作者: Posa, Luca ; Ettaoussi, Mohamed ; López-Canul, Martha ; Gregorio, Danilo De ; Gobbi, Gabriella ; Catoire, Helene ; He, Qianzi ; Rouleau, Guy ; Comai, Stefano ; Sasson, Tania ; Beaulieu, Jean Martin ; Ochoa-Sanchez, Rafael

Sleep disorders affect millions of people around the world and have a high comorbidity with psychiatric disorders. While current hypnotics mostly increase non-rapid eye movement sleep (NREMS), drugs acting selectively on enhancing rapid eye movement sleep (REMS) are lacking. This polysomnographic study in male rats showed that the first-in-class selective melatonin MT1receptor partial agonist UCM871 increases the duration of REMS without affecting that of NREMS. The REMS-promoting effects of UCM871 occurred by inhibiting, in a dose–response manner, the firing activity of the locus ceruleus (LC) norepinephrine (NE) neurons, which express MT1receptors. The increase of REMS duration and the inhibition of LC-NE neuronal activity by UCM871 were abolished by MT1pharmacological antagonism and by an adeno-associated viral (AAV) vector, which selectively knocked down MT1receptors in the LC-NE neurons. In conclusion, MT1receptor agonism inhibits LC-NE neurons and triggers REMS, thus representing a novel mechanism and target for REMS disorders and/or psychiatric disorders associated with REMS impairments.

2023-12-01·Pharmacological Research

Melatonin MT1 receptors as a target for the psychopharmacology of bipolar disorder: A translational study

Article

作者: Manchia, Mirko ; Suprani, Federico ; Pinna, Ilaria ; Valtorta, Flavia ; Carpiniello, Bernardo ; Comai, Stefano ; Arru, Laura ; Acconcia, Clementina ; Pulcinelli, Vittoria ; Cherchi, Laura ; Monzani, Elena ; Pinna, Federica ; Russo, Luigi ; Garzilli, Mario ; Guiso, Beatrice ; Corrias, Carolina ; Sut, Stefania ; Scebba, Francesca ; Somaini, Giulia ; Tassan Mazzocco, Margherita ; De Girolamo, Sofia ; Cambiaghi, Marco ; Nasini, Sofia ; Iaselli, Maria Novella ; Gobbi, Gabriella ; Squassina, Alessio ; Pisanu, Claudia ; Angeloni, Debora ; Dall'Acqua, Stefano ; De Gregorio, Danilo ; Paribello, Pasquale

The treatment of bipolar disorder (BD) still remains a challenge. Melatonin (MLT), acting through its two receptors MT₁ and MT₂, plays a key role in regulating circadian rhythms which are dysfunctional in BD. Using a translational approach, we examined the implication and potential of MT₁ receptors in the pathophysiology and psychopharmacology of BD. We employed a murine model of the manic phase of BD (Clock mutant (ClockΔ19) mice) to study the activation of MT₁ receptors by UCM871, a selective partial agonist, in behavioral pharmacology tests and in-vivo electrophysiology. We then performed a high-resolution Nuclear Magnetic Resonance study on isolated membranes to characterize the molecular mechanism of interaction of UCM871. Finally, in a cohort of BD patients, we investigated the link between clinical measures of BD and genetic variants located in the MT₁ receptor and CLOCK genes. We demonstrated that: 1) UCM871 can revert behavioral and electrophysiological abnormalities of ClockΔ19 mice; 2) UCM871 promotes the activation state of MT₁ receptors; 3) there is a significant association between the number of severe manic episodes and MLT levels, depending on the genetic configuration of the MT₁ rs2165666 variant. Overall, this work lends support to the potentiality of MT₁ receptors as target for the treatment of BD.

2023-09-01·Life Sciences

Agomelatine inhibits platelet aggregation through melatonin receptor-dependent and independent mechanisms

Article

作者: Vicente, Julia Modesto ; Lescano, Caroline Honaiser ; Mónica, Fabiola Zakia ; Anhê, Gabriel Forato ; Bordin, Silvana ; Gobbi, Gabriella

AIMSMelatonin is known to inhibit platelet aggregation induced by arachidonic acid (AA). In the present study we investigated whether agomelatine (Ago), an antidepressant with agonist activity at melatonin receptor 1 (MT1) and MT2 could reduce platelets aggregation and adhesion.MAIN METHODSHuman platelets from healthy donors were used to test the in vitro effects of Ago in the presence of different platelet activators. We performed aggregation and adhesion assays, thromboxane B₂ (TxB₂), cAMP and cGMP measurements, intra-platelet calcium registration and flow cytometry assays.KEY FINDINGSOur data revealed that different concentrations of Ago reduced AA- and collagen-induced human platelet aggregation in vitro. Ago also reduced AA-induced increase in thromboxane B₂ (TxB₂) production, intracellular calcium levels and P-selectin expression at plasma membrane. The effects of Ago in AA-activated platelets were likely dependent on MT1 as they were blocked by luzindole (a MT1/MT2 antagonist) and mimicked by the MT1 agonist UCM871 in a luzindole-sensitive manner. The MT2 agonist UCM924 was also able to inhibit platelet aggregation, but this response was not affected by luzindole. On the other hand, although UCM871 and UCM924 reduced collagen-induced platelet aggregation and adhesion, inhibition of collagen-induced platelet aggregation by Ago was not mediated by melatonin receptors because it was not affected by luzindole.SIGNIFICANCEThe present data show that Ago suppresses human platelet aggregation and suggest that this antidepressant may have the potential to prevent atherothrombotic ischemic events by reducing thrombus formation and vessel occlusion.

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适应症	最高研发状态	国家/地区	公司	日期
焦虑症	临床前	加拿大	McGill University	-
睡眠-觉醒节律障碍	临床前	加拿大	McGill University	-
温度障碍	临床前	加拿大	McGill University	-
抑郁症	药物发现	加拿大	McGill University	-