Intranasal administration of isradipine preferentially targets the brain

Abstract

Parkinsons disease (PD) is the second most common neurodegenerative disease. Despite a concerted effort on the part of the scientific community, there is no proven strategy for slowing PD progression. Nevertheless, there are several potential drug targets that if functionally modified could alter disease course. Preclinical, epidemiological and clinical trial data suggest that Cav1 Ca2+ channels are one such target. Dihydropyridines (DHPs) are voltage-dependent, negative allosteric modulators of Cav1 Ca2+ channels that are approved for human use. However, the brain concentration of DHPs that can be safely achieved in humans with oral dosing is limited because of the widespread distribution of these channels, particularly in the vasculature. Intranasal administration of DHPs is a potential alternative delivery strategy that has been used with compounds that have similar limitations. To test the viability of this drug administration strategy, mice were intranasally or orally administered the DHP isradipine mixed in one of three vehicles. Plasma and brain concentrations of isradipine were then determined using liquid chromatography/mass spectroscopy at subsequent times. These studies demonstrated that intranasal administration of isradipine was able to achieve higher brain concentrations than those in the plasma, and these differences persisted for hours. Thus, intranasal administration of DHPs could be used to achieve high levels of Cav1 Ca2+ channel inhibition in the brain without producing unwanted peripheral side-effects.