Repurposing the Dihydropyridine Calcium Channel Inhibitor Nicardipine as a Nav1.8 Inhibitor In Vivo for Pitt Hopkins Syndrome.

Abstract

Individuals with the rare genetic disorder Pitt Hopkins Syndrome (PTHS) do not have sufficient expression of the transcription factor 4 (TCF4) which is located on chromosome 18. TCF4 is a basic helix-loop-helix E protein that is critical for the normal development of the nervous system and the brain in humans. PTHS patients lacking sufficient TCF4 frequently display gastrointestinal issues, intellectual disability and breathing problems. PTHS patients also commonly do not speak and display distinctive facial features and seizures. Recent research has proposed that decreased TCF4 expression can lead to the increased translation of the sodium channel Nav1.8. This in turn results in increased after-hyperpolarization as well as altered firing properties. We have recently identified through a drug repurposing screenan FDA approved dihydropyridine calcium antagonist nicardipine used to treat angina, which inhibited Nav1.8. We have now performed behavioral testing in groups of 10 male Tcf4(± ) PTHS mice dosing by oral gavage at 3mg/kg once a day for 3weeks using standard methods to assess sociability, nesting, fear conditioning, self-grooming, open field and test of force. Nicardipine returned this spectrum of behavioral deficits in the Tcf4(± ) PTHS mouse model to WT levels and resulted in statistically significant results. These in vivo results in the well characterized Tcf4(± ) PTHS mice may suggest the potential to test this already approved drug further in a clinical study with PTHS patients or suggest the potential for use off label under compassionate use with their physician.