Melatonin limits paclitaxel-induced mitochondrial dysfunction in vitro and protects against paclitaxel-induced neuropathic pain in the rat

Acknowledgements Thank you to Professor Ahmet Hoke (Johns Hopkins, Baltimore, USA) for the gift of DRG cells; and to Professor Patrick M. Dougherty (MD Anderson Cancer Center, Texas, USA) for sharing his expertise in the rat model. Funding The study was funded by the Association of Anaesthetists of Great Britain and Ireland, the British Journal of Anaesthesia/Royal College of Anaesthetists and the Melville Trust.Peer reviewedPublisher PD

Monoaminergic and histaminergic strategies and treatments in brain diseases

The monoaminergic systems are the target of several drugs for the treatment of mood, motor and cognitive disorders as well as neurological conditions. In most cases, advances have occurred through serendipity, except for Parkinson's disease where the pathophysiology led almost immediately to the introduction of dopamine restoring agents. Extensive neuropharmacological studies first showed that the primary target of antipsychotics, antidepressants, and anxiolytic drugs were specific components of the monoaminergic systems. Later, some dramatic side effects associated with older medicines were shown to disappear with new chemical compounds targeting the origin of the therapeutic benefit more specifically. The increased knowledge regarding the function and interaction of the monoaminergic systems in the brain resulting from in vivo neurochemical and neurophysiological studies indicated new monoaminergic targets that could achieve the efficacy of the older medicines with fewer side-effects. Yet, this accumulated knowledge regarding monoamines did not produce valuable strategies for diseases where no monoaminergic drug has been shown to be effective. Here, we emphasize the new therapeutic and monoaminergic-based strategies for the treatment of psychiatric diseases. We will consider three main groups of diseases, based on the evidence of monoamines involvement (schizophrenia, depression, obesity), the identification of monoamines in the diseases processes (Parkinson's disease, addiction) and the prospect of the involvement of monoaminergic mechanisms (epilepsy, Alzheimer's disease, stroke). In most cases, the clinically available monoaminergic drugs induce widespread modifications of amine tone or excitability through neurobiological networks and exemplify the overlap between therapeutic approaches to psychiatric and neurological conditions. More recent developments that have resulted in improved drug specificity and responses will be discussed in this review.peer-reviewe

Etude moléculaire et pharmacologique du récepteur H3 de l'histamine

PARIS5-BU Saints-Pères (751062109) / SudocSudocFranceF

Constitutive activity of the histamine H3 receptor

International audienceConstitutive activity has been mainly recorded for numerous overexpressed and/or mutated receptors. The histamine H 3 receptor (H 3R) is a target of choice to study the physiological relevance of this process. In rodent brain, postsynaptic H 3Rs show high constitutive activity, and presynaptic H 3 autoreceptors that show constitutive activity have a predominant role in inhibiting the activity of histamine neurons. H 3R inverse agonists abrogate this constitutive brake and enhance histamine release in vivo. Some of these inverse agonists have entered clinical trials for the treatment of cognitive and food intake disorders. Studies performed in vitro and in vivo with proxyfan show that this H 3R ligand is a ‘protean agonist’ – that is, a ligand with a spectrum of activity ranging from full agonism to full inverse agonism depending on the level of H 3R constitutive activity. Consistent with its physiological and therapeutic relevance, the constitutive activity of H 3R thus has a major function in the brain and regulates the activity of H 3R-targeted drugs

Effects of Betahistine at Histamine H3 Receptors: Mixed Inverse Agonism/Agonism In Vitro and Partial Inverse Agonism In Vivo

International audienceWe previously suggested that therapeutic effects of betahistine in vestibular disorders result from its antagonist properties at histamine H3 receptors (H3Rs). However, H3Rs exhibit constitutive activity and most H3R antagonists act as inverse agonists. Here, we have first investigated the effects of betahistine at recombinant H3R isoforms. On inhibition of cAMP formation and [3H]arachidonic acid release, betahistine behaved as a nanomolar inverse agonist and a micromolar agonist. Both effects were suppressed by pertussis toxin, were found at all isoforms tested, and were not detected in mock cells, confirming interactions at H3Rs. The inverse agonist potency of betahistine and its affinity on [125I]iodoproxyfan binding were similar in rat and human. We have then investigated the effects of betahistine on histamine neuron activity, by measuring tele-methylhistamine (t-MeHA) levels in the brain of mice. Its acute intraperitoneal administration increased t-MeHA levels with an ED50 of 0.4 mg/kg, indicating inverse agonism. At higher doses, t-MeHA levels gradually returned to basal levels, a profile probably resulting from agonism. After acute oral administration, betahistine increased t-MeHA levels with an ED50 of 2 mg/kg, a rightward shift likely due to almost complete first-pass metabolism. In each case, the maximal effect of betahistine was lower than that of ciproxifan, indicating partial inverse agonism. After an oral 8-day treatment, the only effective dose of betahistine was of 30 mg/kg, indicating that a tolerance had developed. These data strongly suggest that therapeutic effects of betahistine result from an enhancement of histamine neuron activity induced by inverse agonism at H3 autoreceptors

Oligomérisation des protéines humaines et virales à sept domaines transmembranaires

Les récepteurs couplés aux protéines G (RCPG), aussi appelés protéines à sept domaines transmembranaires (7TM), représentent la plus grande famille de protéines. Elle comprend, chez l’homme, environ 900 membres. Ces protéines se lient à une grande variété de ligands ce qui entraîne l’activation de voies de signalisation impliquées dans divers processus cellulaires. Certaines protéines à 7TM, communément appelés orphelines, n’ont pas de ligand identifié, mais semblent jouer un rôle important dans la modulation de la fonction cellulaire via leurs activités constitutives ou leurs interactions avec d’autres protéines à 7TM. Certains virus synthétisent des protéines orphelines à 7TM homologues aux récepteurs de chimiokines humains pour détourner les fonctions de la cellule hôte et promouvoir leur réplication et leur dissémination. En effet, les protéines virales à 7TM sont capables de former des homomères ou des hétéromères avec d’autres protéines virales à 7TM, voire avec des protéines à 7TM de la cellule hôte. L’hétéromérisation des protéines virales à 7TM constitue une stratégie pertinente pour contrôler les fonctions de la cellule hôte

Potential molecular interactions between the histamine H3 receptor and the dopamine D2 receptor in the rat striatum

International audienc