘survival time’. The protective effects of phenytoin were defined at the cellular, tissue and organ levels, and a unifying hypothesis for the mechanism of action of phenytoin became established, based on its prevention of intracellular sodium accumulation. Phenytoin can be loaded rapidly, to achieve therapeutic serum concentrations within a few days; this is important because, as suggested by experimental studies, neuroprotection for relapses should be started as early as possible during the acute inflammatory injury phase 2. Studies on retinoprotection evaluated the protective effect of phenytoin on clinical endpoints in optic neuritis and glaucoma. Retinoprotection in optic neuritis secondary to multiple sclerosis can be tested using clinical, electrophysiological and imaging techniques 3. The thickness of unmyelinated axons, in the retinal nerve fibre layer (RNFL) affected by retrograde degeneration in optic neuritis can be measured sensitively and non-invasively using optical coherence tomography (OCT) 4. Therefore, the RNFL thickness provides a plausible biomarker of axonal loss. The retinoprotective effect of phenytoin was supported in a recent clinical phase II proof-of-concept study in multiple sclerosis patients affected by optic neuritis 5. The authors considered OCT evaluation, using the measurement of RNFL thickness, as the primary outcome measure. They found phenytoin use to be associated with a significant reduction in the loss of RNFL thickness and macular volume after acute optic neuritis, suggesting that phenytoin has a protective effect on the ganglion cells, their axons and the optic nerve. Although the results of this study represented a major advancement, and were undeniably encouraging, future studies should include more frequent OCT sampling, as well as more detailed OCT segmentation-derived retinal measures. Basically, structural endpoints, such as the thickness of the RNFL, along with OCT segmentation methods to estimate ganglion neurone integrity, might be considered for widely testing and exploring the use of phenytoin as a retinoprotective drug in glaucoma and optic neuritis. At the average concentration achieved in this trial, phenytoin was an almost pure activity-dependent inhibitor of voltage-gated sodium channels in an episode of inflammatory demyelination. It is conceivable that other sodium-channel inhibitors could also be neuroprotective in patients with acute optic neuritis and in other types of relapse in multiple sclerosis, in view of the similarities between acute optic neuritis and other types of relapse 6. Future studies should establish more precisely the optimal therapeutic window for neuroprotection in relapses. What happens in the eye seems to mirror the rest of the brain, so potentially this approach could be used to treat more than just eye attacks, but any flare-up of the disease. We believe that neuroprotective drugs such as phenytoin could complement existing immunomodulating therapies and potential remyelination approaches. Key ligands in this article are hyperlinked to corresponding entries in http://www.guidetopharmacology.org, the common portal for data from the IUPHAR/BPS Guide to PHARMACOLOGY 7. There are no competing interests to declare.
DOI: 10.1111/bcp.13435
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2761275930