Riluzole confers neuroprotection by increasing the amount of HSF1 for a more robust heat shock response

Abstract

Induction of the heat shock response (HSR) is a primary and conserved genetic response to diverse stressors, mediated by activation of the HSF1 transcription factor, culminating in the induction of heat shock proteins (HSPs) that function as chaperones and proteases for the protection and recovery from cell damages. The relevance of HSPs in neurodegeneration is supported by a large body of evidence that mis-folding & aggregation of specific proteins are central to pathogenesis of the diseases, and that induction of the HSR is attenuated in neurons. We used an hsp70-firefly luciferase reporter gene in a HTS format to identify drugs that either induce or enhance the HSR in neuroprogenitor cells. We showed that riluzole, a FDA approved drug for ALS, is a modest inducer but a robust co-inducer of the HSR; the enhanced HSR correlates with increased cell survival and decreased activation of caspase 3/7 under oxidative stress. Analysis of the amount and distribution of HSF1 showed that riluzole increased the amount of latent HSF1 in the cytosolic compartment, and this allowed for a greater mobilization and activation of HSF1 under conditions of stress. Our result suggests that the use of rilzuole and elicitor of the HSR (include drugs such as NSAIDs) would give synergistic induction of HSPs to boost neuron survival, and could provide the basis for combinatorial therapeutics development in the prevention and treatment of neurodegeneration.