Evidence from a mouse model supports repurposing an anti-asthmatic drug, bambuterol, against Alzheimer's disease by administration through an intranasal route.

Abstract

Bambuterol is a long-acting anti-asthmatic prodrug which releases terbutaline. Terbutaline is an agonist of the β₂-adrenergic receptors which is formed by decarbamoylation of bambuterol by butyrylcholinesterase. Inhibition of the latter, as well as activation of β₂-AR, are of interest for the treatment of Alzheimer's disease (AD). Combining these two activities, bambuterol could express a good clinical efficacy against AD. The present work firstly confirmed the capacity of bambuterol to display in cellulo neuroprotective activities, reduction of Tau hyperphosphorylation and preservation of synapses in rat hippocampal neuronal cultures intoxicated with Aβ peptides. Further, bambuterol, in the form of a liposomal gel, showed a good bioavailability in CNS after intranasal administration, which should reduce any side effects linked to peripheral terbutaline release. Indeed, even if the latter is more selective than other β₂-mimetics towards bronchial β₂-AR, cardiovascular effects (tachycardia, arrhythmias…) could occur upon cardiac β₁-AR activation. Finally, intranasal administration of low doses of bambuterol gel in mice intoxicated with Aβ peptides, prevented long-term spatial memory impairment and showed beneficial effects on the survival of neurons and on synapse preservation.