Sodium channel inhibitors alter the progress of tangle development in a mouse model of dementia

Abstract

ABSTRACTSodium channel inhibitors have been reported to protect against a range of neuroinflammatory and neurodegenerative diseases. Here the effect of chronic administration of two Na+channel inhibitors with different mechanisms of action, phenytoin and GS967 are tested in mouse models of different stages of Alzheimer’s disease. Subtle changes in the distribution of plaque sizes were observed inAppNLGF/NLGFmouse at 3 months of age, after being fed control or drug-supplemented chow from weaning onwards, with phenytoin treatment resulting in a significant increase in the frequency of the smallest plaques and a decrease in large plaques. The later pathology of neurofibrillary tangles was studied, in old age, by supplementing the food of transgenic mice with a P301L mutation in Tau. Chronic administration of Na+inhibitors from 15 months of age resulted in a decrease in the density of MC1-positive neurofibrillary tangles, possibly due to effects on microglial Na+channels. The density of microglial cells was strongly correlated with the density of neurofibrillary tangles but only in mice treated with the Na+inhibitors.