👤 Andreas Meisel

Hypoactive sexual desire disorder (HSDD) is the most reported sexual dysfunction among premenopausal women worldwide. Bremelanotide, trade name Vyleesi, has been approved by the United States Food and Drug Administration to treat HSDD. However, despite approval, very little is known about its neurobiological mechanism of action. In this study, we utilized a female Syrian hamster model to investigate the effects of bremelanotide on melanocortin receptor expression in the mesolimbic dopamine system and sexual reward. We found that the majority of melanocortin 3 and 4 (MC4R) receptor mRNA is expressed in dopamine neurons in the ventral tegmental area (VTA). Fewer neurons express MC4R in the nucleus accumbens (NAc) or dorsal striatum, where they rarely colocalize with neurons expressing dopamine D1 or D2 receptors. Instead, MC4R mRNA is expressed in nucleus accumbens interneurons. Neither the low nor the high dose of bremelanotide had an effect on the expression of melanocortin receptor mRNA in the mesolimbic dopamine system. Finally, sexual experience resulted in a conditioned place preference (CPP) in female Syrian hamsters, though bremelanotide treatment failed to enhance sexual reward in this test. The results of this study are discussed in conjunction with similar studies in rats, with the conclusion that bremelanotide does not act on the VTA-NAc reward circuit and does not enhance the rewarding effects of sexual interactions. Show less

Myasthenia gravis (MG) lacks disease-specific biomarkers that can support monitoring of disease activity or guide treatment decisions. This study aimed to validate serum inflammatory proteins as MG-specific biomarkers by comparing their specificity to controls and individuals with other autoimmune neurological disorders, including multiple sclerosis (MS) and chronic inflammatory demyelinating polyneuropathy (CIDP). In this multicentre cross-sectional study, serum from 200 acetylcholine receptor antibody seropositive (AChR+) MG patients, 192 matched controls, 93 MS patients, and 51 CIDP patients was analyzed using a 92-plex inflammation panel (Olink PEA). Logistic regression, principal component analysis, and Boruta machine learning algorithms identified differentially expressed proteins. MG subgroups were defined by age at onset, disease severity, and immunosuppressive treatment. Fourteen proteins significantly distinguished MG from controls, including AXIN1 (OR: 0.24), IL7 (OR: 9.38), ST1A1 (OR:0.42), IL10 (OR:3.62), CASP-8 (OR:1.61), and TNFSF14 (OR:0.50) (Bonferroni-corrected p < 0.00135). AXIN1, ST1A1, STAMBP, CDCP1, and SIRT2 were specific for MG, separating it from MS and CIDP. Shared markers across disorders included IL6, IL8, STAMBP, and TNFSF14. A 15-protein profile, including FGF-23 and CXCL9, correlated with MG severity. Subgroup analyses revealed distinct protein patterns by age and treatment. TRANCE and CD6 were reduced in immunosuppressed patients, whereas EN-RAGE, IL10, and TNFRSF9 varied in those receiving biologicals. This study validates the MG-specific serum proteomic biomarkers AXIN1, STAMBP, ST1A1, CDCP1, and SIRT2 and identifies signatures associated with severity, onset, and treatment. These findings support the use of blood-based biomarkers for monitoring and stratification in MG clinical trials and care. Show less

Melanocortin 3 receptors (MC3R) and melanocortin 4 receptors (MC4R) are vital in regulating a variety of functions across many species. For example, the dysregulation of these receptors results in obesity and dysfunction in sexual behaviors. Only a handful of studies have mapped the expression of MC3R and MC4R mRNA across the central nervous system, with the primary focus on mice and rats. Because Syrian hamsters are valuable models for functions regulated by melanocortin receptors, our current study maps the distribution of MC3R and MC4R mRNA in the Syrian hamster telencephalon, diencephalon, and midbrain using RNAscope. We found that the expression of MC3R mRNA was lowest in the telencephalon and greatest in the diencephalon, whereas the expression of MC4R mRNA was greatest in the midbrain. A comparison of these findings to previous studies found that MC3R and MC4R expression is similar in some brain regions across species and divergent in others. In addition, our study identifies novel brain regions for the expression of MC3Rs and MC4Rs, and identifies cells that co-express bothMC3 and MC4 receptors within certain brain regions. Show less