Riluzole prodrug alters hippocampal glutamatergic function: a mechanism for the amelioration of synaptic plasticity and memory deficits observed in a preclinical Alzheimer’s disease model

Abstract

Glutamate-mediated hippocampal hyperexcitability has been linked to the progression of Alzheimer’s disease (AD). Previous research suggests that drugs aimed at mediating glutamate dysregulation may also be useful AD therapies. We previously showed that riluzole ameliorated glutamate excitotoxicity and cognitive deficits in the rTg(P301L)4510 mouse model. To further investigate and support our initial findings, we tested an improved drug formulation called troriluzole, a glutamate-modulating prodrug. Simultaneously, we used the 3xTg-AD mouse model strain to support that our findings are not unique to any mouse model. The 3xTg-AD mouse model expresses both tau and amyloid beta pathology, thereby offering a more translational AD model. Troriluzole-treated 3xTg-AD mice exhibited restored synaptic plasticity and memory in the Morris water maze and improved measures of extracellular glutamate in the hippocampus. These results validate that 1) troriluzole has a similar mechanism of action as its parent drug, riluzole, and 2) troriluzole has therapeutic potential in Alzheimer’s disease. Troriluzole has previously demonstrated an improved safety profile and PK parameters, and because of these reasons, it should be further investigated as an AD therapeutic.