Le récepteur H3 de l’histamine : une cible pour de nouveaux traitements des troubles de l’éveil et de la cognitionThe histamine H3 receptor: a new target for the treatment of arousal and cognitive disorders

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Résumé

Le récepteur H3 de l’histamine a été découvert dans les années 1980 par notre groupe en tant qu’autorécepteur présynaptique inhibant la synthèse et la libération de l’histamine dans le cerveau du rat. Seize ans plus tard, le clonage du récepteur H3 humain a permis de mettre en évidence des isoformes du récepteur, des différences pharmacologiques d’espèces et une forte activité constitutive (ou spontanée) du récepteur. Toutes ces données moléculaires sont actuellement prises en compte dans l’élaboration des ligands du récepteur H3 à visée thérapeutique. Les agonistes inverses H3, en augmentant l’activité des neurones à histamine, augmentent l’éveil et les performances cognitives chez l’animal. Cette nouvelle classe de molécules suscite un intérêt considérable de la part des compagnies pharmaceutiques et de nombreux programmes de développement clinique des agonistes inverses HH3 sont actuellement conduits pour le traitement des troubles de l’éveil et de la cognition.

Summary

The histamine H3 receptor was identified in the 80's by our group as a presynaptic autoreceptor inhibiting histamine synthesis and release in the rat brain. Sixteen years later, cloning of the related human H3 receptor revealed the existence of isoforms, species pharmacological differences and a high constitutive (spontaneous) activity of the receptor. All these molecular findings have to be taken into account for optimizing aimed at clinical applications ligands. H3 receptor inverse agonists, by increasing histamine neuron activity, promote arousal and enhance cognitive performances. Pharmaceutical firms have shown considerable interest for this new class of drugs and many programmes of clinical development of H3 receptor inverse agonists for the treatment of arousal and cognitive disorders are presently being conducted.

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    • Histaminergic Modulation of Recognition Memory

      2018, Handbook of Behavioral Neuroscience
      Citation Excerpt :

      Through extensive cross-talks with other GPCRs, they can also engage Gq/11 signalling and activate PLA2, Akt/GSK3 and MAP kinase pathways, all of which play important roles in axonal and synaptic plasticity and a variety of brain disorders (Haas et al., 2008). The histamine H3R is located on histaminergic neuron somata, dendrites and axon varicosities, as well as on the axon varicosities and somata of other neurons, providing negative feedback to inhibit histamine synthesis and the release of histamine or other transmitters, including glutamate (Brown and Reymann, 1996; Doreulee et al., 2001), acetylcholine (Arrang, 2007; Blandina et al., 1996) and GABA (Jang et al., 2001; Yamamoto et al., 1997). In keeping with their role as autoreceptors and heteroreceptors, H3R are heterogeneously distributed among areas known to receive histaminergic projections (Hu et al., 2007).

    Présentation devant les Académies nationales de pharmacie et de médecine, lors d’une séance commune, le 29 novembre 2006, à l’École du Val-de-Grâce, Paris.

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