The PDE4 inhibitor roflumilast improves memory in rodents at non-emetic doses

Abstract

Enhancement of central availability of the second messenger cAMP is a promising approach to improve cognitive function. Pharmacological inhibition of phosphodiesterase type 4 (PDE4), a group of cAMP hydrolyzing enzymes in the brain, has been shown to improve cognitive performances in rodents and monkeys. However, inhibition of PDE4 is generally associated with severe emetic side-effects. Roflumilast, an FDA-approved PDE4 inhibitor for treatment of chronic obstructive pulmonary disease (COPD), is yielding only mild emetic side effects. In the present study we investigate the potential of roflumilast as a cognition enhancer and to determine the potential coinciding emetic response in comparison to rolipram, a classic PDE4 inhibitor with pronounced emetic effects. Cognition enhancement was evaluated in mice and it was found that both roflumilast and rolipram enhanced memory in an object location task (0.03mg/kg), whereas only roflumilast was effective in a spatial Y-maze (0.1mg/kg). Emetic potential was measured using competition of PDE4 inhibition for α2-adrenergic receptor antagonism in which recovery from xylazine/ketamine-mediated anesthesia is used as a surrogate marker. While rolipram displayed emetic properties at a dose 10 times the memory-enhancing dose, roflumilast only showed increased emetic-like properties at a dose 100 times the memory-enhancing dose. Moreover, combining sub-efficacious doses of the approved cognition-enhancer donepezil and roflumilast, which did not improve memory when given alone, fully restored object recognition memory deficit in rats induced by the muscarinic receptor antagonist scopolamine. These findings suggest that roflumilast offers a more favorable window for treatment of cognitive deficits compared to rolipram.

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

“…Although roflumilast is considered as a non-selective inhibitor for all PDE4 isoforms, in particular the PDE4B and PDE4D isoforms in the hippocampus [109], it might be suggested that it has differences in intrinsic properties still. This could also be concluded from our previous preclinical work comparing pro-cognitive and emetic-like effects in mice between roflumilast and the similarly non-selective PDE4 inhibitor rolipram [107]. Rolipram induced emetic-like effects at pro-cognitive doses, while roflumilast had a significant difference between the high doses inducing emesis-like behavior and low doses improving cognition.…”

“…Of note, PDE inhibitors have narrow dose-response ranges in preclinical animal research. They mostly have only one to two optimum doses when using a log scale [107,108]. This makes it difficult to titrate the effective dose for human studies.…”

Roflumilast Reduces Cerebral Inflammation in a Rat Model of Experimental Subarachnoid Hemorrhage

“…In vivo , roflumilast mitigates the tobacco smoke-induced lung inflammation, pulmonary vascular remodeling and hypertension [18]. Roflumilast is the brain penetrant; its concentration in the brain increases in a dose-dependent manner [19, 20]. It is effective on hypertension-induced impairment of learning and >memory [19] and the cognitive deficit in rodents at non-emetic doses [20].…”

The effects of the soluble guanylate cyclase stimulator riociguat on memory performance in healthy volunteers with a biperiden-induced memory impairment

“…The most common side-effects seen in association with the use of riociguat are headache, dizziness, dyspepsia, peripheral oedema, nausea, diarrhoea and vomiting. Based on our experience with roflumilast in animals (Vanmierlo et al 2016) and humans (Heckman et al 2018; Van Duinen et al 2018), the formula of Reagan-Shaw et al (2008) was used to calculate the appropriate dose. Therefore, we suggested that a dose of 0.5 and 1.0 mg was sufficient to improve memory performance.…”