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. 2011 Dec;164(8):2054-63.
doi: 10.1111/j.1476-5381.2011.01524.x.

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

O Bruno  1 , E Fedele, J Prickaerts, L A Parker, E Canepa, C Brullo, A Cavallero, E Gardella, A Balbi, C Domenicotti, E Bollen, H J M Gijselaers, T Vanmierlo, K Erb, C L Limebeer, F Argellati, U M Marinari, M A Pronzato, R Ricciarelli
Affiliations

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

O Bruno et al. Br J Pharmacol. 2011 Dec.

Abstract

Background and purpose: Strategies 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-β (Aβ) levels.

Experimental approach: To 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 Aβ peptides were measured in hippocampal tissues and cultured N2a cells by elisa.

Key results: GEBR-7b increased hippocampal cAMP, did not influence Aβ 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 implications: Our 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.

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Figures

Figure 1
Figure 1
Chemical structure of GEBR-7b.
Figure 2
Figure 2
Influence of rolipram and GEBR-7b on the discrimination index (d2) in the object location test in rats (means ± SEM). A difference from the vehicle condition is depicted with asterisks (Bonferroni's comparison t-test: *P < 0.05). A difference from zero is depicted with hashes (one-sample t-tests: #P < 0.05, ##P < 0.01, ###P < 0.001). n = 22–24.
Figure 3
Figure 3
Influence of rolipram and GEBR-7b on the discrimination index (d2) in the object location in mice (means ± SEM). A difference from the vehicle condition is depicted with asterisks (Bonferroni's comparison t-test: *P < 0.05, **P < 0.01). A difference from zero is depicted with hashes (one-sample t-tests: #P < 0.05, ##P < 0.01, ###P < 0.001). n = 14–16, except for the vehicle group, where n = 23.
Figure 4
Figure 4
Influence of rolipram and GEBR-7b on the discrimination index (d2) in the object recognition test in rats (means ± SEM). A difference from the vehicle condition is depicted with asterisks (Bonferroni's comparison t-test: *P < 0.05, **P < 0.01). A difference from zero is depicted with hashes (one-sample t-tests: ###P < 0.001). n = 21–23.
Figure 5
Figure 5
Influence of rolipram and GEBR-7b on conditioned gaping in rats. Graph presents mean number (±SEM) of gapes elicited by the 5 min intra-oral infusion of 17% sucrose solution paired with the various conditioning drugs across three conditioning trials (trials 1–3) and the test trial (trial 4). Vehicle (n = 5), 0.003 mg·kg−1 GEBR-7b (n = 6), 0.3 mg·kg−1 GEBR-7b (n = 5), 0.3 mg·kg−1 rolipram (n = 7). Bonferroni's post hoc comparison test: **P < 0.01 versus the other conditions tested in trial 4.
Figure 6
Figure 6
Influence of rolipram and GEBR-7b on the recovery time after xylazine/ketamine induced α2-adrenoceptor-mediated anaesthesia in mice (means ± SEM). A difference from the vehicle condition is depicted with asterisks (Bonferroni's comparison t-test: *P < 0.05, ***P < 0.001; n = 5–7 per group).
Figure 7
Figure 7
Effects of rolipram and GEBR-7b on cAMP extracellular levels in hippocampi of freely moving rats. Rolipram or GEBR-7b was infused through the dialysis probe after three consecutive basal samples had been collected and for the time indicated by the horizontal bar. The data represent means ± SEM of four (rolipram) or five (GEBR-7b) independent experiments (Bonferroni's comparison test: *P < 0.05, **P < 0.01 and ***P < 0.001 vs. basal level).
Figure 8
Figure 8
Effect of GEBR-7b on Aβ levels in vivo and in vitro. (A) Effect of GEBR-7b on the hippocampal content of Aβ40 and Aβ42. Rats were injected i.p. with the indicated doses of drug or vehicle and killed either 6 or 18 h after the treatment. Hippocampal homogenates were subjected to soluble Aβ40 and Aβ42 specific elisa. Data, calculated as pmol·g−1 protein, are expressed as a percentage (means ± SD; n = 3) of the corresponding control group. (B) Effect of GEBR-7b on the secretion of Aβ40 and Aβ42 in neuronal cultured cells. Conditioned media from N2a cells treated for 24 h with GEBR-7b or DMSO were subjected to specific Aβelisa. Results are expressed as means ± SD for four independent experiments. Statistically significant differences were not detected either in (A) or in (B) (P > 0.05 vs. the corresponding control group).
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