In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist

Panayi, Fany; Sors, Aurore; Bert, Lionel; Martin, Baptiste; Rollin-Jego, Gaëlle; Billiras, Rodolphe; Carrié, Isabelle; Albinet, Karine; Danober, Laurence; Rogez, Nathalie; Thomas, Jean‐Yves; Pira, Luigi; Bertaina-Anglade, Valérie; Lestage, Pierre

doi:10.1016/j.ejphar.2017.03.008

Cited by 16 publications

(16 citation statements)

References 36 publications

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“…Indeed, in separate experiments, we showed that the acute as well as chronic administration of S 38093 in rats, by antagonizing presynaptic H 3 receptors, has been shown to rapidly and dose-dependently increase the release of ACh in the ventral hippocampus and the PFC of rats (intracerebral microdialysis, see supplemental data and Panayi et al, 2014). On the other hand, the well-known AChEI Donepezil, given alone, also increased ACh level in the synaptic cleft after acute administration.…”

Section: Discussionmentioning

confidence: 92%

“…Mice were allocated to administration of vehicle (purified water), S 38093 ( S1 : 0.1 mg/kg; S2 : 0.3 mg/kg; S3 : 1.0 mg/kg) or Donepezil ( Don1 : 0.1 mg/kg; Don2 : 0.3 mg/kg), or a combination of both S 38093 and Donepezil at the same doses with N = 12 in each group. S 38093 and Donepezil doses were determined according to previous data (Béracochéa et al, 2008; Panayi et al, 2014). Before behavioral testing, all mice received for nine consecutive days a daily esophageal administration of S 38093, Donepezil, vehicle or S 38093 + Donepezil combinations, administered at a volume of 10 mL/kg.…”

Section: Methodsmentioning

confidence: 99%

“…It is also effective in working memory paradigms in middle-aged mice (spontaneous alternation or concurrent serial alternation) and in aged monkeys (delayed matching to sample task). These effects are thought to be mediated by an enhanced release of neurotransmitters especially ACh and histamine, which are indeed observed by microdialysis in the prefrontal cortex (PFC) and the hippocampus of rats after S 38093 administration (Panayi et al, 2014)…”

Section: Introductionmentioning

confidence: 94%

“…S 38093 is an inverse agonist/antagonist of H3 receptors, which has shown procognitive properties at a mean pharmacological dose of 0.3 mg/kg (Panayi et al, 2014). Indeed, it improves performance in episodic-like memory paradigm both in adult rats (object recognition with natural forgetting or scopolamine-induced amnesia) and aged mice (relational memory task).…”

Section: Introductionmentioning

confidence: 99%

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The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

Sors

Krazem

Kehr³

et al. 2016

Front. Pharmacol.

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Donepezil, an acetylcholinesterase inhibitor, induces only moderate symptomatic effects on memory in Alzheimer’s disease patients. An alternative strategy for treatment of cognitive symptoms could be to act simultaneously on both histaminergic and cholinergic pathways, to create a synergistic effect. To that aim, 14 month old C57/Bl6 mice were administered per oesophagy during nine consecutive days with Donepezil (at 0.1 and 0.3 mg/kg) and S 38093 (at 0.1, 0.3, and 1.0 mg/kg), a H3 histaminergic antagonist developed by Servier, alone or in combination and tested for memory in a contextual memory task that modelized the age-induced memory dysfunction. The present study shows that the combination of Donepezil and S 38093 induced a dose-dependent synergistic memory-enhancing effect in middle-aged mice with a statistically higher size of effect never obtained with compounds alone and without any pharmacokinetic interaction between both compounds. We demonstrated that the memory-enhancing effect of the S 38093 and Donepezil combination is mediated by its action on the septo-hippocampal circuitry, since it canceled out the reduction of CREB phosphorylation (pCREB) observed in these brain areas in vehicle-treated middle-aged animals. Overall, the effects of drug combinations on pCREB in the hippocampus indicate that the synergistic promnesiant effects of the combination on memory performance in middle-aged mice stem primarily from an enhancement of neural activity in the septo-hippocampal system.

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Section: Discussionmentioning

confidence: 92%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 94%

Section: Introductionmentioning

confidence: 99%

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The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

Sors

Krazem

Kehr³

et al. 2016

Front. Pharmacol.

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“…In vitro , S 38093 displays a moderate affinity for cloned rat, and human H3 receptors (Ki = 8.8 and 1.1 μmol/L, respectively) with no affinity for other histaminergic receptors. S 38093 behaved as a moderate inverse agonist at rat and human H3 receptors (EC50 = 9 and 1.7 μmol/L, respectively)(Panayi et al., ; Sors et al., ). Suspensions of S 38093‐2 in 1% (w/v) Hydroxyethylcellulose (HEC) in sterile water were prepared under sterile conditions.…”

Section: Methodsmentioning

confidence: 99%

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats

Chaumette

Chapuy

Berrocoso

et al. 2017

European Journal of Pain

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Background: Histamine H3 receptors are mainly expressed on CNS neurons, particularly along the nociceptive pathways. The potential involvement of these receptors in pain processing has been suggested using H3 receptor inverse agonists. Methods: The antinociceptive effect of S 38093, a novel inverse agonist of H3 receptors, has been evaluated in several neuropathic pain models in rat and compared with those of gabapentin and pregabalin. Results: While S 38093 did not change vocalization thresholds to paw pressure in healthy rats, it exhibited a significant antihyperalgesic effect in the Streptozocin-induced diabetic (STZ) neuropathy model after acute and chronic administration and, in the chronic constriction injury (CCI) model only after chronic administration, submitted to the paw-pressure test. Acute S 38093 administration at all doses tested displayed a significant cold antiallodynic effect in a model of acute or repeated administration of oxaliplatin-induced neuropathy submitted to cold tail immersion, cold allodynia being the main side effect of oxaliplatin in patients. The effect of S 38093 increased following chronic administration (i.e. twice a day during 5 days) in the CCI and STZ models except in the oxaliplatin models where its effect was already maximal from the first administration The kinetics and size of effect of S 38093 were similar to gabapentin and/or pregabalin. Finally, the antinociceptive effect of S 38093 could be partially mediated by a2 adrenoreceptors desensitization in the locus coeruleus. Conclusions: These results highlight the interest of S 38093 to relieve neuropathic pain and warrant clinical trials especially in chemotherapeutic agent-induced neuropathic pain. Significance: S 38093, a new H3 antagonist/inverse agonist, displays antiallodynic and antihyperalgesic effect in neuropathic pain, especially in oxaliplatin-induced neuropathy after chronic administration. This effect of S 38093 in neuropathic pain could be partly mediated by a2 receptors desensitization in the locus coeruleus.

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Histaminergic Modulation of Recognition Memory

Provensi

Costa

Passani

2018

Handbook of Object Novelty Recognition

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In vivo pharmacological profile of S 38093, a novel histamine H3 receptor inverse agonist

Cited by 16 publications

References 36 publications

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

The Synergistic Enhancing-Memory Effect of Donepezil and S 38093 (a Histamine H3 Antagonist) Is Mediated by Increased Neural Activity in the Septo-hippocampal Circuitry in Middle-Aged Mice

Effects of S 38093, an antagonist/inverse agonist of histamine H3 receptors, in models of neuropathic pain in rats

Histaminergic Modulation of Recognition Memory

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