Distribution, physiology and pharmacology of relaxin‐3/RXFP3 systems in brain

Ma, Sherie; Smith, Craig; Błasiak, Anna; Gundlach, Andrew L.

doi:10.1111/bph.13659

Cited by 72 publications

(91 citation statements)

References 139 publications

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“…Because rats have been widely used in previous investigations of relaxin-3 and relaxin-3 B-chain peptides (see Kumar et al, 2017;Ma, Smith, Blasiak, & Gundlach, 2017), rats were used to allow comparison of the current results with the previous literature. Rats were also appropriate because they have been widely used in translational pharmacological research on anxiety, depression, and other neuropsychiatric disorders (Lezak, Missig, & Carlezon, 2017;Pollak, Rey, & Monje, 2010).…”

Section: Compliance With Requirements For Studies Using Animalsmentioning

confidence: 99%

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

Marwari

Poulsen

Shih

et al. 2019

British J Pharmacology

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Background and PurposeDepression and anxiety are common causes of disability, and innovative tools and potential pharmacological targets are actively sought for prevention and treatment. Therapeutic strategies targeting the relaxin‐3 peptide or its primary endogenous receptor, RXFP3, for the treatment of major depression and anxiety disorders have been limited by a lack of compounds with drug‐like properties. We proposed that a hydrocarbon‐stapled mimetic of relaxin‐3, when administered intranasally, might be uniquely applicable to the treatment of these disorders.Experimental ApproachWe designed a series of hydrocarbon‐stapled relaxin‐3 mimetics and identified the most potent compound using in vitro receptor binding and activation assays. Further, we assessed the effect of intranasal delivery of relaxin‐3 and the lead stapled mimetic in rat models of anxiety and depression.Key ResultsWe developed an i,i+7 stapled relaxin‐3 mimetic that manifested a stabilized α‐helical structure, proteolytic resistance, and confirmed agonist activity in receptor binding and activation in vitro assays. The stapled peptide agonist enhanced food intake after intracerebral infusion in rats, confirming in vivo activity. We showed that intranasal delivery of the lead i,i+7 stapled peptide or relaxin‐3 had orexigenic effects in rats, indicating a potential clinically translatable route of delivery. Further, intranasal administration of the lead i,i+7 stapled peptide exerted anxiolytic and antidepressant‐like activity in anxiety‐ and depression‐related behaviour paradigms.Conclusions and ImplicationsOur preclinical findings demonstrate that targeting the relaxin‐3/RXFP3 receptor system via intranasal delivery of an i,i+7 stapled relaxin‐3 mimetic may represent an effective treatment approach for depression, anxiety, and related neuropsychiatric disorders.

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Section: Compliance With Requirements For Studies Using Animalsmentioning

confidence: 99%

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

Marwari

Poulsen

Shih

et al. 2019

British J Pharmacology

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“…The relaxin‐3/relaxin‐3 receptor (RXFP3) system represents another example of a modulatory peptide/receptor system that is versatile in function, 42,43 although with a far more discrete, restricted anatomical distribution of peptide‐positive neurones in the brain than many other peptides 42 . Indeed, a broad network of relaxin‐3‐containing neuronal projections arise from several small groups of neurones in the midbrain and brainstem, with the largest and best‐characterised located within the nucleus incertus and others within the pontine raphe nucleus and the ventrolateral PAG 44 .…”

Section: Relaxin: a Prototype ‘Brain Stem Ascending’ Regulatory Peptidementioning

confidence: 99%

“…Indeed, a broad network of relaxin‐3‐containing neuronal projections arise from several small groups of neurones in the midbrain and brainstem, with the largest and best‐characterised located within the nucleus incertus and others within the pontine raphe nucleus and the ventrolateral PAG 44 . Nucleus incertus relaxin‐3 neurones are responsive to peripheral and sensory and stress‐related inputs, 45 and project widely to RXFP3‐rich areas throughout the brain, where they influence arousal, 46 hypothalamic, limbic and sensory activity, 47,48 as well as spatial memory and navigation via interactions with the septohippocampal system 42,49,50 . The pharmacology of RXFP3 51 has developed progressively over the last decade, driven by the production of RXFP3‐selective chimeric, truncated, stapled and single‐chain peptides, 52,53 as well as the recent report of a potent, small organic molecule agonist 54 .…”

Section: Relaxin: a Prototype ‘Brain Stem Ascending’ Regulatory Peptidementioning

confidence: 99%

Regulatory peptides and systems biology: A new era of translational and reverse‐translational neuroendocrinology

Eiden

Gundlach

Grinevich

et al. 2020

J Neuroendocrinology

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Recently, there has been a resurgence in regulatory peptide science as a result of three converging trends. The first is the increasing population of the drug pipeline with peptide-based therapeutics, mainly in, but not restricted to, incretin-like molecules for treatment of metabolic disorders such as diabetes. The second is the development of genetic and optogenetic tools enabling new insights into how peptides actually function within brain and peripheral circuits to accomplish homeostatic and allostatic regulation. The third is the explosion in defined structures of the G-protein coupled receptors to which most regulatory peptides bind and exert their actions.These trends have closely wedded basic systems biology to drug discovery and development, creating a "two-way street" on which translational advances travel from basic research to the clinic, and, equally importantly, "reverse-translational" information is gathered, about the molecular, cellular and circuit-level mechanisms of action of regulatory peptides, comprising information required for the fine-tuning of drug development through testing in animal models. This review focuses on a small group of 'influential' peptides, including oxytocin, vasopressin, pituitary adenylate cyclase-activating polypeptide, ghrelin, relaxin-3 and glucagon-like peptide-1, and how basic discoveries and their application to therapeutics have intertwined over the past decade. K E Y W O R D S neuroendocrinology, regulatory peptide, therapeutics, translation How to cite this article: Eiden LE, Gundlach AL, Grinevich V, et al. Regulatory peptides and systems biology: A new era of translational and reverse-translational neuroendocrinology.

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“…Smaller nuclei of relaxin-3 neurons are also present in various areas throughout the brain, such as in the periaqueductal grey, pontine raphe and an area dorsal to the substantia nigra (Tanaka et al 2005;Ma et al 2007). Relaxin-3 has been implicated in several behaviours consistent with its proposed role as an arousal system (Smith et al 2014b;Ma et al 2016). For example, characterisation of relaxin-3 knockout (KO) and relaxin-3 receptor (RXFP3) KO mice revealed a hypoactive phenotype present during the dark phase (Smith et al 2012;Hosken et al 2015), and RXFP3 activation in rats is associated with an increase in food intake (Ganella et al 2012), suggesting involvement in motivated behaviours.…”

Section: Introductionmentioning

confidence: 97%

Relaxin-3/RXFP3 signalling in mouse hypothalamus: no effect of RXFP3 activation on corticosterone, despite reduced presynaptic excitatory input onto paraventricular CRH neurons in vitro

et al. 2017

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Relaxin-3/RXFP3 signalling is proposed to be involved in the neuromodulatory control of arousal- and stress-related neural circuits. Furthermore, previous studies in rats have led to the proposal that relaxin-3/RXFP3 signalling is associated with activation of the hypothalamic-pituitary-adrenal axis, but direct evidence for RXFP3-related actions on the activity of hypothalamic corticotropin-releasing hormone (CRH) neurons is lacking. In this study, we investigated characteristics of the relaxin-3/RXFP3 system in mouse hypothalamus. Administration of an RXFP3 agonist (RXFP3-A2) intra-cerebroventricularly or directly into the paraventricular nucleus of hypothalamus (PVN) of C57BL/6J mice did not alter corticosterone levels. Similarly, there were no differences between serum corticosterone levels in Rxfp3 knockout (C57BL/6J) and wild-type mice at baseline and after stress, despite detection of the predicted stress-induced increases in serum corticosterone. We examined the nature of the relaxin-3 innervation of PVN in wild-type mice and in Crh-IRES-Cre;Ai14 mice that co-express the tdTomato fluorophore in CRH neurons, identifying abundant relaxin-3 fibres in the peri-PVN region, but only sparse fibres associated with densely packed CRH neurons. In whole-cell voltage-clamp recordings of tdTomato-positive CRH neurons in these mice, we observed a reduction in sEPSC frequency following local application of RXFP3-A2, consistent with an activation of RXFP3 on presynaptic glutamatergic afferents in the PVN region. These studies clarify the relationship between relaxin-3/RXFP3 inputs and CRH neurons in mouse PVN, with implications for the interpretation of current and previous in vivo studies and future investigations of this stress-related signalling network in normal and transgenic mice, under normal and pathological conditions.

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Distribution, physiology and pharmacology of relaxin‐3/RXFP3 systems in brain

Abstract: This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.

Cited by 72 publications

References 139 publications

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

Intranasal administration of a stapled relaxin‐3 mimetic has anxiolytic‐ and antidepressant‐like activity in rats

Regulatory peptides and systems biology: A new era of translational and reverse‐translational neuroendocrinology

Relaxin-3/RXFP3 signalling in mouse hypothalamus: no effect of RXFP3 activation on corticosterone, despite reduced presynaptic excitatory input onto paraventricular CRH neurons in vitro

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