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Numerous studies are focused on nanoparticle penetration into the brain functionalizing them with ligands useful to cross the blood–brain barrier. However, cell targeting is also crucial, given that cerebral pathologies frequently affect specific brain cells or areas. Functionalize nanoparticles with the most appropriate targeting elements, tailor their physical parameters, and consider the brain's complex anatomy are essential aspects for precise therapy and diagnosis. In this review, we addressed the state of the art on targeted nanoparticles for drug delivery in diseased brain regions, outlining progress, limitations, and ongoing challenges. We also provide a summary and overview of general design principles that can be applied to nanotherapies, considering the areas and cell types affected by the most common brain disorders. We then emphasize lingering uncertainties that hinder the translational possibilities of nanotherapies for clinical use. Finally, we offer suggestions for continuing preclinical investigations to enhance the overall effectiveness of precision nanomedicine in addressing neurological conditions. This article is categorized under:Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological DiseaseTherapeutic Approaches and Drug Discovery > Emerging Technologies [ABSTRACT FROM AUTHOR]

BackgroundThe neuropeptide oxytocin (OT) is a key regulator of social and emotional behaviors. The effects of OT are context dependent, and it has been proposed that OT increases the salience of both positive and negative social cues. Here we tested whether the bed nucleus of the stria terminalis (BNST) mediates anxiogenic effects of OT.MethodsFirst, we studied the effects of systemic administration of an OT receptor (OTR) antagonist L-368,899 on social behavior in male and female California mice exposed to social defeat. We examined the effect of L-368,899 on G protein activation and used early growth response factor 1 immunohistochemistry to identify potential sites of OTR action. Finally, we examined the effects of L-368,899 infused in the BNST on behavior.ResultsA single dose of systemic L-368,899 increased social approach in stressed female mice and decreased social approach in male mice naïve to defeat. L-368,899 prevented OT activation of G proteins and did not activate G proteins in the absence of OT. Intranasal OT, which reduces social approach in female mice but not male mice, increased early growth response factor 1 immunoreactivity in the nucleus accumbens core and anteromedial BNST in female mice but not in male mice. Stressed female mice that received an infusion of L-368,899 into the anteromedial BNST but not the nucleus accumbens core increased social approach and decreased social vigilance responses.ConclusionsOur results suggest that OTR activation in anteromedial BNST induces a vigilance response in which individuals avoid, yet attend to, unfamiliar social contexts. Our results suggest that OTR antagonists may have unappreciated therapeutic potential for stress-induced psychiatric disorders.

Intranasal administration of oxytocin (OXT) might be a promising new adjunctive therapy for mental disorders characterized by social behavioral alterations such as autism and schizophrenia. Despite promising initial studies in humans, it is not yet clear the specificity of the behavioral effects induced by chronic intranasal OXT and if chronic intranasal OXT could have different effects compared with single administration. This is critical for the aforementioned chronic mental disorders that might potentially involve life-long treatments. As a first step to address these issues, here we report that chronic intranasal OXT treatment in wild-type C57BL/6J adult mice produced a selective reduction of social behaviors concomitant to a reduction of the OXT receptors throughout the brain. Conversely, acute intranasal OXT treatment produced partial increases in social behaviors towards opposite-sex novel-stimulus female mice, while on the other hand, it decreased social exploration of same-sex novel stimulus male mice, without affecting social behavior towards familiar stimulus male mice. Finally, prolonged exposure to intranasal OXT treatments did not alter, in wild-type animals, parameters of general health such as body weight, locomotor activity, olfactory and auditory functions, nor parameters of memory and sensorimotor gating abilities. These results indicate that a prolonged over-stimulation of a 'healthy' oxytocinergic brain system, with no inherent deficits in social interaction and normal endogenous levels of OXT, results in specific detrimental effects in social behaviors. [ABSTRACT FROM AUTHOR]

Receptor coupling to different G-proteins and ß-arrestins has been described for a number of GPCRs (Gprotein- coupled receptors), suggesting a multi-state model of receptor activation in which each receptor can assume a number of different active conformations, each capable of promoting the coupling to a specific effector. Consistently, functional-selective ligands and biased agonists have been described to be able to induce and/or stabilize only a subset of specific active conformations. Furthermore, GPCR mutants deficient in selective coupling have been reported. Functional selective ligands and receptor mutants thus constitute unique tools to dissect the specific roles of different effectors, in particular among the Gi/o family. In the present mini-review, we focus on (i) the identification of functional selective OXT (oxytocin)- derived peptides capable of activating single Gi/o isoforms, namely G11 or G13; and (ii) the characterization of an SS (somatostatin) receptor SST5 mutant selectively impaired in its GoA coupling. These analogues and receptor mutants represent unique tools for examining the contribution of Gi/o isoforms in complex biological responses and open the way for the development of drugs with peculiar selectivity profiles. [ABSTRACT FROM AUTHOR]

Despite intensive investigation over the past 20 years, the specific role played by individual Gi protein family members in mediating complex cellular effects is still largely unclear. Therefore, we investigated the role of specific Gi proteins in mediating somatostatin (SS) effects in somatotroph cells. Because our previous data showed that SS receptor type 5 (SST5) carrying a spontaneous R240W mutation in the third intracellular loop had a similar ability to inhibit intracellular cAMP levels to the wild-type protein but failed to mediate inhibition of growth hormone (GH) release and cell proliferation, we used this model to check specific receptor-G-protein coupling by a bioluminescent resonance energy transfer analysis. In HEK293 cells, wild-type SST5 stimulated the activation of Gαi1-3 and GαoA, B, whereas R240W SST5 maintained the ability to activate Gαi1-3 and GαoB, but failed to activate the splicing variant GαoA. To investigate the role of the selective deficit in GαoA coupling, we co-transfected human adenomatous somatotrophs with SST5 and a pertussis toxin (PTX)-resistant GaoA (GαoA(PTX-r)) protein. In PTX-treated cells, GαoA(PTX-r) rescued the ability of the selective SST5 analog BIM23206 to inhibit extracellular signal-related kinase 1/2 (ERK1/2) phosphorylation, GH secretion and intracellular cAMP levels. Moreover, we demonstrated that silencing of GαoA completely abolished SST5-mediated inhibitory effects on GH secretion and ERK1/2 phosphorylation, but not on cAMP levels. In conclusion, by analysing the coupling specificity of human SST5 to individual Gαi and Gαo subunits, we identified a crucial role for GαoA signalling in human pituitary cells. [ABSTRACT FROM AUTHOR]

Primary ovarian insufficiency (POI) is a critical fertility defect characterized by an anticipated and silent impairment of the follicular reserve, but its pathogenesis is largely unexplained. The frequent maternal inheritance of POI together with a remarkable dependence of ovarian folliculogenesis upon mitochondrial biogenesis and bioenergetics suggested the possible involvement of a generalized mitochondrial defect. Here, we verified the existence of a significant correlation between blood and ovarian mitochondrial DNA (mtDNA) content in a group of women undergoing ovarian hyperstimulation (OH), and then aimed to verify whether mtDNA content was significantly altered in the blood cells of POI women. We recruited 101 women with an impaired ovarian reserve: 59 women with premature ovarian failure (POF) and 42 poor responders (PR) to OH. A Taqman copy number assay revealed a significant mtDNA depletion (P<0.001) in both POF and PR women in comparison with 43 women of similar age and intact ovarian reserve, or 53 very old women with a previous physiological menopause. No pathogenic variations in the mitochondrial DNA polymerase c (POLG) gene were detected in 57 POF or PR women with low blood mtDNA content. In conclusion, blood cell mtDNA depletion is a frequent finding among women with premature ovarian aging, suggesting that a still undetermined but generalized mitochondrial defect may frequently predispose to POI which could then be considered a form of anticipated aging in which the ovarian defect may represent the first manifestation. The determination of mtDNA content in blood may become an useful tool for the POI risk prediction. [ABSTRACT FROM AUTHOR]

Rationale: Oxytocin (OT) and arginine-vasopressin (AVP) regulate social behavior in mammals. Zebrafish ( Danio rerio) allows higher throughput and ease in studying human brain disorders. Objectives: This study investigated in zebrafish the effect of non-mammalian homologs isotocin (IT) and vasotocin (AVT) in comparison with OT/AVP on social behavior and fear response to predator. The mechanism was studied using the most human selective OT and AVP receptor antagonists. Methods: Zebrafish were injected i.m. with increasing doses (0.001-40 ng/kg) of the neuropeptides. DesGly-NH- d(CH)-[ d-Tyr,Thr]OVT) for OT receptor, SR 49059 for V1a subtype receptor, and SSR-149415 for V1b subtype receptor were injected i.m. 10 min before each agonist. Results: All the peptides increased social preference and reduced fear to predator response in a dose-dependent manner interpolated by symmetrical parabolas. AVT/AVP were more potent to elicit anxiolytic than social effect while IT and OT were equally potent. All the antagonists dose-dependently inhibited both the effects induced by the neuropeptides. The ratio between the ED50 obtained for blocking the OT-induced effects on social preference and fear response to predator was very high only for desglyDTTyrOVT (160). SR49059 showed the highest ratio in blocking AVP-induced effects (807). The less selective antagonist appeared to be SSR149415. Conclusions: For the first time, IT/AVT and OT/AVP were found to modulate in zebrafish, social behavior, unrelated to sex, and fear to predator response through at least two different receptors. Zebrafish is confirmed as a valid, reliable model to study deficit in social behavior characteristic of some psychiatric disorders. [ABSTRACT FROM AUTHOR]

A correction to the article "Specific roles of Gi protein family members revealed by dissecting SST5 coupling in human pituitary cells" by Erika Peverelli and colleagues that was published in previous issue is presented.

Numerous studies are focused on nanoparticle penetration into the brain functionalizing them with ligands useful to cross the blood-brain barrier. However, cell targeting is also crucial, given that cerebral pathologies frequently affect specific brain cells or areas. Functionalize nanoparticles with the most appropriate targeting elements, tailor their physical parameters, and consider the brain's complex anatomy are essential aspects for precise therapy and diagnosis. In this review, we addressed the state of the art on targeted nanoparticles for drug delivery in diseased brain regions, outlining progress, limitations, and ongoing challenges. We also provide a summary and overview of general design principles that can be applied to nanotherapies, considering the areas and cell types affected by the most common brain disorders. We then emphasize lingering uncertainties that hinder the translational possibilities of nanotherapies for clinical use. Finally, we offer suggestions for continuing preclinical investigations to enhance the overall effectiveness of precision nanomedicine in addressing neurological conditions. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Neurological Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies., (© 2024 The Author(s). WIREs Nanomedicine and Nanobiotechnology published by Wiley Periodicals LLC.)

Chemokines are key regulators of leukocyte migration and play fundamental roles in immune responses. The chemokine system includes a set of over 40 ligands which engage in a promiscuous fashion a panel of over 25 receptors belonging to a distinct family of 7 transmembrane-domain receptors (7TM) widely expressed on a variety of cells. Although responses evoked by chemokine receptors have long been considered the result of balanced activation of the G protein- and β-arrestin-dependent signaling modules, evidence is accumulating showing that these receptors are capable, as other 7TMs, to activate different signaling modules in a ligand- and cell/tissue-specific manner. This biased signaling, or functional selectivity, confers a hitherto largely uncharacterized level of complexity to the chemokine system and challenges our present understanding of its redundancy. At the same time, it also provides new insights of relevance for chemokine receptors targeting drug development plans. Here, we provide current methods to study biased signaling of chemokine receptors by dissecting G proteins and β-arrestins activation upon chemokine stimulation., (© 2016 Elsevier Inc. All rights reserved.)

The ability of GPCRs to assemble into multimeric complexes is one of the most recently studied and discussed topics for many reasons, including the possibility that GPCR assemblies show a distinct pharmacological profile offering an innovative avenue for the drug synthesis. In addition, the possible differential coupling of monomeric versus multimeric GPCRs to G proteins and other downstream partners, as well as the signaling, the regulation through desensitization and internalization, and the subcellular localization can well represent additional factors that contribute to GPCR-mediated physiopathological states. The standard biochemical techniques used to identify GPCR interactions, such as coimmunoprecipitation, have obvious limitations owing to the use of nonphysiological buffers and detergents that disrupt the natural cell environment and biological interactions and preclude the analysis of subcellular localization and compartmentalization. In the past decade, new biophysical proximity assays based on the resonance energy transfer (RET) between two chromophores allow the study of dimerization in intact living cells, thus proving more information on GPCR physiological roles. In this chapter, we detail the application of two RET techniques based on fluorescence (FRET) and bioluminescence (BRET) to the study of GPCR dimerization and describe the results that can be obtained., (Copyright © 2013 Elsevier Inc. All rights reserved.)