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Serotonin, or 5-hydroxytryptamine (5-HT), is an important neurotransmitter 1 , 2 that activates the largest subtype family of G-protein-coupled receptors 3 . Drugs that target 5-HT 1A , 5-HT 1D , 5-HT 1E and other 5-HT receptors are used to treat numerous disorders 4 . 5-HT receptors have high levels of basal activity and are subject to regulation by lipids, but the structural basis for the lipid regulation and basal activation of these receptors and the pan-agonism of 5-HT remains unclear. Here we report five structures of 5-HT receptor–G-protein complexes: 5-HT 1A in the apo state, bound to 5-HT or bound to the antipsychotic drug aripiprazole; 5-HT 1D bound to 5-HT; and 5-HT 1E in complex with a 5-HT 1E - and 5-HT 1F -selective agonist, BRL-54443. Notably, the phospholipid phosphatidylinositol 4-phosphate is present at the G-protein–5-HT 1A interface, and is able to increase 5-HT 1A -mediated G-protein activity. The receptor transmembrane domain is surrounded by cholesterol molecules—particularly in the case of 5-HT 1A , in which cholesterol molecules are directly involved in shaping the ligand-binding pocket that determines the specificity for aripiprazol. Within the ligand-binding pocket of apo-5-HT 1A are structured water molecules that mimic 5-HT to activate the receptor. Together, our results address a long-standing question of how lipids and water molecules regulate G-protein-coupled receptors, reveal how 5-HT acts as a pan-agonist, and identify the determinants of drug recognition in 5-HT receptors. Cryo-electron microscopy structures of three different serotonin receptors in complex with serotonin and other agonists provide insights into the role of lipids in regulating these receptors and the structural basis of ligand recognition.

Glioblastoma is an incurable and highly malignant brain tumor that poses challenges in surgical and chemotherapeutic treatments. Aripiprazole (ARP), an antipsychotic drug, exerts cytotoxic effects against various cancers. In the present study, we compared the inhibitory effect of ARP on cell proliferation with that of its main metabolite, OPC-14857 (OPC), using glioblastoma cell lines (U251, T98G, and U87 cells) to explore their potential for repurposing against brain tumors. Both demonstrated more potent anticancer activity than temozolomide, the current standard clinical therapy for malignant glioblastoma. Additionally, we assessed their effects on the cell cycle, cytoskeleton, cell migration, and protein expression. The anti-proliferative and anti-migratory activities of OPC were similar to those of ARP. Moreover, there were no differences in the effects of cell death inhibitors on the anticancer activities of ARP and OPC. However, the two compounds exhibited distinct activity profiles. Exposure to OPC was suggested to induce G2/M phase cell cycle arrest and to suppress cell proliferation and migration, potentially by affecting actin and altering its subcellular localization. ARP and OPC enhanced doxorubicin (DOX) efficacy, likely via P-glycoprotein inhibition; known for ARP, suggested for structurally similar OPC. Treatment with ARP or OPC reduced the expression of survivin, an anti-apoptotic protein, suggesting an increase in apoptotic susceptibility. Although our observations were limited to in vitro studies, our findings suggest that OPC may have sustained anticancer effects even when ARP is metabolized in humans. Therefore, if ARP can be used for drug repurposing in glioblastoma, the long-term effects of OPC could be anticipated.

Aims/hypothesisSecond-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity.MethodsWe analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques.ResultsTreatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction.Conclusions/interpretationBoth SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.

Cholesterol is essential for normal brain function and development. Genetic disruptions of sterol biosynthesis result in intellectual and developmental disabilities. Developing neurons synthesize their own cholesterol, and disruption of this process can occur by both genetic and chemical mechanisms. Many commonly prescribed medications interfere with sterol biosynthesis, including haloperidol, aripiprazole, cariprazine, fluoxetine, trazodone and amiodarone. When used during pregnancy, these compounds might have detrimental effects on the developing brain of the offspring. In particular, inhibition of dehydrocholesterol-reductase 7 (DHCR7), the last enzyme in the biosynthesis pathway, results in accumulation of the immediate cholesterol precursor, 7-dehydrocholesterol (7-DHC). 7-DHC is highly unstable, giving rise to toxic oxysterols; this is particularly pronounced in a mouse model when both the mother and the offspring carry the Dhcr7+/- genotype. Studies of human dermal fibroblasts from individuals who carry DCHR7+/- single allele mutations suggest that the same gene*medication interaction also occurs in humans. The public health relevance of these findings is high, as DHCR7-inhibitors can be considered teratogens, and are commonly used by pregnant women. In addition, sterol biosynthesis inhibiting medications should be used with caution in individuals with mutations in sterol biosynthesis genes. In an age of precision medicine, further research in this area could open opportunities to improve patient and fetal/infant safety by tailoring medication prescriptions according to patient genotype and life stage.

Mutations in both copies in the gene encoding 7-dehydrocholesterol reductase (DHCR7) cause Smith–Lemli–Opitz Syndrome (SLOS), which is characterized by a toxic elevation in 7-dehydrocholesterol (7-DHC). Aripiprazole (ARI) exposure, independent of genetic mutations, also leads to elevation of 7-DHC. We investigated the combined effect of a single-copy Dhcr7+/− mutation and maternal ARI exposure on the developing offspring brain. We generated a time-pregnant mouse model where WT and Dhcr7+/− embryos were maternally exposed to ARI or vehicle (VEH) from E12 to E19 (5 mg/kg). Levels of cholesterol, its precursors, ARI and its metabolites were measured at P0. We found that ARI and its metabolites were transported across the placenta and reached the brain of offspring. Maternal ARI exposure led to decreased viability of embryos and increased 7-DHC levels, regardless of maternal or offspring Dhcr7 genotype. In addition, Dhcr7+/− pups were more vulnerable to maternal ARI exposure than their WT littermates, and maternal Dhcr7+/− genotype also exacerbated offspring response to ARI treatment. Finally, both 7-DHC levels and 7-DHC/cholesterol ratio is the highest in Dhcr7+/− pups from Dhcr7+/− mothers exposed to ARI, underscoring a potentially dangerous interaction between maternal genotype×embryonic genotype×treatment. Our findings have important clinical implications. SLOS patients should avoid drugs that increase 7-DHC levels such as ARI, trazodone and haloperidol. In addition, treatment with 7-DHC elevating substances might be potentially unsafe for the 1–1.5% of population with single-allele disruptions of the DHCR7 gene. Finally, prenatal and parental genetic testing for DHCR7 should be considered before prescribing sterol-interfering medications during pregnancy.

Background Despite recent progress in understanding the molecular mechanisms regulating aging and lifespan, and the pathways involved being conserved in different species, a full understanding of the aging process has not been reached. In particular, increasing evidence suggests an active role for the nervous system in lifespan regulation, with sensory neurons, as well as serotonin and GABA signaling, having been shown to regulate lifespan in Caenorhabditis elegans ( C. elegans ). However, the contribution of additional neural factors, and a broad understanding of the role of the nervous system in regulating aging remains to be established. Here, we examine the impact of the dopamine system in regulating aging in C. elegans . Results We report that mutations of DOP-4, a dopamine D1-like receptor (D1R), and DOP-2, a dopamine D2-like receptor (D2R) oppositely affected lifespan, fast body movement span, reproductive lifespan, and developmental rate in C. elegans . Activation of D2R using aripiprazole, an antipsychotic drug, robustly extended both lifespan and healthspan. Conversely, inhibition of D2R using quetiapine shortened worm lifespan, further supporting the role of dopamine receptors in lifespan regulation. Mechanistically, D2R signaling regulates lifespan through a dietary restriction mechanism mediated by the AAK-2-DAF-16 pathway. The DAG-PKC/PKD pathway links signaling between dopamine receptors and the downstream AAK-2-DAF-16 pathway to transmit longevity signals. Conclusions These data demonstrated a novel role of dopamine receptors in lifespan and dietary restriction regulation. The clinically approved antipsychotic aripiprazole holds potential as a novel anti-aging drug.

The aim of this study was to design a novel carrier for enhancing the bioavailability of the poorly water-soluble drug, aripiprazole (ARP). Silicosan, the applied carrier, was obtained by chemical interaction between tetraethyl orthosilicate (TEOS) and chitosan HCl. Different ARP-loaded silicosan particles were successfully prepared in absence and presence of one of the following surfactants; Tween 80, Poloxamer 407 and cetyltrimethylammonium bromide (CTAB). The prepared ARP-loaded silicosan particles were thoroughly investigated for their structures using FTIR, XRD, and DSC analysis as well as their particle size, zeta potential, flowability, drug content, and in vitro drug release efficiencies. The prepared ARP-loaded silicosan particles were characterized by amorphous structure, high drug entrapment efficiency and a remarkable improvement in the release of aripiprazole in simulated gastric fluid. SEM and EDX revealed that the morphology and silica atom content in the prepared ARP-loaded silicosan particles were affected by the used surfactant in their formulations. The selected ARP-loaded silicosan particles were subjected to in vivo study using rabbits. The obtained pharmacokinetic results showed that the relative bioavailability for orally administered ARP-loaded silicosan particles (SC-2-CTAB) was 66% higher relative to the oral suspension (AUC 0-10h was 16.38 ± 3.21 and 27.23 ± 2.35 ng.h/mL for drug powder and SC-2-CTAB formulation, respectively). The obtained results suggested the unique-structured silicosan particles to be used as successful vehicle for ARP.

The binding of drugs to plasma protein is frequently altered in certain types of renal diseases. We recently reported on the effects of oxidation and uremic toxins on the binding of aripiprazole (ARP) to human serum albumin. In our continuing investigations, we examined the binding of ARP to plasma pooled from patients with chronic renal dysfunction. We examined the issue of the molecular basis for which factors affect the changes in drug binding that accompany renal failure. The study was based on the statistical relationships between ARP albumin binding and biochemical parameters such as the concentrations of oxidized albumin and uremic toxins. The binding of ARP to plasma from chronic renal patients was significantly lower than healthy volunteers. A rational relationship between the ARP binding rate and the concentration of toxins, including indoxyl sulphate (IS) and p-cresyl sulphate (PCS), was found, particularly for IS. Moreover, multiple regression analyses that involved taking other parameters such as PCS or oxidized albumin ratio to IS into account supports the above hypothesis. In conclusion, the limited data reported in this present study indicates that monitoring IS in the blood is a very important determinant in the dosage plan for the administration of site II drugs such as ARP, if the efficacy of the drug in renal disease is to be considered.

Introduction The use of second-generation antipsychotics (SGA) has been associated with metabolic changes. However, there are differences in the metabolic profile between SGAs. We have previously observed that ziprasidone had a more benign early metabolic profile compared to aripiprazole and quetiapine. However, a long-term follow-up is preferred to detect clinically relevant impairment in metabolic parameters. We aimed to compare the effect of aripiprazole, ziprasidone, and quetiapine on metabolic measures in first-episode non-affective psychosis patients after 1 year of treatment. Material and methods One hundred and sixty-five drug-naïve patients, suffering from a first episode of non-affective psychosis, were randomly assigned to receive quetiapine, ziprasidone, or aripiprazole. Weight and glycemic/lipid parameters were recorded at baseline and after 1 year of treatment. Results After 1 year of antipsychotic treatment, we found significant increments in weight, BMI, total cholesterol, LDL-cholesterol, triglycerides, and the triglyceride/HDL index in the sample as a whole. These changes produced a significant rise in the percentage of patients with obesity, hypercholesterolemia, and hypertriglyceridemia. However, when comparing the differential effect of each antipsychotic medication, we found no significant differences in any of the metabolic parameters between antipsychotics groups after 1 year of treatment. Conclusion We concluded that the antipsychotics studied present similar metabolic profiles. However, the primary exposure to SGAs during the first year of psychosis was associated with significant increases in weight and metabolic parameters, leading to increments in obesity, hypertriglyceridemia, and hypercholesterolemia.

Aripiprazole (ARP), an atypical antipsychotic, suffers from poor aqueous solubility and extensive hepatic metabolism, resulting in limited brain bioavailability. This study aimed to develop and optimize nanostructured lipid carriers (NLCs) for intranasal delivery of ARP to enhance nose-to-brain transport and improve therapeutic outcomes for schizophrenia. ARP-loaded NLCs were formulated using a high-shear homogenization followed by ultrasonication. A 3² factorial design was employed to optimize the formulation variables. The prepared NLCs were characterized for particle size, polydispersity index, zeta potential, drug loading, and entrapment efficiency. Further evaluations included SEM, in-vitro drug release, ex-vivo permeation, hemolytic activity, nasal ciliotoxicity, and stability studies. The optimized formulation (A4), consisting of 2.5% stearic acid and oleic acid (solid lipid phase), Tween 80 (surfactant), and PEG 400 (co-surfactant), demonstrated favorable physicochemical properties: particle size of 99.6 nm, zeta potential of − 36.7 mV, PDI of 0.249, drug loading of 20.96%, and entrapment efficiency of 96.23%. The in-vitro release showed a biphasic pattern over 72 h, fitting the Fickian diffusion model. Ex-vivo studies confirmed enhanced drug permeation across nasal mucosa. Toxicity studies indicated excellent biocompatibility. Stability studies revealed that the formulation was more stable at 5 ± 0.3 °C compared to higher storage temperatures. The results indicated that the optimized intranasal ARP-NLCs developed in this study offer a novel and promising approach for improved brain targeting in schizophrenia, potentially enhancing therapeutic efficacy and patient adherence by enabling sustained drug release and avoiding first-pass metabolism.