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Pimavanserin, a 5HT_2A receptor inverse agonist, rapidly suppresses A? production and related pathology in a mouse model of Alzheimer's disease.

ABSTRACT: Amyloid-? (A?) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate A? generation, we postulated that 5HT_2A -Rs may regulate A? as well. We treated APP/PS1 transgenic mice with the selective 5HT_2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) A? levels in real-time using in vivo microdialysis. Both compounds reduced ISF A? levels by almost 50% within hours, but had no effect on A? levels in 5HT_2A -R knock-out mice. The A?-lowering effects of Pimavanserin were blocked by extracellular-regulated kinase (ERK) and NMDA receptor inhibitors. Chronic administration of Pimavanserin by subcutaneous osmotic pump to aged APP/PS1 mice significantly reduced CSF A? levels and A? pathology and improved cognitive function in these mice. Pimavanserin is FDA-approved to treat Parkinson's disease psychosis, and also has been shown to reduce psychosis in a variety of other dementia subtypes including Alzheimer's disease. These data demonstrate that Pimavanserin may have disease-modifying benefits in addition to its efficacy against neuropsychiatric symptoms of Alzheimer's disease. Read the Editorial Highlight for this article on page 560.

SUBMITTER: Yuede CM

PROVIDER: S-EPMC7946332 | biostudies-literature | 2021 Mar

REPOSITORIES: biostudies-literature

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Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease.

Yuede Carla M CM Wallace Clare E CE Davis Todd A TA Gardiner Woodrow D WD Hettinger Jane C JC Edwards Hannah M HM Hendrix Rachel D RD Doherty Brookelyn M BM Yuede Kayla M KM Burstein Ethan S ES Cirrito John R JR

Journal of neurochemistry 20210110 5

Amyloid-β (Aβ) peptide aggregation into soluble oligomers and insoluble plaques is a precipitating event in the pathogenesis of Alzheimer's disease (AD). Given that synaptic activity can regulate Aβ generation, we postulated that 5HT2A -Rs may regulate Aβ as well. We treated APP/PS1 transgenic mice with the selective 5HT2A inverse agonists M100907 or Pimavanserin systemically and measured brain interstitial fluid (ISF) Aβ levels in real-time using in vivo microdialysis. Bot ...[more]

PMID: 33278025

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Project description:Ariadne is a non-hallucinogenic analog in the phenylalkylamine chemical class of psychedelics that is closely related to an established synthetic hallucinogen, 2,5-dimethoxy-4-methyl-amphetamine (DOM), differing only by one methylene group in the α-position to the amine. Ariadne has been tested in humans including clinical trials at Bristol-Myers Company that indicate a lack of hallucinogenic effects and remarkable therapeutic effects, such as rapid remission of psychotic symptoms in schizophrenics, relaxation in catatonics, complete remission of symptoms in Parkinson's disease (PD), and improved cognition in geriatric subjects. Despite these provocative clinical results, the compound has been abandoned as a drug candidate and its molecular pharmacology remained unknown. Here, we report a detailed examination of the in vitro and in vivo pharmacology of Ariadne and its analogs, and propose a molecular hypothesis for the lack of hallucinogenic effects and the therapeutic potential of this compound class. We also provide a summary of previous clinical and preclinical results to contextualize the molecular signaling data. Our results show that Ariadne is a serotonin 5-HT2 receptor agonist, exhibits modest selectivity over 5-HT1 receptors, has no relevant activity at 5-HT4,5,7 and other aminergic receptors, and no substantial affinity at plasma membrane monoamine transporters. Compared to DOM, Ariadne shows lower signaling potency and efficacy in multiple signaling pathways examined (Gq, G11, and β-arrestin2) coupled to 5-HT2A receptors. We confirmed the shift in signaling for an α-propyl analog and provide a molecular docking rationale for the progressive decrease in signaling potency with the growing length of the α-substituent. Ariadne versus DOM exhibits no apparent change in the relative preference between Gq/11 activation and β-arrestin2 recruitment; instead, there is a small but consistent drop in efficacy in these signaling channels. Ariadne acts as a 5-HT2A agonist in vivo in mice and shows markedly attenuated head twitch response (HTR) in comparison to its hallucinogenic analogs, consistent with previous studies in rabbits, cats, and dogs. Hence, we propose the lower 5-HT2A receptor signaling efficacy of this compound class as an explanatory model for the lack of hallucinogenic effects of Ariadne in humans and the dramatically attenuated hallucinosis-like effects in animals (5-HT2A signaling efficacy hypothesis). In terms of reverse translation of the noted clinical therapeutic effects, we used an auxilin knockout model of Parkinson's disease where Ariadne rescued severe motor deficits in this mouse line, on par with the effects of l-DOPA, a notable finding considering Ariadne's lack of activity at dopamine receptors and transporters. Ariadne emerges as a prototype of a new drug class, non-hallucinogenic 5-HT2A agonists, with considerable therapeutic potential across psychiatric and neurological indications.

Project description:Background:All current approved antipsychotic drugs against schizophrenia spectrum disorders share affinity for the dopamine receptor (D2R). However, up to one-third of these patients respond insufficiently, and in some cases, side-effects outweigh symptom reduction. Previous data have suggested that a subgroup of antipsychotic-naïve patients will respond to serotonin 2A receptor (2AR) blockade. Aims:This investigator-initiated, translational, proof-of-concept study has overall two aims; 1) To test the clinical effectiveness of monotherapy with the newly approved drug against Parkinson's disease psychosis, pimavanserin, in antipsychotic-free patients with first-episode schizophrenia spectrum disorders; 2) To characterize the neurobiological profile of responders to pimavaserin. Materials and Equipment:Forty patients will be enrolled in this 6-week open label, one-armed trial with the selective serotonin 2AR antagonist (pimavanserin 34 mg/day). At baseline, patients will undergo: positron emission tomography (PET) imaging of the serotonin 2AR using the radioligand [¹¹C]Cimbi-36; structural magnetic resonance imaging (MRI); MR spectroscopy of cerebral glutamate levels and diffusion tensor imaging; cognitive and psychopathological examinations; electrocardiogram, and blood sampling for genetic- and metabolic analyses. Outcome Measures:The primary clinical endpoint will be reduction in the Positive and Negative Syndrome Scale (PANSS) positive score. Secondary clinical endpoints comprise multiple clinical ratings (positive and negative symptoms, depressive-, obsessive-compulsive symptoms, quality of life, social functioning, sexual functioning, and side-effects). PET, MRI, and cognitive parameters will be used for in-depth neuropsychiatric characterization of pimavanserin response. Anticipated Results:Clinically, we expect pimavanserin to reduce psychotic symptoms with similar effect as observed with conventional antipsychotics, for which we have comparable historical data. We expect pimavanserin to induce minimal side-effects. Neurobiologically, we expect psychotic symptom reduction to be most prominent in patients with low frontal serotonin 2AR binding potential at baseline. Potential pro-cognitive and brain structural effects of pimavanserin will be explored. Perspectives:Sub-Sero will provide unique information about the role serotonin 2AR in antipsychotic-free, first-episode psychosis. If successful, Sub-Sero will aid identification of a "serotonergic subtype" of schizophrenia spectrum patients, thereby promoting development of precision medicine in clinical psychiatry. Clinical Trial Registration:ClinicalTrials, identifier NCT03994965.

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Pimavanserin, a 5HT_2A receptor inverse agonist, rapidly suppresses A? production and related pathology in a mouse model of Alzheimer's disease.

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Pimavanserin, a 5HT<sub>2A</sub> receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease.

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Pimavanserin, a 5HT2A receptor inverse agonist, rapidly suppresses A? production and related pathology in a mouse model of Alzheimer's disease.

Publications

Pimavanserin, a 5HT<sub>2A</sub> receptor inverse agonist, rapidly suppresses Aβ production and related pathology in a mouse model of Alzheimer's disease.

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OmicsDI is part of the ELIXIR infrastructure

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Pimavanserin, a 5HT_2A receptor inverse agonist, rapidly suppresses A? production and related pathology in a mouse model of Alzheimer's disease.