S 38093, a histamine H3 antagonist/inverse agonist, promotes hippocampal neurogenesis and improves context discrimination task in aged mice

Jean-Philippe Guilloux,Elisabeth Mocaer,Aurore Sors,Alice Hu,Indira Mendez-David,Benjamin A Samuels,Maryam Mekiri,Denis J David,René Hen,Alain M Gardier,Marjorie Levinstein,Charlène Faye

doi:10.1038/srep42946

Abstract

Strategies designed to increase adult hippocampal neurogenesis (AHN) may have therapeutic potential for reversing memory impairments. H3 receptor antagonists/inverse agonists also may be useful for treating cognitive deficits. However, it remains unclear whether these ligands have effects on AHN. The present study aimed to investigate the effects of a 28-day treatment with S 38093, a novel brain-penetrant antagonist/inverse agonist of H3 receptors, on AHN (proliferation, maturation and survival) in 3-month-old and in aged 16-month-old mice. In addition, the effects of S 38093 treatment on 7-month-old APPSWE Tg2576 transgenic mice, a model of Alzheimer’s disease, were also assessed. In all tested models, chronic treatment with S 38093 stimulated all steps of AHN. In aged animals, S 38093 induced a reversal of age-dependent effects on hippocampal brain-derived neurotrophic factor (BDNF) BDNF-IX, BDNF-IV and BDNF-I transcripts and increased vascular endothelial growth factor (VEGF) expression. Finally, the effects of chronic administration of S 38093 were assessed on a neurogenesis-dependent “context discrimination (CS) test” in aged mice. While ageing altered mouse CS, chronic S 38093 treatment significantly improved CS. Taken together, these results provide evidence that chronic S 38093 treatment increases adult hippocampal neurogenesis and may provide an innovative strategy to improve age-associated cognitive deficits.

Highlights

Modulation of the histaminergic H3 subtype receptor has been proposed for the treatment of cognitive deficits observed in Alzheimer’s disease (AD)[13,14,15]
The total number of DCX+ cells was unchanged after either chronic S 38093 or fluoxetine administration (Fig. 1C), chronic S 38093 (0.3 mg/ kg/d) or fluoxetine treatment significantly increased the number of DCX+ cells with tertiary dendrites (p < 0.05 and p < 0.01, respectively, Fig. 1D)
We suggest that such strategies may be useful for treating hippocampal memory impairments as those seen during normal ageing[8] or for preserving cognitive capacity[26]. This is the first study suggesting that H3 receptor antagonists/inverse agonists may be a novel strategy for increasing adult hippocampal neurogenesis, and H3 may be a new target for treating depression[27] or cognitive deficits[13,14,15]

Summary

Introduction

Modulation of the histaminergic H3 subtype receptor has been proposed for the treatment of cognitive deficits observed in Alzheimer’s disease (AD)[13,14,15]. In this study we investigated the effects of chronic S 38093 administration (0.3, 1 and 3 mg/kg/day p.o., 28 days) on hippocampal neurogenesis (proliferation, maturation and survival) in different mouse models, in young adult, aged and AD transgenic mice (APPSWE Tg2576).

Results

Conclusion