Effects of the 5-HT 6 receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex

Mørk, Arne; Russell, Rasmus Vinther; Jong, Inge E.M. de; Smagin, Gennady

doi:10.1016/j.ejphar.2017.02.010

Cited by 22 publications

(6 citation statements)

References 48 publications

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“…The combination of idalopirdine (2 mg/kg) and donepezil (0.3 mg/kg) was also evaluated. The choice of doses in this single-dose pharmacological study was based on previous studies that demonstrated that these doses of idalopirdine and donepezil result in clinically relevant exposure of both compounds, high 5-HT6 receptor occupancy up to an hour after administration and synergistic pharmacological effects on neuronal activity and neurotransmitter release in both the cortex and hippocampus (Amat-Foraster et al, 2016; Herrik et al, 2016; Mork et al, 2017). The vehicle control was 5% HpBeta cyclodextrin in distilled water.…”

Section: Methodsmentioning

confidence: 99%

“…Such potentiation of the effects of donepezil could contribute to the procognitive effects of idalopirdine observed in donepezil-treated AD patients. Further, studies also showed that idalopirdine monotherapy increases gamma oscillations and extracellular levels of monoamines and glutamate in the rat prefrontal cortex (Amat-Foraster et al, 2016; Mork et al, 2017), suggesting that the effects of idalopirdine extend beyond just amplification of the effects of donepezil. Indeed, 5-HT 6 receptor antagonists have been shown to regulate multiple neurotransmitter systems (reviewed in: Dawson, 2011).…”

Section: Introductionmentioning

confidence: 98%

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The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

et al. 2017

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The 5-HT6 receptor is a promising target for cognitive disorders, in particular for Alzheimer's disease (AD) and other CNS disorders. The high-affinity and selective 5-HT6 receptor antagonist idalopirdine (Lu AE58054) is currently in development for mild-moderate AD as adjunct therapy to acetylcholinesterase inhibitors (AChEIs). We studied the effects of idalopirdine alone and in combination with the AChEI donepezil on brain activity using BOLD (Blood Oxygen Level Dependent) functional magnetic resonance imaging (fMRI) in the awake rat. Idalopirdine (2 mg/kg, i.v.) alone had a modest effect on brain activity, resulting in activation of eight brain regions at the peak response. Of these, the cholinergic diagonal band of Broca, the infralimbic cortex, the ventral pallidum, the nucleus accumbens shell, and the magnocellular preoptic area were shared with the effects of donepezil (0.3 mg/kg, i.v.). Donepezil alone activated 19 brain regions at the peak response, including several cortical regions, areas of the septo-hippocampal system and the serotonergic raphe nucleus. When idalopirdine and donepezil were combined, there was a robust stimulation pattern with activation of 36 brain regions spread across the extended-amygdala-, striato-pallidal, and septo-hippocampal networks as well as the cholinergic system. These findings indicate that, whilst idalopirdine and donepezil recruit a number of overlapping regions including one of the forebrain cholinergic nuclei, the synergistic effect of both compounds extends beyond the cholinergic system and the effects of donepezil alone toward recruitment of multiple neural circuits and neurotransmitter systems. These data provide new insight into the mechanisms via which idalopirdine might improve cognition in donepezil-treated AD patients.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

et al. 2017

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“…Neurotransmitters are substances that transmit information between neurons in the brain, and they represent the basis of brain physiological functions . Studies have shown that DA and NE in the cerebrospinal fluid of patients with Alzheimer’s disease are abnormally expressed at low levels, which is significantly related to the severity of the disease. − In this study, the levels of NE, E, and DA in the brain tissue of AD rats were lower than those in the control group while the level of 5-HT was increased, and the possible mechanism is that the proportion of monoamine neurotransmitters in the normal nervous system is moderate and mutually restrictive . The results of this study showed that the levels of Asp, Gly, Tau, and γ-GABA in the brain tissue of AD rats were higher than those in the control group while the Glu concentrations were reduced.…”

Section: Resultsmentioning

confidence: 56%

((E)-N-(4-(((2-Amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) Ameliorated Aβ_1–42-Induced Alzheimer’s Disease in SD Rats by Inhibiting Oxidative Stress and Apoptosis

Ding

Wang

et al. 2021

ACS Chem. Neurosci.

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Our study investigated the protective effects of ((E)-N-(4-(((2-amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) 9b, a novel glycogen synthase kinase-3β (GSK-3β) inhibitor, on the learning and memory function of rats with amyloid-β 1−42 (Aβ 1−42 )-induced Alzheimer's disease (AD) and explored the possible mechanisms. Sixty male Sprague-Dawley (SD) rats were randomly divided into five groups: the control, Aβ, donepezil, and low-dose and highdose 9b groups. The rats in the Aβ, donepezil, and two 9b intervention groups received a single microinjection of 10 μg of Aβ 1−42 into the hippocampus followed by intragastric administration of 0.5% sodium carboxymethyl cellulose (CMC-Na), 12 (mg/kg)/d donepezil hydrochloride and 6 or 18 (mg/kg)/d compound 9b for 28 days, while the rats in the control group were treated with the vehicles. Learning and memory impairment were attenuated, the activities of superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), acetylcholinesterase (AChE), and adenosine triphosphatase (ATPase) in the brain tissue were significantly increased (p < 0.05), and the concentrations of Aβ 1−42 , phospho-tau (p-tau), and malondialdehyde (MDA) in the brain tissue were significantly decreased (p < 0.05) in the compound 9b group compared to the Aβ group. In addition, compound 9b regulated the imbalance in the concentrations of neurotransmitters and alleviated severe damage and apoptosis in the brains of the rats exposed to Aβ 1−42 . The novel GSK-3β inhibitor 9b could improve learning and memory dysfunction caused by Aβ 1−42 through its antioxidant and antiapoptotic effects.

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“…Approved AD drugs and 5-HT 6 R ligands in preclinical and *clinical trials and Se-containing compounds with neuroprotective activity. ,,− ,− ,,,− …”

Section: Introductionmentioning

confidence: 99%

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

Pyka,

Haberek,

Więcek

et al. 2024

J. Med. Chem.

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Alzheimer's disease (AD) has a complex and notfully-understood etiology. Recently, the serotonin receptor 5-HT 6 emerged as a promising target for AD treatment; thus, here a new series of 5-HT 6 R ligands with a 1,3,5-triazine core and selenoether linkers was explored. Among them, the 2-naphthyl derivatives exhibited strong 5-HT 6 R affinity and selectivity over 5-HT 1A R (13−15), 5-HT 7 R (14 and 15), and 5-HT 2A R (13). Compound 15 displayed high selectivity for 5-HT 6 R over other central nervous system receptors and exhibited low risk of cardio-, hepato-, and nephrotoxicity and no mutagenicity, indicating its "drug-like" potential. Compound 15 also demonstrated neuroprotection against rotenone-induced neurotoxicity as well as antioxidant and glutathione peroxidase (GPx)-like activity and regulated antioxidant and pro-inflammatory genes and NRF2 nuclear translocation. In rats, 15 showed satisfying pharmacokinetics, penetrated the blood−brain barrier, reversed MK-801-induced memory impairment, and exhibited anxiolytic-like properties. 15's neuroprotective and procognitive-like effects, stronger than those of the approved drug donepezil, may pave the way for the use of selenotriazines to inhibit both causes and symptoms in AD therapy.

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Effects of the 5-HT 6 receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex

Cited by 22 publications

References 48 publications

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

((E)-N-(4-(((2-Amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) Ameliorated Aβ_1–42-Induced Alzheimer’s Disease in SD Rats by Inhibiting Oxidative Stress and Apoptosis

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

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Effects of the 5-HT 6 receptor antagonist idalopirdine on extracellular levels of monoamines, glutamate and acetylcholine in the rat medial prefrontal cortex

Cited by 22 publications

References 48 publications

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

The Serotonin Receptor 6 Antagonist Idalopirdine and Acetylcholinesterase Inhibitor Donepezil Have Synergistic Effects on Brain Activity—A Functional MRI Study in the Awake Rat

((E)-N-(4-(((2-Amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) Ameliorated Aβ1–42-Induced Alzheimer’s Disease in SD Rats by Inhibiting Oxidative Stress and Apoptosis

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT6 Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease

Contact Info

Product

Resources

About

((E)-N-(4-(((2-Amino-5-phenylpyridin-3-yl)imino)methyl)pyridin-2-yl)cyclopropanecarboxamide) Ameliorated Aβ_1–42-Induced Alzheimer’s Disease in SD Rats by Inhibiting Oxidative Stress and Apoptosis

First-in-Class Selenium-Containing Potent Serotonin Receptor 5-HT₆ Agents with a Beneficial Neuroprotective Profile against Alzheimer’s Disease