GEBR-7b, a novel PDE4D selective inhibitor that improves memory in rodents at non-emetic doses

Abstract

BACKGROUND AND PURPOSEStrategies designed to enhance cerebral cAMP have been proposed as symptomatic treatments to counteract cognitive deficits. However, pharmacological therapies aimed at reducing PDE4, the main class of cAMP catabolizing enzymes in the brain, produce severe emetic side effects. We have recently synthesized a 3-cyclopentyloxy-4-methoxybenzaldehyde derivative, structurally related to rolipram, and endowed with selective PDE4D inhibitory activity. The aim of the present study was to investigate the effect of the new drug, namely GEBR-7b, on memory performance, nausea, hippocampal cAMP and amyloid-b (Ab) levels. EXPERIMENTAL APPROACHTo measure memory performance, we performed object recognition tests on rats and mice treated with GEBR-7b or rolipram. The emetic potential of the drug, again compared with rolipram, was evaluated in rats using the taste reactivity test and in mice using the xylazine/ketamine anaesthesia test. Extracellular hippocampal cAMP was evaluated by intracerebral microdialysis in freely moving rats. Levels of soluble Ab peptides were measured in hippocampal tissues and cultured N2a cells by ELISA. KEY RESULTSGEBR-7b increased hippocampal cAMP, did not influence Ab levels and improved spatial, as well as object memory performance in the object recognition tests. The effect of GEBR-7b on memory was 3 to 10 times more potent than that of rolipram, and its effective doses had no effect on surrogate measures of emesis in rodents. CONCLUSION AND IMPLICATIONSOur results demonstrate that GEBR-7b enhances memory functions at doses that do not cause emesis-like behaviour in rodents, thus offering a promising pharmacological perspective for the treatment of memory impairment.

PDE Inhibition and cognition enhancement

“…Of note, there is a discrepancy between the relatively low expression of PDE5 and PDE4D mRNA in the human brain and studies report cognition enhancing effects of these inhibitors in rats and mice [13,20]. It could be argued that mRNA levels may not be directly related with enzyme levels.…”

Phosphodiesterases as Therapeutic Targets for Alzheimer's Disease

“…75 However, 3-cyclopentyloxy-4-methoxybenzaldehyde (GEBR-7b), a recently developed novel and selective PDE4D inhibitor, is 3−10 times more potent as a memory enhancer than rolipram, and it can exert these effects at doses that do not produce emesis-like symptoms in rodents. 76 Inhibition of brain PDE4 without emetic side effects may also be achieved by allosteric modulation (see section 8). It should be however noted that it is not entirely clear whether PDE4 inhibition alone is the sole basis of emesis.…”

A Nonhuman Primate PET Study: Measurement of Brain PDE4 Occupancy by Roflumilast Using (R)-[11C]Rolipram

“…Regarding PDE4 subtypes, PDE4D is considered to be related to cognitive improvement [34,35] while PDE4B is also considered to be involved in the cognitive function [36]. It would be worth investigating in future the relationship among treatment with roflumilast, PDE4 occupancy, and effects on cognitive domains in preclinical and clinical settings.…”