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Abstract The stomach-derived hormone ghrelin regulates essential physiological functions. The ghrelin receptor (GHSR) has ligand-independent actions; therefore, GHSR gene deletion may be a reasonable approach to investigate the role of this system in feeding behaviors and diet-induced obesity (DIO). Here, we investigate the effects of a long-term (12-month) high-fat (HFD) versus regular diet on obesity-related measures in global GHSR-KO and wild-type (WT) Wistar male and female rats. Our main findings are that the GHSR gene deletion protects against DIO and decreases food intake during HFD in male but not in female rats. GHSR gene deletion increases thermogenesis and brain glucose uptake in male rats and modifies the effects of HFD on brain glucose metabolism in a sex-specific manner, as assessed with small animal positron emission tomography. We use RNA-sequencing to show that GHSR-KO rats have upregulated expression of genes responsible for fat oxidation in brown adipose tissue. Central administration of a novel GHSR inverse agonist, PF-5190457, attenuates ghrelin-induced food intake, but only in male, not in female mice. HFD-induced binge-like eating is reduced by inverse agonism in both sexes. Our results support GHSR as a promising target for new pharmacotherapies for obesity.

Abstract Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM. PSAM4 is a triple mutant PSAM derived from the α7 nicotinic receptor (α7L131G,Q139L,Y217F). Although having no constitutive activity as a ligand-gated ion channel, PSAM4 has been coupled to the serotonin 5-HT3 receptor (5-HT3R) and to the glycine receptor (GlyR). Treatment with the partner PSEM to activate PSAM4-5-HT3 or PSAM4-GlyR, causes neuronal activation or silencing, respectively. A suitably designed radioligand may enable selective visualization of the expression and location of PSAMs with positron emission tomography (PET). Here, we evaluated uPSEM792, an ultrapotent PSEM for PSAM4-GlyR, as a possible lead for PET radioligand development. We labeled uPSEM792 with the positron-emitter, carbon-11 (t 1/2 = 20.4 min), in high radiochemical yield by treating a protected precursor with [11C]iodomethane followed by base deprotection. PET experiments with [11C]uPSEM792 in rodents and in a monkey transduced with PSAM4-GlyR showed low peak radioactivity uptake in brain. This low uptake was probably due to high polarity of the radioligand, as evidenced by physicochemical measurements, and to the vulnerability of the radioligand to efflux transport at the blood–brain barrier. These findings can inform the design of a more effective PSAM4 based PET radioligand, based on the uPSEM792 chemotype.

Abstract Cocaine binds to the dopamine (DA) transporter (DAT) to regulate cocaine reward and seeking behavior. Zinc (Zn2+) also binds to the DAT, but the in vivo relevance of this interaction is unknown. We found that Zn2+ concentrations in postmortem brain (caudate) tissue from humans who died of cocaine overdose were significantly lower than in control subjects. Moreover, the level of striatal Zn2+ content in these subjects negatively correlated with plasma levels of benzoylecgonine, a cocaine metabolite indicative of recent use. In mice, repeated cocaine exposure increased synaptic Zn2+ concentrations in the caudate putamen (CPu) and nucleus accumbens (NAc). Cocaine-induced increases in Zn2+ were dependent on the Zn2+ transporter 3 (ZnT3), a neuronal Zn2+ transporter localized to synaptic vesicle membranes, as ZnT3 knockout (KO) mice were insensitive to cocaine-induced increases in striatal Zn2+. ZnT3 KO mice showed significantly lower electrically evoked DA release and greater DA clearance when exposed to cocaine compared to controls. ZnT3 KO mice also displayed significant reductions in cocaine locomotor sensitization, conditioned place preference (CPP), self-administration, and reinstatement compared to control mice and were insensitive to cocaine-induced increases in striatal DAT binding. Finally, dietary Zn2+ deficiency in mice resulted in decreased striatal Zn2+ content, cocaine locomotor sensitization, CPP, and striatal DAT binding. These results indicate that cocaine increases synaptic Zn2+ release and turnover/metabolism in the striatum, and that synaptically released Zn2+ potentiates the effects of cocaine on striatal DA neurotransmission and behavior and is required for cocaine-primed reinstatement. In sum, these findings reveal new insights into cocaine’s pharmacological mechanism of action and suggest that Zn2+ may serve as an environmentally derived regulator of DA neurotransmission, cocaine pharmacodynamics, and vulnerability to cocaine use disorders.

Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) are a powerful tool for neuroscience, but the standard DREADD ligand, CNO, has significant drawbacks. Here the authors report two novel high-potency DREADD ligands and a novel DREADD radiotracer for imaging purposes.

Alcoholic hepatitis, a common cause of liver failure, lacks effective treatment. Here, the authors show altered hepatic HNF4a isoform expression and hypermethylation of its target genes in patients. HNF4a dysregulation is improved in vitro by TGFb or PPARg modulation suggesting potential therapeutic avenues.

Background: Tuberculum sellae meningiomas (TSM) account for 3–10% of intracranial meningiomas. Visual loss is the presenting symptom in up to 80% of cases. Surgical management poses a great challenge due to tumor proximity to neurovascular structures such as the optic nerve and the internal carotid artery (ICA); hence, there is controversy regarding the optimal approach. The aim of this study is to determine differences in visual outcomes between transcranial (TCA) and endoscopic endonasal (EEA) approaches. Methods: A retrospective study including 29 patients with TSM surgically treated by TCA or EEA between 2011 and 2023 in a single referral center was conducted. Pre-and post-operative neuro-ophthalmologic evaluations, focusing on visual acuity and campimetry, were evaluated. Results: Sixteen (55.16%) patients were intervened through a TCA and the remaining 13 (44.84%) via an EEA. The lesions in each group were similar in terms of pre- operative volume (15.12 vs 12.9 cm3, p = 0.497) and neurovascular invasion (optic canal invasion 48.26 vs 41.37%, p = 0.664; ICA 44.81 vs 31.03%, p = 0.797). There were no significant differences in visual outcomes between both approaches; TCA presented an improvement of 5.18 points in visual fields (p = 0.140), whereas EEA had an improvement of 17.39 points in visual acuity (p = 0.114). Conclusion: EEA seems to offer greater improvement in visual acuity than TCA. However, the ideal approach should be individualized; taking into account the tumor’s volume and invasiveness, as well as the patient's visual complaints.

Craniopharyngiomas (CPs) are Rathke’s cleft-derived benign tumors originating most commonly in the dorsum sellae and representing 2% of intracranial neoplasms. CPs represent one of the more complex intracranial tumors due to their invasive nature, encasing neurovascular structures of the sellar and parasellar regions, making its resection a major challenge for the neurosurgeon with important postoperative morbidity. Nowadays, an endoscopic endonasal approach (EEA) provides an “easier” way for CPs resection allowing a direct route to the tumor with direct visualization of the surrounding structures, diminishing inadvertent injuries, and providing a better outcome for the patient. In this article, we include a comprehensive description of the EEA technique and nuances in CPs resection, including three illustrated clinical cases.

Objetivo: Evaluar y comparar desenlaces de pacientes con aneurismas de arteria cerebral media (ACM) tratados mediante clipaje microquirúrgico o terapia endovascular, y proponer un algoritmo de tratamiento basado en evidencia. Material y métodos: Estudio retrospectivo de 77 pacientes con 95 aneurismas de ACM. Se recabaron variables demográficas, clínicas y morfológicas de los aneurismas tratados. Se dividieron a los pacientes en dos grupos dependiendo del tratamiento recibido y se compararon los desenlaces clínicos y radiológicos al final del seguimiento a un año entre ambos grupos. Resultados: La edad promedio fue 51.4 años. 50 pacientes (65%) fueron sometidos a clipaje microquirúrgico y 27 (35%) a terapia endovascular. 54 pacientes (70%) presentaron hemorragia subaracnoidea, quienes fueron tratados mediante microcirugía en mayor proporción que aquellos con aneurismas no rotos. Los desenlaces clínicos, incluyendo el estado funcional, fueron similares entre ambos grupos al año de seguimiento, aún tras ajustar el análisis por presentación clínica. El grupo de microcirugía presentó una menor proporción de aneurismas residuales (OR = 0.09; p < 0.001). Conclusiones: En pacientes con aneurismas de ACM, los desenlaces clínicos a un año son similares entre clipaje microquirúrgico y terapia endovascular. Sin embargo, la microcirugía se asocia a un menor riesgo de aneurismas residuales.

Pituitary adenomas (PAs) can be unpredictable and aggressive tumors. No reliable markers of their biological behavior have been found. Here, a proteomic analysis was applied to identify proteins in the expression profile between invasive and non-invasive PAs to search for possible biomarkers. A histopathological and immunohistochemical (adenohypophyseal hormones, Ki-67, p53, CD34, VEGF, Flk1 antibodies) analysis was done; a proteomic map was evaluated in 64 out of 128 tumors. There were 107 (84%) invasive and 21 (16%) non-invasive PAs; 80.5% belonged to III and IV grades of the Hardy–Vezina classification. Invasive PAs (n = 56) showed 105 ± 43 spots; 86 ± 32 spots in non-invasive PAs (n = 8) were observed. The 13 most prominent spots were selected and 11 proteins related to neoplastic process in different types of tumors were identified. Hint1 (Histidine triad nucleotide-binding protein 1) high expression in invasive PA was found (11.8 ± 1.4, p = 0.005), especially at high index (>10; p = 0.0002). High Hint1 expression was found in invasive VEGF positive PA (13.8 ± 2.3, p = 0.005) and in Flk1 positive PA (14.04 ± 2.28, p = 0.006). Hint1 is related to human tumorigenesis by its interaction with signaling pathways and transcription factors. It could be related to invasive behavior in PAs. This is the first report on Hint expression in PAs. More analysis is needed to find out the possible role of Hint in these tumors.