DLPA

In the author's clinical experience, concurrent treatment with DL-phenylalanine (DLPA) often appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain. An analysis of this phenomenon suggests that it may be mediated, at least in part, by up-regulation of the 'endogenous analgesia system' (EAS), a neural pathway that projects caudally from medullary nuclei to the dorsal horn of the spinal column; when stimulated by chronic pain or therapeutic measures such as opiates or acupuncture, the EAS suppresses activation of second-order pain-receptive neurons in the dorsal horn, and thereby alleviates pain. Since serotonin and enkephalins are key neurotransmitters in the EAS, it is reasonable to predict that measures which promote serotonin activity (such as 5-hydroxytryptophan and serotonin-reuptake inhibitors) as well as enkephalin activity (such as D-phenylalanine, an enkephalinase inhibitor) should potentiate EAS-mediated analgesia - a view consistent with much previous medical research. Comprehensive support of the EAS with well-tolerated nutrients and pharmaceuticals may amplify the analgesic efficacy of chronic opiate therapy, while enabling dosage reductions that minimize opiate side-effects. Analogously, this approach may complement the efficacy of acupuncture and other analgesic measures that activate the EAS. Copyright 2000 Harcourt Publishers Ltd. The formation in vivo of 3,4-dihydroxyphenylalanine (DOPA) from 3-hydroxy-DL-phenylalanine (m-tyrosine). Hollunger G, Persson SA.

Hypertrophic scars, characterized by excessive fibroblast activation, present significant clinical challenges. Current treatments (e.g., laser, surgery, steroids) face limitations: Surgery is costly and associated with high recurrence rates, while pharmacological interventions often induce pain and exhibit low bioavailability or efficacy. To address this, we engineered a novel chiral supramolecular biomaterial derived from L-/D-phenylalanine and D-phenylalanine (L/DP) with well-defined nanostructure and optical activity. L/DP achieved biomimetic integration and stereoselective regulating of integrin β1 (ITGβ1) in scar tissue. In vitro, LP suppressed fibroblast proliferation by downregulating ITGβ1 (72%), inhibiting FAK/PI3K/AKT signaling and TGF-β1. In vivo (rabbit ear HS model), LP reduced scar thickness (54%), collagen deposition (39%), and α-SMA expression (45%), outperforming conventional drugs by 23%. This chirality-directed strategy provides a drug-free, painless, and highly effective HS therapy via integrin-mediated remodeling of the scar microenvironment and holds substantial clinical promise. © 2026. The Author(s).

ETHNOPHARMACOLOGICAL RELEVANCE: Acute pharyngitis is described as "acute throat impediment" in TCM, characterized by sudden, severe throat pain with redness and swelling of the pharyngeal region; in severe cases it can cause dysphagia and respiratory compromise, substantially degrading quality of life. Total mogrosides (TMG) are the active constituents of Siraitia grosvenorii and are commonly used to treat respiratory disorders, exerting throat-soothing and anti-swelling effects. These compounds display pronounced antioxidant and anti-inflammatory activities. Although these bioactivities have been confirmed, the precise mechanisms by which TMG alleviate pharyngitis have not yet been fully elucidated. AIM OF THE STUDY: The present study evaluates the therapeutic potential of TMG in acute pharyngitis and elucidates its underlying mechanism, with particular emphasis on the PI3K/AKT-NF-κB-NLRP3 signaling axis and the regulation of oxidative stress. MATERIALS AND METHODS: The chemical composition of TMG was characterized using UPLC-Q-TOF-MS/MS analysis. An ammonia-irritated mice model of acute pharyngitis was established and divided into control, model, positive drug, and TMG treatment groups at varying doses. Histopathological and molecular evaluations were employed to assess alterations in pharyngeal tissue, inflammatory mediators, signaling proteins, and oxidative stress markers. In parallel, LPS-stimulated RAW264.7 cells were used to examine the influence of TMG-containing serum on cell viability, nitric oxide production, reactive oxygen species generation, and NLRP3 inflammasome activation. Moreover, untargeted metabolomics was conducted to investigate the modulatory effects of TMG on serum metabolic profiles in the mouse model. RESULTS: A total of 41 mogroside constituents were identified in TMG. Treatment with TMG markedly alleviated pharyngeal tissue injury in pharyngitis mice, suppressed the production of pro-inflammatory cytokines, enhanced the anti-inflammatory cytokine IL-10, and reduced the expression of relative inflammation proteins. Mechanistic analysis revealed that TMG downregulated the PI3K/AKT-NF-κB pathway and inhibited NLRP3 inflammasome activat

Calcitonin gene-related peptide (CGRP) activation could play a causal role in the pathophysiology of chronic rhinosinusitis (CRS), a long-term inflammatory disease of the nasal cavity and paranasal sinuses. This study investigated the efficacy and safety of rimegepant 75 mg orally disintegrating tablet, a CGRP receptor antagonist, versus placebo for acute treatment of CRS. This double-blind, randomized, placebo-controlled, phase 2/3 trial enrolled adults with CRS in the United States. Participants were randomized 1:1 to rimegepant or placebo stratified by the presence or absence of nasal polyps. Participants were dispensed a single dose of study drug administered when they experienced a qualifying facial pain/pressure/fullness (Numeric Rating Scale [NRS] ≥6). The primary efficacy endpoint was a change from baseline [CFB] at 2 hours post dose in the intensity of facial pain/pressure/fullness) with baseline NRS score ≥6. Secondary endpoints included a CFB at 2 hours post dose in the NRS score for nasal obstruction/congestion and nasal discharge, and Total Nasal Symptom Score (TNSS); proportion of participants reporting headache pain relief at 2 hours post dose; and proportion of participants using rescue medication within 24 hours post dose. Efficacy outcomes were evaluated using a linear model. Of 261 participants (mean age: 49.3 years) randomized to rimegepant (n = 131) or placebo (n = 130), 96 and 100 had evaluable data for efficacy analyses. No significant treatment differences (P > 0.05) were observed between groups for the primary (CFB at 2 hours post dose in the NRS score for intensity of facial pain/pressure/fullness, least-squares mean difference [95% CI] -0.1 [-0.7, 0.5]) and secondary outcomes. There were no serious safety findings. To our knowledge, this study is the first to explore the use of CGRP receptor antagonists for CRS. Although no treatment differences were identified, the findings could contribute to the design of future clinical trials and better disease understanding. Trial registration ClinicalTrials.gov NCT05248997. Copyright: © 2026 Franjic et al. This is an open access article distributed under the terms of the Creative Commons Attrib

Phenylketonuria (PKU) is an inherited metabolic disorder causing elevated phenylalanine (Phe) levels and neurocognitive impairment if left untreated. While dietary therapy remains the treatment standard, adherence declines during adolescence. Pegvaliase, an injectable enzyme therapy approved for adults > 18 years in the United States, lowers Phe levels while allowing dietary flexibility. This study examines pegvaliase use in adolescents, focusing on efficacy, discontinuation patterns, and predictors of success. We conducted a retrospective chart review from four metabolic centers with 53 individuals with PKU (age 14-22 years) who initiated pegvaliase through March 2025. Data included demographics, treatment response, side effects, and discontinuation reasons. Mean pretreatment Phe was 716 μmol/L, which decreased by 44% post-treatment initiation. Sixty-four percent of individuals achieved efficacy with a mean Phe of 231 μmol/L (60% decrease) after 14 months at mean dose of 37.4 mg/day. Common side effects included injection site reactions in 77%, joint pain in 64%, rash in 45%, headaches in 26%, fatigue in 19%, fever and/or chills in 13%, GI symptoms in 13%, and anaphylaxis in 9%. Discontinuation occurred in 24.5% of this cohort, with rates significantly higher in 12th graders (40%) and college students (32%) versus 9th-11th graders (5.5%). Pegvaliase may lower Phe levels in adolescents, reaching target blood Phe goals (≤ 360 μmol/L) once efficacy is achieved. Treatment showed better sustainability when initiated earlier in adolescence. The higher discontinuation during transitional years (12th grade/college) suggests treatment challenges increase during these periods. Earlier initiation, when family support is typically stronger, may improve outcomes. These findings support reconsidering current age restrictions for pegvaliase therapy. © 2026 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.

INTRODUCTION: The anticancer drug camptothecin (CPT) has limited clinical applications due to severe toxic reactions. METHODS: We combined CPT with PHBVHHx (PHA) nanoparticles by a modified emulsion method for the first time construct a novel nanomedical drug (CPT-PHA-NPs, CPNs). RESULTS: In vitro experiments verified the drug loading level (89%), sustained-release properties (40% release within 48 h; near-complete release over 21 days), and inhibition ability of the compound on HT-29 cell activity (IC50 = 0.44 μM). In vivo, CPN-treated mice showed significantly less body weight reduction (P < 0.05 from day 7) and markedly improved liver and kidney function markers compared to controls. Histological analysis confirmed that CPN effectively prevented hepatocyte necrosis and renal inflammation observed with free CPT, demonstrating higher biosafety and lower toxicity. Crucially, 16S rRNA sequencing revealed that CPT severely depleted probiotics (Akkermansia, Lactobacillus, Candidatus_Arthromitus, and Bacilli_unclassified) while promoting pathogenic taxa (Lachnospiraceae_NK4A136_group, [Eubacterium]_xylanophilum_group, and Faecalibaculum), whereas CPNs attenuated these microbial disruptions. Metabolomics further showed CPNs' milder effects on phenylalanine and essential amino acid metabolism vs. CPT. DISCUSSION: In conclusion, this novel type of nanomaterial not only possesses excellent performance but also can reduce the impact of CPT on tissues, intestinal flora and serum metabolism, providing a new strategy for anti-tumor treatment that takes into account both microbial homeostasis and metabolic safety.

Conditioning regimens prior to hematopoietic stem cell transplantation (HSCT) are highly intensive and associated with significant toxicity, which can influence survival and quality of life. This study aimed to analyze the incidence of gastrointestinal, hematological toxicity, changes in quality of life, and cognitive functions in lymphoma patients undergoing autologous HSCT with BEAM/BeEAM conditioning. A total of 27 lymphoma patients indicated for autologous HSCT were enrolled in this prospective observational study from January 2020 to August 2023. Data collection was performed at admission and at the end of hospitalization, prior to discharge. Monitored parameters included laboratory tests (hematology and biochemistry), patient-reported quality of life assessed using the QLQ-C30 questionnaire, and perceived cognitive function evaluated using the FACT-Cog questionnaire. Mucositis of any grade occurred in 25 patients (92.6%), with diarrhea being the most common gastrointestinal symptom (any grade 85.2%, grade 3-4 37.0%). Diarrhea severity was generally independent of age, baseline blood counts, engraftment, weight loss, or hospitalization, except for an association between severe diarrhea and lower pre-transplant TSH (p=0.03). All patients experienced grade 1-2 weight loss, and 81.5% developed febrile neutropenia. Quality of life declined during transplantation, notably in role functioning, social functioning, and cognitive performance, alongside worsening fatigue, nausea/vomiting, pain, appetite loss, and diarrhea (all p-values <0.05). FACT-Cog scores showed no significant cognitive decline. The 2-year overall survival was 92.1% (95% CI 81.6-100%), while patients with SII >520.81 had lower survival (82.5%, 95% CI 60.4-100%, p=0.04), with higher SII significantly associated with worse outcomes. Autologous transplantation and the BEAM/BeEAM conditioning regimen are associated with considerable mucosal and hematologic toxicity. Patients are at risk of infections, nutritional deficits due to reduced intake, and deterioration in quality of life.

High-dose melphalan (MEL) combined with autologous stem cell transplantation (ASCT) effectively treats multiple myeloma (MM) but often causes oral mucositis (OM), affecting patient outcomes. This study aims to evaluate the effectiveness of an enhanced oral care model in preventing MEL-induced OM. This retrospective study reviewed the medical records of 87 patients with MM who underwent ASCT at the First Affiliated Hospital of Soochow University between December 2019 and February 2022. According to the oral care protocols that had been implemented during their hospitalization, patients were classified into 2 groups: a control group (n = 49) that had received routine oral care and an observation group (n = 38) that had received an enhanced oral care regimen. All patients had received cryotherapy during MEL infusion as part of standard supportive care. The enhanced oral care protocol included prolonged (30-second) gargling with oropharyngeal involvement, cheek puffing exercises, and nurse-supervised education to ensure proper technique and adherence. Relevant clinical data were extracted from medical records, including the incidence, severity, onset, and healing time of OM; pain scores; neutrophil counts; nutritional status; weight change; and length of hospital stay. Baseline characteristics were comparable between groups. The observation group experienced significantly shorter hospital stays and less weight loss (P < .05). OM onset was delayed, and fewer patients developed OM in the observation group (P < .05). At OM healing, the observation group had higher neutrophil counts and better nutritional scores (P < .05). No significant differences were observed in OM pain, severity, or healing duration. Overall, the enhanced regimen improved recovery and reduced OM incidence and impact. However, the retrospective single-center design and limited sample size may restrict the generalizability of these findings, which should be validated in larger prospective studies. Enhanced oral care - incorporating standardized gargling techniques, patient education, and cryotherapy - effectively reduces OM incidence and improves clinical outcomes in MM patients undergoing ASCT. Opti

Dysphagia in Parkinson's disease (PD) may lead to medication or 'pill retention', compromising drug delivery and mimicking other pathology on imaging. We report an octogenarian with advanced PD who presented after an unwitnessed fall, throat pain, hoarseness and cough when swallowing. A CT of the neck suggested a soft tissue mass in the piriform recess. Endoscopic evaluation instead revealed a large collection of retained levodopa tablets above the epiglottis with active aspiration. Management with crushed medication in thickened feeds, allied-health involvement and palliative-focused care was instituted; the patient died several weeks later due to an ischaemic stroke. This case highlights that (1) retained oral PD medications can present as a suspicious neck mass, (2) pill size and formulation must be tailored when dysphagia is present, and (3) early dysphagia screening and multidisciplinary management in PD patients are essential to prevent motor 'off' periods, aspiration and misdiagnosis. © BMJ Publishing Group Limited 2025. No commercial re-use. See rights and permissions. Published by BMJ Group.

ETHNOPHARMACOLOGICAL RELEVANCE: Gelsemium elegans Benth. (G. elegans) is a highly toxic medicinal plant traditionally used to treat pain and inflammatory disorders. Accidental ingestion or misuse often causes severe poisoning and death, primarily due to respiratory depression. Its most toxic alkaloid, gelsenicine, undergoes rapid metabolism in vivo. The lack of specific biomarkers hinders timely and accurate assessment of poisoning severity. AIM OF THE STUDY: This study combined untargeted metabolomics with machine learning (ML) to distinguish gelsenicine-induced fatal intoxication (GFI) from multiple hypoxia-related deaths in mice. Key discriminatory metabolites were identified, and a serum-based classification model was established and validated to support precise clinical diagnosis and forensic identification. METHODS: Serum samples were collected from GFI and three non-drug-related deaths (NDRD) groups: cervical dislocation (CD), compressive asphyxia (CA), and asphyxia due to ambient-hypoxia (ADAT). Untargeted metabolomic profiling was performed using UPLC-HRMS. Differential metabolites were identified with Compound Discoverer and SIMCA software. Biomarker selection and model construction were conducted on the MetaboAnalyst platform using random forest (RF)-based receiver operating characteristic (ROC) analysis. Model performance was evaluated across multiple ML algorithms. Sensitivity was tested with GFI samples at 1, 2, and 4 mg/kg doses, and specificity was assessed against three other neurotoxicant-related fatal intoxications (ONDFIs): isoflurane (IFI), carbon monoxide (COFI), and methamphetamine (MFI). RESULTS: Metabolomic analysis revealed significant differences between GFI and NDRD groups. Three key metabolites, creatinine, valylserine (Val-Ser), and tyrosyl-phenylalanine (Tyr-Phe), were selected to develop a classification model. The model showed promising predictive performance with area under the curve (AUC) values above 0.9 across multiple algorithms. It accurately identified GFI across different exposure doses and distinguished GFI from ONDFIs with reasonable accuracy. Further targeted metabolomics analysis suggested that creatinine levels exhib

Persistent and chronic hyperglycaemia in Type II diabetic mellitus (DM) is known to cause oxidative stress, which exacerbates underlying metabolic disorders, contributing to the progression of complications such as diabetic peripheral neuropathy (DPN). Palm tocotrienol-rich fraction (TRF) is renowned for its potent antioxidative and neuroprotective properties and might have the potential to halt or mitigate the severity of DPN. This study aimed to investigate the effects of palm TRF on diabetic rats with peripheral neuropathy and to identify the correlation between plasma metabolomic alterations and DPN parameters. Male Sprague Dawley (SD) rats were randomly divided into normal control and DM groups in which Type II DM was induced using a high-fat diet and a low-dose streptozotocin (STZ) (35 mg/kg). Successful diabetic rats were randomly divided and received daily oral treatments of palm olein (vehicle), metformin (70 mg/kg), TRF (60 mg/kg), or a combination of TRF and metformin for 12 weeks. Behavioural parameters, serum biomarkers, and plasma metabolomic profiling were assessed at 0 (baseline) and 12 weeks of intervention. From the behavioural parameters, improvement in the symptoms of thermal hyperalgesia and mechanical allodynia was seen with TRF interventions, either alone or in combination with metformin. A significant reduction in the neurofilament light (NEFL) chain, accompanied by a notable increase in nerve growth factor (NGF) levels in the serum of treatment groups, was also observed. From the plasma samples, findings reveal that TRF increases metabolites related to neurotransmitter pathways (acetylcholine, choline, phenylalanine, tryptophan) and decreases inflammatory metabolites (kynurenine, prostaglandin) compared to untreated diabetic rats. These metabolites, except for prostaglandin, showed positive correlations with pain sensitivity. In contrast, prostaglandin showed opposite correlations with pain and nerve damage markers, suggesting its potential role in inflammation and axonal injury.

INTRODUCTION: Metabolomic alterations have been linked to a range of neurological conditions. Investigating temporal changes in serum metabolomic profiles, regardless of the type of brain injury may reveal prognostic indicators. RESEARCH QUESTION: We hypothesize that specific metabolomic signatures, conserved across different acute brain injuries, can serve as robust predictors of patient outcomes. MATERIAL AND METHODS: In this longitudinal prospective observational study, serum samples were collected early (2 ± 1 day) and late (6 ± 2 days) post-injury from a total of 73 patients with ischemic stroke (n = 30), aneurysmal subarachnoid hemorrhage (n = 30), and traumatic brain injury (n = 13). Outcomes were categorized as favorable (modified Rankin Scores (mRS) 0-3) and unfavorable (mRS 4-6) three months post-injury. Metabolomic profiling (Orbitrap mass spectrometry) of 462 metabolites, analyzed using statistical and machine learning methods, identified significant outcome differences (p < 0.05, FDR-corrected). RESULTS: Early-stage samples indicated good prognostic power with a combination of uridine, tryptophan, and lactic acid (AUC 88.8 %, OR 5.29, p < 0.0001). Late-stage samples showed high discriminatory accuracy with a combination of prostaglandin J2, gamma-linolenic acid, N-acetyl-L-alanine, uridine, N-alpha-acetyl-L-asparagine, 3-hydroxy-3-methylglutarate, propionate, and creatinine (AUC 94.4 %, OR 14.5, p < 0.0001). Pathway analyses revealed significant associations with glycolysis/gluconeogenesis, pyrimidine metabolism, and tryptophan metabolism at early stages, and fatty acid biosynthesis, pyruvate metabolism, phenylalanine metabolism, and tryptophan metabolism at later stages. DISCUSSION AND CONCLUSION: These findings underscore the dynamic nature of metabolomic profiles in acute brain injuries and highlight common metabolites as significant prognostic markers across brain injury types. © 2025 The Authors.

Phenylketonuria (PKU) is an autosomal recessive disorder caused by a deficiency of phenylalanine hydroxylase (PAH), leading to the accumulation of phenylalanine (Phe) and an increased risk of developmental disorders. Treatment involves a Phe-restricted diet, amino acid supplements, and for a subset of patients, a tetrahydrobiopterin (BH4) chaperone. Managing PKU during pregnancy is challenging due to changing protein and energy needs, stricter Phe control, nausea, and unpalatable supplements. In rare cases of simultaneous maternal and fetal PKU, Phe tolerance may increase less throughout gestation, raising the demands on the patient and caregivers. There are few reports and no guidelines on the management of PKU during pregnancies in which both mother and fetus have PKU, hereafter referred to as maternal-fetal PKU (mfPKU). This report outlines our approach for successfully managing two consecutive mfPKU pregnancies. We emphasize a patient-centered approach, focusing on patient education and close collaboration with a multidisciplinary metabolic team. This involves regular monitoring of body weight, blood Phe levels, and calorie intake through an online food diary to tailor individual recommendations for natural protein restriction and amino acid supplements. © 2025 The Author(s). JIMD Reports published by John Wiley & Sons Ltd on behalf of SSIEM.

CLINICAL CHARACTERISTICS: Untreated tyrosinemia type I usually presents either in young infants with severe liver involvement or later in the first year with liver dysfunction and renal tubular dysfunction associated with growth failure and rickets. Untreated children may have repeated, often unrecognized, neurologic crises lasting one to seven days that can include change in mental status, abdominal pain, peripheral neuropathy, and/or respiratory failure requiring mechanical ventilation. Death in the untreated child usually occurs before age ten years, typically from liver failure, neurologic crisis, or hepatocellular carcinoma. Newborn screening / early diagnosis and combined treatment with nitisinone and a low-tyrosine diet has resulted in a greater than 90% survival rate, normal growth, improved liver function, prevention of cirrhosis, correction of renal tubular acidosis, and improvement in secondary rickets. DIAGNOSIS/TESTING: The diagnosis of tyrosinemia type I can be established in a proband by identification of increased succinylacetone concentration in the blood and urine or biallelic pathogenic variants in FAH by molecular genetic testing. MANAGEMENT: Targeted therapies: Nitisinone; low-phenylalanine, low-tyrosine diet; liver transplantation for children with severe liver failure at presentation and failure to respond to nitisinone therapy or malignant changes in hepatic tissue. Supportive care: Additional treatment (especially for those not receiving nitisinone) includes: antihypertensive medications and/or referral to nephrologist for management of hypertension; correction of metabolic acidosis, restoring calcium and phosphate balance, and 25-hydroxyvitamin D supplementation for osteoporosis/rickets; management of liver disease per hepatologist; treatment of hepatocellular carcinoma per oncologist/hepatologist; nutrition support per metabolic dietician; frequent feeds and avoidance of fasting to prevent hypoglycemia; developmental services and educational support as needed; provide written protocols and letters for emergency management; transitional care plan. Acute inpatient treatment for neurologic crises includes intravenous glucose, antihyperten

Two adolescent female patients, who were referred independently of each other, presented with progressive gait disturbances that worsened over the course of the day. Symptoms began in early childhood with foot instability and progressed to clubfoot, pain, and limping. MRI of the neuroaxis did not reveal any central nervous system abnormalities. Genetic testing identified the same intronic variant of uncertain significance in GCH1 in both individuals. Subsequent investigations uncovered a previously unrecognized familial relationship between the two patients, belonging to an extended family in which six women were affected by a gait disorder. Previous diagnoses within the family included childhood-onset spasticity and psoriatic arthritis. The familial GCH1 variant was confirmed in all symptomatic individuals, as well as in two asymptomatic female carriers. RNA sequencing revealed a splicing defect caused by the GCH1 near splice-site variant. A robust clinical response to L-DOPA therapy confirmed the diagnosis of DOPA-responsive dystonia (DRD) in this family. This case highlights the phenotypic variability of DRD, which frequently leads to misdiagnosis and delays in appropriate treatment. Careful assessment of family history and recognition of diurnal symptom fluctuations are key to identifying this highly treatable condition. Thieme. All rights reserved.

Current treatments for neuropathic pain often provide limited relief and are associated with significant side effects. Transcutaneous auricular vagus nerve stimulation (taVNS) shows promise as a non-pharmacological analgesic approach; however, its optimal therapeutic configuration and underlying brain mechanisms remain incompletely understood. This study investigated the analgesic effects of taVNS on neuropathic pain in a mouse model induced by partial sciatic nerve ligation (PSL), exploring mechanisms and optimizing configurations. PSL-induced neuropathic pain in mice, characterized by mechanical allodynia, was significantly alleviated by taVNS. The most robust analgesic effects were observed with multiple bilateral taVNS sessions, administered once daily for three consecutive days, with effects persisting for at least 48 h post-stimulation. Immunohistochemical analysis of c-Fos expression revealed that taVNS increased neural activity in the dorsal raphe nucleus (DRN), a key source of serotonin, while simultaneously reducing activity in the central amygdala (CeA), a region critical for pain processing and affective responses. Further experiments demonstrated that the analgesic effects of taVNS were abolished by systemic administration of p-chlorophenylalanine, an inhibitor of serotonin synthesis. These findings underscore the critical role of serotonin signaling in mediating taVNS-induced analgesia for neuropathic pain. The study also highlights the importance of stimulation parameters, identifying a multiple bilateral configuration as particularly effective. Our results suggest that taVNS, potentially acting via the DRN-serotonergic system to modulate limbic structures like the CeA, holds significant potential as a non-pharmacological therapeutic option for managing neuropathic pain. © 2025. The Author(s).

BACKGROUND: Pain is a common and often underestimated non-motor symptom in Parkinson's disease (PD), affecting quality of life (QOL) and frequently associated with motor fluctuations. Although the pathophysiological mechanisms underlying pain in PD remain unclear, most hypothesize the involvement of dopaminergic and non-dopaminergic pathways. OBJECTIVE: To evaluate the effect of MAO-B and COMT inhibitors, used as add-on therapies to levodopa, on pain thresholds in people with PD (pwPD) with motor fluctuations, either with or without pain. METHODS: This prospective cohort study enrolled 40 pwPD with motor fluctuations who were started on selegiline, rasagiline, safinamide, or opicapone. Pain thresholds (tactile, pain, and tolerance) were assessed using electrical stimulation at baseline and after 3 and 6 months. Normative data were collected from 11 healthy subjects. Outcome measures in pwPD targeted motor impairment (UPDRS), pain perception (King's PD Pain Scale), mood, fatigue, sleep, and QOL. RESULTS: PwPD showed higher tactile thresholds and lower pain and pain tolerance thresholds than controls. At 6 months, both rasagiline and safinamide significantly improved pain thresholds and tolerance compared to opicapone. Experiencing pain was more frequent in women and was associated with anxiety, poor sleep, and motor complications. Regression analyses revealed that cognitive status, sex, disease duration, age, anxiety levels and treatment with MAO-B inhibitors were key modulators of pain processing. CONCLUSION: Pain processing is altered in pwPD, independently of subjective pain complaints. MAO-B inhibitors, particularly safinamide and rasagiline, appear to restore pain thresholds and improve QOL, supporting their role in managing pain in PD.

INTRODUCTION: Chronic facial pain (CFP) includes a range of conditions such as musculoskeletal, neurovascular, and neuropathic disorders affecting the facial and jaw regions, often causing significant distress to patients. OBJECTIVES: This study aims to investigate the metabolomic profile of patients with CFP, focusing on salivary metabolites as potential biomarkers for pain diagnosis and management. METHODS: Metabolomics investigation was performed using combined liquid chromatography with mass spectrometry (UPLC-MS) for metabolic profiling. RESULTS: A comprehensive analysis was conducted, utilizing both untargeted and targeted metabolomics to examine 28 metabolites previously associated with pain conditions. The results revealed significant differences in 18 metabolites between the CFP group and a control group, with seven metabolites consistently showing elevated levels regardless of gender: DL-Isoleucine, DL-Glutamine, DL-Citrulline, D-(+)-Pyroglutamic acid, DL-Tryptophan, DL-Phenylalanine, and Spermidine. CONCLUSIONS: The findings suggest a potential link between specific salivary metabolites and CFP, highlighting the complexity of pain mechanisms. Further research is needed to understand the causality and implications of these metabolic changes, which could lead to more targeted and personalized approaches in managing pain. © 2025. The Author(s).

The arginine-phenylalanine-amide neuropeptide receptor family comprises a subclass within the G protein-coupled receptor superfamily with crucial roles in physiological regulation. These receptors recognize and bind neuropeptides with an arginine-phenylalanine-amide motif, thereby participating in a variety of biological processes such as energy metabolism, pain perception, and reproductive functions. In this review, we explore the physiological and pathological processes involving these receptors and delve into the structure-activity relationships of their ligand peptides, clarifying the key structural motifs within these neuropeptides that determine their biological activity, pharmacological potency, and receptor selectivity. Particular emphasis is placed on their roles in modulating nociception, regulating appetite, and maintaining reproductive health. Additionally, we discuss the therapeutic potential of structure-based drug design targeting these receptors based on existing cryo-electron microscopy structures. The available structural insights into ligand-binding pockets and G protein-receptor interaction interfaces provide a clear perspective and valuable complement to ligand optimization.

A 52-year-old woman presented to the rheumatology department with a 6-year history of progressively limited hand mobility, bilateral joint pain, and worsening hand deformities. Examination revealed asymmetric deformities of both hands, more pronounced on the left (Fig, A), without joint tenderness, swelling, or Heberden's and Bouchard's nodes. Laboratory tests, including C-reactive protein, rheumatoid factor, anticyclic citrullinated peptide antibody, antinuclear antibody, antidouble-stranded DNA antibody, and anti-Smith antibody, revealed no abnormalities. Hand X-rays showed no evidence of inflammatory arthritis. Treatment with nonsteroidal anti-inflammatory drugs and corticosteroids was ineffective. She was referred to the neurology clinic, where neurological examination revealed bradykinesia and increased muscle tone in all 4 limbs, especially the left upper limb, without tremor or postural instability. Brain and cervical spine magnetic resonance imaging were unremarkable. Fluorine-18-L-dihydroxyphenylalanine (¹⁸F-DOPA) positron emission tomography/computed tomography showed decreased dopamine metabolism in the bilateral striatum, which was more pronounced on the right (Fig, B). A diagnosis of striatal hand deformities (SHD) was made, and her symptoms improved with levodopa.

BACKGROUND: There is a remarkable overlap between structures involved in pain perception and the pathophysiology of Parkinson's disease (PD). Recent efforts to allocate pain into mechanistic subtypes require a better understanding of central pain processing in PD patients. OBJECTIVES: The aim of this study was to show electrophysiological evidence for altered central pain processing in a patient group with PD, taking their reported pain, somatosensory profile, and motor symptoms as well as pharmacotherapy into account. METHODS: The laser-evoked-potential (LEP)-habituation paradigm and quantitative sensory testing were applied to PD patients (n = 41) in the off-l-dopamine (levodopa) state. The development of LEP amplitudes and laser pain ratings over the course of 100 painful stimuli was compared to those of an age-matched control group (n = 24). The Unified Parkinson's Disease Rating Scale (UPDRS) III and the painDETECT questionnaire and medical history, including pharmacotherapy, were assessed and analyzed in context with LEP and pain habituation aiming to find an electrophysiological proxy for central sensitization. RESULTS: Patients exhibited a significantly reduced capacity for LEP habituation regardless of clinically reported pain and sensory profile. No association of EEG data has been found with the mean l-DOPA equivalent dose taken by the patients. CONCLUSIONS: We hereby report electrophysiological evidence for an impaired central pain modulation in PD patients regardless of pain presentation and individual sensation. Further exploration of abnormal central pain processing in PD using methods like the LEP habituation paradigm or conditioned pain modulation protocol is needed in larger cohorts. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society. © 2025 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

RATIONALE: Serotonin (5-HT) is a monoamine neuromodulator that plays a key role in the organization of the central nervous system. 5-HT alterations may be associated to the emergence of social deficits and psychiatric disorders, including anxiety, depression, and substance abuse disorders. Notably, disruption of the 5-HT system during sensitive periods of development seems to exert long-term consequences, including altered anxiety responses and problematic use of alcohol. OBJECTIVE: We analyzed, in mice, the effects of transient 5-HT depletion at gestation (a developmental stage when medial prefrontal cortex (mPFC) 5-HT levels depend exclusively on placental 5-HT availability) on 5-HT central synthesis and reuptake at weaning. We also explored if 5-HT disruption at the embryonic stage influences behavioral outcomes that may serve as a proxy for autistic- or anxiety-like phenotypes. METHODS: C57/BL6 male and female mice, born from dams treated with a 5-HT synthesis inhibitor (PCPA; 4-Chloro-DL-phenylalanine methyl ester hydrochloride) at gestational days (G)13.5-16.5, were subjected to a behavioral battery that assesses social preference and novelty, compulsive behavior, stereotypies, and ethanol's anti-anxiety effects, at postnatal days (P) 21-28. Afterwards, expression of the genes that encode for 5-HT synthesis (Tph2) and SERT (5-HT transporter) were analyzed in mPFC via real-time RT-PCR. Dopamine 2 receptor (D2R) expression was also analyzed via RT-PCR to further explore possible effects of PCPA on dopaminergic transmission. RESULTS: Transient 5-HT disruption at G13.5-16.5 reduced Tph2 expression of both male and female mice in mPFC at P23. Notably, female mice also exhibited higher SERT expression and reduced D2R expression in mPFC. Mice derived from 5-HT depleted dams displayed heightened compulsive behavior at P21, when compared to control mice. Alcohol anti-anxiety effects at early adolescence (P28) were exhibited by mice derived from 5-HT depleted dams, but not by control counterparts. No social deficits or stereotyped behaviors were observed. CONCLUSION: Transient 5-HT inhibition at gestation resulted in altered expression of genes involved in 5-HT synt

RATIONALE: Serotonin (5-HT) plays an important role in the organization of the central nervous system and in the development of social interaction deficits and psychiatric disorders, including anxiety, depression, and addiction disorders. Notably, disruption of the 5-HT system during sensitive periods of development exerts long-term consequences, including altered anxiety response and problematic use of alcohol. OBJECTIVE: we analyzed, in mice, the effects of transient 5-HT depletion at infancy or adolescence on subsequent anxiety-like behavior and alcohol intake during adolescence. METHODS: C57/BL6 male and female mice were administered a 5-HT synthesis inhibitor (PCPA; 4-chloro-DL-phenylalanine methyl ester hydrochloride) at infancy (postnatal days 14-16 [PD14-16]) or adolescence (PD40-42). Eleven (± 1) days after treatment, mice were assessed for ethanol intake in daily two-bottle choice tests and for anxiety response via the elevated plus maze. RESULTS: Female, but not male, mice transiently depleted of 5-HT at adolescence (but not those depleted at the perinatal stage) exhibited a significant reduction in anxiety response, which was accompanied by a significant reduction on alcohol intake. CONCLUSION: Transient 5-HT inhibition at adolescence may act, in females, as a protective factor for the emergence of anxiety disorders and problematic use of alcohol during adolescence.

Major depressive disorder (MDD) is a chronic and disabling psychiatric disorder characterized by a wide range of signs/symptoms, including cognitive dysfunction. Vortioxetine (VOR) is a multimodal antidepressant drug with pro-cognitive actions in animal models and MDD patients. The VOR-mediated blockade of 5-HT3-R in a subpopulation of GABA interneurons enhances pyramidal neuron activity in rat medial prefrontal cortex, an effect possibly underlying its pro-cognitive action. Brain oscillations are involved in regulation of cognitive function. We therefore examined VOR effects on oscillatory activity in four brain areas of freely-moving rats (prelimbic cortex, PrL; nucleus accumbens, NAc; dorsal hippocampus, dHPC; paraventricular thalamic nucleus, PVA), in standard and in serotonin-depleted rats showing recognition memory deficits. 4-chloro-dl-phenylalanine (pCPA) markedly reduced low frequency oscillations (LFO, mainly 1 Hz oscillations) and enhanced theta oscillations in PrL and NAc. It also reduced gamma and high frequency oscillations (HFO) in PVA. Subchronic VOR and escitalopram (ESC) treatments had little effect on oscillatory activity in standard rats. However, VOR -but not ESC- prevented recognition memory deficits in 5-HT-depleted rats, and normalized LFO and theta powers in PrL and NAc. In parallel, VOR -but not ESC- prevented the deficit in PrL-dHPC gamma coherence, but not the decrease in gamma and HFO powers in PVA. Overall, this supports a prominent role of serotonergic neurotransmission on brain oscillatory activity, particularly in cortico-striatal pathways linked to short-term recognition memory. Further, VOR prevented pCPA-induced cognitive deficits by normalizing oscillatory activity at lower frequencies in the PrL-NAc pathway, also normalizing the PrL-dHPC coherence at gamma frequencies.

Rationale: The mechanisms responsible for the unique antidepressant properties of ketamine have only been partly resolved. Recent preclinical reports implicate the neurotransmitter serotonin [5-hydroxytryptamine (5-HT)] in the antidepressant-like response of ketamine, and modulation of 5-HT1B receptors has been hypothesized to attain an important role. Objectives: To evaluate the role of endogenous stimulation of 5-HT1B heteroreceptors in the antidepressant-like activity of S-ketamine. Method: Flinders sensitive line (FSL) rats, a genetic model of depression, were depleted of endogenous 5-HT by 4-chloro-DL-phenylalanine methyl ester HCl administration (pCPA; 86 mg/kg/day for 3 days). In pCPA-pretreated and control FSL rats, the acute and sustained effects of a single dose of S-ketamine (15 mg/kg) and the selective 5-HT1B receptor agonist CP94253 (1-6 mg/kg) alone and in combination with S-ketamine were studied in the forced swim test (FST), a commonly used assay that detects antidepressant activity. Results: pCPA pretreatment decreased cortical 5-HT levels to ∼6% but did not affect the baseline behavioral phenotype of FSL rats. S-ketamine demonstrated acute and sustained antidepressant-like activity, both of which were abolished by 5-HT depletion. Combining S-ketamine with a sub-effective dose of CP94253 (1 mg/kg) rescued S-ketamine's acute and sustained antidepressant-like effects, when CP94253 was administered 2 h prior to the FST. Co-administration of S-ketamine and CP94253 did not affect the plasma level of either compound, suggesting that the observed behavioral interaction could not be ascribed to a kinetic drug-drug interaction. Conclusion: 5-HT1B receptor activation during testing appears to be critical for S-ketamine's antidepressant-like potentials in this model.

This study presents anxiolytic- and antidepressant-like effects of a methanolic extract of Morinda citrifolia Linn. (noni) fruit (MMC) in well-established mouse models of anxiety and depression. The administration of MMC (1 g/kg, p.o.) and diazepam (1 mg/kg, i.p.) significantly attenuated anxiety-like behaviour in mice by increasing the percentage of time spent and number of entries in the open arms in the elevated plus maze (EPM), and significantly enhanced the exploration in the light box in the light/dark test (LDT). The pre-treatment with flumazenil (6 mg/kg, i.p.) or bicuculline (3 mg/kg, i.p.) or WAY 100635 (1 mg/kg, i.p.) antagonized the anxiolytic-like effect elicited by MMC (1 g/kg, p.o.). These results suggest the possible involvement of benzodiazepine-GABAAergic and serotonergic mechanisms in the anxiolytic-like effect of noni fruit. Meanwhile, in the antidepressant study, the administration of MMC (0.5 and 0.75 g/kg, p.o.) and desipramine (30 mg/kg, i.p.) significantly reduced the duration of immobility in the tail suspension test (TST). Furthermore, pre-treatment of mice with 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA; 100 mg/kg, i.p., an inhibitor of serotonin synthesis) for four consecutive days or a single dose of WAY 100635 (1 mg/kg, i.p., 5HT1A receptor antagonist) or α-methyl-DL-tyrosine (AMPT; 100 mg/kg, i.p., an inhibitor of noradrenaline synthesis) significantly reversed the anti-immobility effect of MMC (0.5 g/kg, p.o.) in TST by indicating the specific involvement of the serotonergic and noradrenergic systems in the antidepressant-like effect of noni fruit. Taken together, these findings suggest that MMC has both anxiolytic- and antidepressant-like activities to be resorted as a valuable alternative therapy for comorbid anxiety and depressive conditions.

RATIONALE: The mechanisms mediating ketamine's antidepressant effect have only been partly resolved. Recent preclinical reports implicate serotonin (5-hydroxytryptamine; 5-HT) in the antidepressant-like action of ketamine. Vortioxetine is a multimodal-acting antidepressant that is hypothesized to exert its therapeutic activity through 5-HT reuptake inhibition and modulation of several 5-HT receptors. OBJECTIVES: The objective of this study was to evaluate the therapeutic-like profiles of S-ketamine, vortioxetine, and the serotonin reuptake inhibitor fluoxetine in response to manipulation of 5-HT tone. METHOD: Flinders Sensitive Line (FSL) rats, a genetic model of depression, were depleted of 5-HT by repeated administration of 4-chloro-DL-phenylalanine methyl ester HCl (pCPA). Using pCPA-pretreated and control FSL rats, we investigated the acute and sustained effects of S-ketamine (15 mg/kg), fluoxetine (10 mg/kg), or vortioxetine (10 mg/kg) on recognition memory and depression-like behavior in the object recognition task (ORT) and forced swim test (FST), respectively. RESULTS: The behavioral phenotype of FSL rats was unaffected by 5-HT depletion. Vortioxetine, but not fluoxetine or S-ketamine, acutely ameliorated the memory deficits of FSL rats in the ORT irrespective of 5-HT tone. No sustained effects were observed in the ORT. In the FST, all three drugs demonstrated acute antidepressant-like activity but only S-ketamine had sustained effects. Unlike vortioxetine, the antidepressant-like responses of fluoxetine and S-ketamine were abolished by 5-HT depletion. CONCLUSIONS: These observations suggest that the acute and sustained antidepressant-like effects of S-ketamine depend on endogenous stimulation of 5-HT receptors. In contrast, the acute therapeutic-like effects of vortioxetine on memory and depression-like behavior may be mediated by direct activity at 5-HT receptors.

Although deep brain stimulation (DBS) shows promising efficacy as a therapy for intractable depression, the neurobiological bases underlying its therapeutic action remain largely unknown. The present study was aimed at characterizing the effects of infralimbic prefrontal cortex (IL-PFC) DBS on several pre-clinical markers of the antidepressant-like response and at investigating putative non-neuronal mechanism underlying DBS action. We found that DBS induced an antidepressant-like response that was prevented by IL-PFC neuronal lesion and by adenosine A1 receptor antagonists including caffeine. Moreover, high frequency DBS induced a rapid increase of hippocampal mitosis and reversed the effects of stress on hippocampal synaptic metaplasticity. In addition, DBS increased spontaneous IL-PFC low-frequency oscillations and both raphe 5-HT firing activity and synaptogenesis. Unambiguously, a local glial lesion counteracted all these neurobiological effects of DBS. Further in vivo electrophysiological results revealed that this astrocytic modulation of DBS involved adenosine A1 receptors and K(+) buffering system. Finally, a glial lesion within the site of stimulation failed to counteract the beneficial effects of low frequency (30 Hz) DBS. It is proposed that an unaltered neuronal-glial system constitutes a major prerequisite to optimize antidepressant DBS efficacy. It is also suggested that decreasing frequency could heighten antidepressant response of partial responders.

Modulation of monoaminergic systems has been the main stream of treatment for patients with mood disorders. However, recent evidence suggests that the glutamatergic system plays an important role in the pathophysiology of these disorders. This study pharmacologically characterized a structurally novel metabotropic glutamate 5 (mGlu5) receptor negative allosteric modulator, DSR-98776, and evaluated its effect on rodent models of depression and mania. First, DSR-98776 in vitro profile was assessed using intracellular calcium and radioligand binding assays. This compound showed dose-dependent inhibitory activity for mGlu5 receptors by binding to the same allosteric site as 2-methyl-6-(phenylethynyl)-pyridine (MPEP), a known mGlu5 inhibitor. The in vivo therapeutic benefits of DSR-98776 were evaluated in common rodent models of depression and mania. In the rat forced swimming test, DSR-98776 (1-3mg/kg) significantly reduced rats immobility time after treatment for 7 consecutive days, while paroxetine (3 and 10mg/kg) required administration for 2 consecutive weeks to reduce rats immobility time. In the mouse forced swimming test, acute administration of DSR-98776 (10-30 mg/kg) significantly reduced immobility time. This effect was not influenced by 4-chloro-DL-phenylalanine methyl ester hydrochloride-induced 5-HT depletion. Finally, DSR-98776 (30 mg/kg) significantly decreased methamphetamine/chlordiazepoxide-induced hyperactivity in mice, which reflects this compound antimanic-like effect. These results indicate that DSR-98776 acts as an orally potent antidepressant and antimanic in rodent models and can be a promising therapeutic option for the treatment of a broad range of mood disorders with depressive and manic states.

Current treatments for depression, including serotonin-specific reuptake inhibitors (SSRIs), are only partially effective, with a high incidence of residual symptoms, relapse, and treatment resistance. Loss of cognitive flexibility, a component of depression, is associated with dysregulation of the prefrontal cortex. Reversal learning, a form of cognitive flexibility, is impaired by chronic stress, a risk factor for depression, and the stress-induced impairment in reversal learning is sensitive to chronic SSRI treatment, and is mimicked by serotonin (5-HT) depletion. Vortioxetine, a novel, multimodal-acting antidepressant, is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, a 5-HT1B receptor partial agonist, a 5-HT1A receptor agonist, and inhibits the 5-HT transporter. Using adult male rats, we first investigated the direct effects of vortioxetine, acting at post-synaptic 5-HT receptors, on reversal learning that was compromised by 5-HT depletion using 4-chloro-DL-phenylalanine methyl ester hydrochloride (PCPA), effectively eliminating any contribution of 5-HT reuptake blockade. PCPA induced a reversal learning impairment that was alleviated by acute or sub-chronic vortioxetine administration, suggesting that post-synaptic 5-HT receptor activation contributes to the effects of vortioxetine. We then investigated the effects of chronic dietary administration of vortioxetine on reversal learning that had been compromised in intact animals exposed to chronic intermittent cold (CIC) stress, to assess vortioxetine's total pharmacological effect. CIC stress impaired reversal learning, and chronic vortioxetine administration prevented the reversal-learning deficit. Together, these results suggest that the direct effect of vortioxetine at 5-HT receptors may contribute to positive effects on cognitive flexibility deficits, and may enhance the effect of 5-HT reuptake blockade.

Depressed patients suffer from cognitive dysfunction, including memory deficits. Acute serotonin (5-HT) depletion impairs memory and mood in vulnerable patients. The investigational multimodal acting antidepressant vortioxetine is a 5-HT3, 5-HT7 and 5-HT1D receptor antagonist, 5-HT1B receptor partial agonist, 5-HT1A receptor agonist and 5-HT transporter (SERT) inhibitor that enhances memory in normal rats in novel object recognition (NOR) and conditioned fear (Mørk et al., 2013). We hypothesized that vortioxetine's 5-HT receptor mechanisms are involved in its memory effects, and therefore investigated these effects in 5-HT depleted rats. Four injections of the irreversible tryptophan hydroxylase inhibitor 4-chloro-dl-phenylalanine methyl ester hydrochloride (PCPA, 86mg/kg, s.c.) induced 5-HT depletion, as measured in hippocampal homogenate and microdialysate. The effects of acute challenge with vortioxetine or the 5-HT releaser fenfluramine on extracellular 5-HT were measured in PCPA-treated and control rats. PCPA's effects on NOR and spontaneous alternation (SA) performance were assessed along with the effects of acute treatment with 5-hydroxy-l-tryptophan (5-HTP), vortioxetine, the selective 5-HT reuptake inhibitor escitalopram, or the 5-HT norepinephrine reuptake inhibitor duloxetine. SERT occupancies were estimated by ex vivo autoradiography. PCPA depleted central 5-HT by >90% in tissue and microdialysate, and impaired NOR and SA performance. Restoring central 5-HT with 5-HTP reversed these deficits. At similar SERT occupancies (>90%) vortioxetine, but not escitalopram or duloxetine, restored memory performance. Acute fenfluramine significantly increased extracellular 5-HT in control and PCPA-treated rats, while vortioxetine did so only in control rats. Thus, vortioxetine restores 5-HT depletion impaired memory performance in rats through one or more of its receptor activities. © 2013 Published by Elsevier B.V. and ECNP.

We previously reported that the investigational multimodal antidepressant, vortioxetine, reversed 5-HT depletion-induced memory deficits while escitalopram and duloxetine did not. The present report studied the effects of vortioxetine and the potential impact of its 5-HT1A receptor agonist and 5-HT3 receptor antagonist properties on 5-HT depletion-induced memory deficits. Recognition and spatial working memory were assessed in the object recognition (OR) and Y-maze spontaneous alternation (SA) tests, respectively. 5-HT depletion was induced in female Long-Evans rats using 4-cholro-DL-phenylalanine methyl ester HCl (PCPA) and receptor occupancies were determined by ex vivo autoradiography. Rats were acutely dosed with vortioxetine, ondansetron (5-HT3 receptor antagonist) or flesinoxan (5-HT1A receptor agonist). The effects of chronic vortioxetine administration on 5-HT depletion-induced memory deficits were also assessed. 5-HT depletion reliably impaired memory performance in both the tests. Vortioxetine reversed PCPA-induced memory deficits dose-dependently with a minimal effective dose (MED) ≤0.1mg/kg (∼80% 5-HT3 receptor occupancy; OR) and ≤3.0mg/kg (5-HT1A, 5-HT1B, 5-HT3 receptor occupancy: ∼15%, 60%, 95%) in SA. Ondansetron exhibited a MED ≤3.0μg/kg (∼25% 5-HT3 receptor occupancy; OR), but was inactive in the SA test. Flesinoxan had a MED ≤1.0mg/kg (∼25% 5-HT1A receptor occupancy; SA); only 1.0mg/kg ameliorated deficits in the NOR. Chronic p.o. vortioxetine administration significantly improved memory performance in OR and occupied 95%, 66%, and 9.5% of 5-HT3, 5-HT1B, and 5-HT1A receptors, respectively. Vortioxetine's effects on SA performance may involve 5-HT1A receptor agonism, but not 5-HT3 receptor antagonism, whereas the effects on OR performance may involve 5-HT3 receptor antagonism and 5-HT1A receptor agonism.

Normal mouse embryo fibroblasts (MEF) are killed by treatment with low doses of interferon gamma (IFN-gamma) in combination with lipopolysaccharide (LPS). This cytotoxicity has previously been shown to represent an active suicidal reaction. Here we show that the time period between first contact with IFN-gamma/LPS (t = 0 h) and cell death (t = 48 h) can be separated into two distinct periods, during which glycolytic metabolism of glucose either has a positive (8-24 h) or a negative (30-48 h) effect on cytotoxicity. During the first period (8-24 h), withdrawal of glucose from the culture medium, or inclusion in the medium of the glycolytic inhibitors deoxy-D-glucose, NaF or iodoacetate, prevented later cell death. During the second period (30-48 h), withdrawal of glucose or supplementation of the culture medium with glycolytic inhibitors was no longer protective; instead it was a requirement for cell suicide to occur. Glycolytic activity during the first period was found to be increased twofold in LPS-treated MEF and almost threefold in IFN-gamma/LPS-treated MEF. A variety of agents were found both to protect cells against IFN-gamma/LPS-induced cytotoxicity and to inhibit increased glycolysis in these cells: glucocorticoids, the serine-type protease inhibitor N-acetyl-DL-phenylalanine-beta-naphthyl ester, the ADP-ribosylation inhibitors 3-aminobenzamide and nicotinamide, and the transcription and translation inhibitors actinomycin and cycloheximide. Mitochondrial function, although normal in LPS-treated cells, was markedly depressed in IFN-gamma/LPS-treated MEF. Specifically, malate- and succinate-driven respiration was found to be impaired. Furthermore, IFN-gamma/LPS-treated MEF contained one-third of the ATP level of LPS-treated MEF. Withdrawal of L-arginine from the culture medium prevented cell death in IFN-gamma/LPS-treated MEF. N-Methyl-L-arginine, which is an inhibitor of nitric oxide (NO.) biosynthesis from L-arginine, also inhibited cell death. In conclusion, we propose that cell death in our experiments is due to an L-arginine/glycolysis-dependent impairment of mitochondrial respiration.

33. Aust J Biol Sci. 1985;38(2):151-63. Effects of phenylalanine and analogues of methionine and phenylalanine on the composition of wool and mouse hair. Reis PJ, Gillespie JM. Administration of the methionine analogue methoxinine (O-methyl-DL-homoserine) to sheep substantially changed the composition of wool; in addition wool fibres were weakened and the staple crimp frequency was reduced for a prolonged period. The proportions of high-tyrosine proteins were reduced by 40-45% whereas the high-sulfur proteins were usually slightly increased. The content of high-tyrosine proteins in wool was still depressed in most sheep 70 days after dosing with methoxinine. These experiments supported a previous finding that the cystine content of wool and its crimp frequency are not causally related. Ethionine, another methionine analogue, did not consistently change the composition of wool. In some sheep there was no change in the proportions of high-tyrosine proteins following administration of ethionine, even though weak wool was produced. This result, together with the lack of association between the content of high-tyrosine proteins and the strength of wool fibres in a sheep given methoxinine plus methionine, indicates that a reduction of the high-tyrosine proteins is not a prerequisite for the production of weak wool. Neither a threefold increase in the phenylalanine intake by mice nor the administration of three analogues of phenylalanine (4-fluoro-DL-phenylalanine, 4-chloro-DL-phenylalanine and beta-(2-thienyl)-DL-alanine) to sheep altered the composition of hair or wool. Fluorophenylalanine was incorporated into all the constituent proteins of wool to the extent of c. 2% of phenylalanine residues. The other analogues studied could not be detected in wool.

34. Arch Psychiatr Nervenkr (1970). 1979 Jul 4;227(1):49-58. doi: 10.1007/BF00585677. DL-phenylalanine versus imipramine: a double-blind controlled study. Beckmann H, Athen D, Olteanu M, Zimmer R. In a double-blind study, DL-phenylalanine (150--200 mg/24 h) or imipramine (150--200 mg/24 h) was administered to 40 depressed patients (20 patients in each group) for 30 days. Diagnoses were established according to the International Classification of Disease (ICD). The AMP system, the Hamilton Depression Scale and the Bf-S self rating questionnaire (von Zerssen et al., 1974) were used to document psychopathological, neurologic, and somatic changes. Twenty-seven patients (14 on imipramine, 13 on phenylalanine) completed the 30-day trial. No statistical difference could be found between these two drug treatment groups (Student's t-test) using the Hamilton Depression Scale and the Bf-S self rating questionnaire. Ratings for anxiety were significantly lower in the imipramine group on days 10 and 20, but not on day 30; in addition, sleep disturbances were more influenced by imipramine on days 1, 5, and 10, but not on days 20 and 30. Separate analysis of psychopathological syndromes as somatic depressive syndrome and retarded depressive syndrome did not show a group difference (0.05 level of significance using a two-way analysis of variance). It is concluded that DL-phenylalanine might have substantial antidepresant properties. However, certain methodological considerations still warrant a careful interpretation.

35. Arzneimittelforschung. 1978;28(8):1283-4. [DL-phenylalanine as an antidepressant. Open study (author's transl)]. [Article in German] Beckmann H, Ludolph E. In an open study dl-phenylalanine in doses from 75--200 mg/day was administered to 20 depressed patients for 20 days. At the end of the trial 12 patients (8 with complete, 4 with good response) could be discharged without any further treatment. 4 patients with partially untypical depressions experienced mild to moderate responses, whereas 4 patients did not respond at all to the phenylalanine administration. Depressive "core symptoms" as depressed mood, retardation and/or agitation were preferentially, anxiety and sleep disturbances moderately and hypochondriasis and compulsiveness were not influenced. It is concluded that dl-phenylalanine might have substantial antidepressant properties and that further controlled investigations are justified.

36. J Neural Transm. 1977;41(2-3):123-34. doi: 10.1007/BF01670277. Dl-phenylalanine in depressed patients: an open study. Beckmann H, Strauss MA, Ludolph E. In an open study dl-phenylalanine in doses from 75-200 mg/day was administered to 20 depressed patients for 20 days. Patients were classified according to the International Classification of Diseases (ICD). The AMP system, the Hamilton depression scale and the von Zerssen self rating questionnaire were used for documentation of psychopathological, neurologic and somatic changes. In addition a global clinical impression was agreed upon by experienced psychiatrists. At the end of the trial 12 patients (8 with complete, 4 with good response) could be discharged without any further treatment. 4 patients with partially untypical depressions experienced mild to moderate responses, whereas 4 patients did not respond at all to the phenylalanine administration. Depressive "core symptoms" as depressed mood, retardation and/or agitation were preferentially, anxiety and sleep disturbances moderately and hypochondriasis and compulsiveness were not influenced. It is concluded that dl-phenylalanine might have substantial antidepressant properties and that further more controlled investigations are warranted.

37. Acta Pharmacol Toxicol (Copenh). 1974 May;34(5):391-8. doi: 10.1111/j.1600-0773.1974.tb03535.x. The formation in vivo of 3,4-dihydroxyphenylalanine (DOPA) from 3-hydroxy-DL-phenylalanine (m-tyrosine). Hollunger G, Persson SA.