BACKGROUND:Migraine is a disabling neurological disorder in which neuropeptides, particularly pituitary adenylate cyclase-activating polypeptide (PACAP), play pathogenic roles. The kynurenine pathway (KP) is increasingly implicated in migraine-related glutamatergic and neuroinflammatory mechanisms. Previously, we showed that the neuroprotective metabolite kynurenic acid attenuates PACAP overexpression following trigeminovascular activation. This study investigated the effects of kynurenine aminotransferase II (KAT-II) inhibition on PACAP expression and KP metabolites during trigeminal sensitization. METHODS:Rats received Complete Freund's Adjuvant (CFA) or saline injection into the right whisker pad. KAT-II inhibitor PF-04859989 (16 and 32 mg/kg) or saline was administered intraperitoneally 72 h later. Blood samples and nucleus trigeminus caudalis (TNC) were collected for PACAP and KP quantification. RESULTS:CFA treatment induced significant PACAP overexpression in the TNC and altered peripheral KP metabolite levels. PF-04859989 further increased PACAP expression, reaching significance at the 16 mg/kg dose, whereas no significant additional effect was observed at 32 mg/kg. In parallel, treatment with PF-04859989 altered peripheral KP metabolite concentrations in the peripheral inflammatory model, predominantly at the lower dose. CONCLUSIONS:This study demonstrates that KAT-II inhibition by PF-04859989 modulates PACAP signaling and KP metabolism under trigeminal inflammatory conditions. These findings support KP-PACAP interactions and may identify novel migraine-related therapeutic targets.

INTRODUCTION:Cognitive impairment (CI) is a significant burden for patients with multiple sclerosis (MS). However crucial its assessment is, longitudinal measurement of cognitive performance is susceptible to learning effect, making the results of repeated evaluations difficult to interpret. Reliable change index (RCI) and standardized regression based norms (SRB) are accepted statistical methods to assess the reliability of a difference score between two observations. Thus, our aims were to provide RCIs and SRBs for all three subtests of the Brief International Cognitive Assessment for MS (BICAMS) battery and to measure the prevalence of true cognitive worsening and improvement. METHODS:We retrospectively evaluated the first interim analysis data of the longitudinal follow-up or our BICAMS prevalence study-cohort after 1-year. We analyzed the data of 242 MS patients. RESULTS:We calculated both the RCIs and the SRBs for all three subtests of the BICAMS battery. According to the RCI, 5.4%, 6.9% and 14.6% worsened while 12.3%, 34.3% and 10.6% improved on the SDMT, BVMT-R and CVLT-II respectively. In case of SRB method, 3.8%, 8.3% and 19.7% worsened while 3.8%, 7.6% and 0.0% improved. The κ values revealed a mild-to-moderate agreement (κ=0.391-0.540; p<0.001). In case of the BVMT-R and the CVLT-II assessments the baseline scores influenced this outcome significantly (BVMT-R: OR: 1.068; 90%CI: 1.001-1.138; CVLT-II: OR: 1.096; 90%CI: 1.041-1.153). CONCLUSION:Comparing the methods, RCI seems to be better in cases with already established CI, while SRB, the more complex method, seemingly detects change better in cognitively intact patients.

The cuprizone (CPZ) animal model is suitable for studying the neurodegenerative processes of multiple sclerosis (MS). Cognitive decline is widespread in MS and markedly impacts patients' quality of life. Alterations in the kynurenine pathway (KP) of tryptophan degradation are also present in MS and its CPZ model. Our aim was to investigate the KP while analyzing cognitive abilities during long-term CPZ exposure and recovery. Mice were fed with 0.2% CPZ for 12 weeks followed by a 4-week recovery phase. At multiple time points during demyelination and remyelination, we analyzed cognitive ability using the Y-Maze test and examined KP metabolites in plasma and brain regions by UHPLC-MS/MS. We observed significant changes in neuroactive KP metabolites, such as kynurenic acid (KYNA), quinolinic acid (QUIN), picolinic acid (PA), and 3-hydroxykynurenine (3-HK), in response to CPZ treatment. As the treatment progressed, several metabolites decreased, while QUIN and PA showed dynamic changes. Metabolite levels tended to normalize during remyelination. In parallel, we detected notable cognitive decline in the CPZ-treated group. Our study firstly confirmed the link between kynurenine metabolite abnormalities in the CPZ model and MS, emphasizing the relevance of the kynurenine metabolite profile for understanding neurodegenerative processes.

Mitochondria orchestrate energy transfer, redox poise, and cell fate. Within this landscape, tryptophan catabolism yields kynurenines (KYNs), a versatile metabolite shaping organelle function. Emerging studies implicate G protein–coupled receptor 35 (GPR35), the aryl hydrocarbon receptor (AhR), and N-methyl-D-aspartate (NMDA) receptors as conduits between extracellular cues and adenosine 5′-triphosphate (ATP) maintenance, calcium handling, mitophagy, and inflammasome restraint. Parallel work links quinolinate driven de novo nicotinamide adenine dinucleotide (NAD⁺) synthesis to tricarboxylic cycle (TCA) control and sirtuin programs across tissues. Yet the field lacks an integrated view that connects receptor pharmacology to NAD⁺ economics and respiration, and it lacks single run clinical assays that quantify both KYN and TCA nodes. This review addresses those gaps by mapping receptor specific mitochondrial mechanisms of KYNA, delineating pathway–cycle crosstalk, and appraising unified liquid chromatography–mass spectrometry (LC–MS) strategies for simultaneous quantification. We synthesize evidence for mitochondrial GPR35 signaling that preserves ATP, AhR programs that tune mitophagy and oxidative defenses, and NMDA antagonism that limits excitotoxic stress. These mechanisms are integrated with quinolinate dependent NAD⁺ biogenesis and α-ketoglutarate checkpoints, then benchmarked against chromatographic and ionization solutions suitable for clinical workflows. Here we highlight a receptor to organelle axis that couples KYN metabolism flux to respiratory control and offer a practical roadmap for standardized, single run LC–MS panels. The framework can sharpen target validation in ischemia, neurodegeneration, psychiatry, and oncology, while de-risking biomarker qualification through harmonized analytics. More broadly, resolving temporal dynamics, compartmental signaling, and cross matrix comparability will accelerate movement from association to intervention and enable decision grade metrics for patient selection, pharmacodynamic readouts, and therapeutic design.

Chronic low-grade inflammation (LGI) is increasingly recognized as a biologically meaningful contributor to heterogeneity in major psychiatric disorders. The tryptophan (Trp)-kynurenine (KYN) metabolic pathway is a leading candidate mechanism because immune and stress-related signals can redirect Trp metabolism toward bioactive KYNs that influence glutamatergic signaling, redox balance, energetics, and immune feedback. In treatment-resistant depression and schizophrenia spectrum psychosis, this pathway is especially relevant because inflammatory burden often coexists with anhedonia, fatigue, cognitive dysfunction, and negative symptoms. Yet the literature remains difficult to integrate. Studies often rely on shallow biomarker panels, inconsistent inflammatory phenotyping, mixed matrices, and incomplete handling of major confounders, including smoking, adiposity, sleep disruption, infection timing, and medication exposure. Interpretation is further complicated by the kynurenic acid (KYNA) paradox and by central-peripheral discrepancies, as KYNA-related findings are strongly shaped by biological context and compartment, with blood measures often diverging from cerebrospinal fluid profiles and therefore not reliably reflecting central branch balance. This review therefore aimed to identify the Trp-KYN nodes most relevant to chronic LGI in psychiatry, synthesize clinical and preclinical evidence by disorder and symptom module, and define realistic near- and long-term research priorities. Here we highlight that Trp-KYN findings become more coherent when interpreted as context-dependent branch-balance signatures rather than standalone biomarkers. This framework can improve comparability, sharpen stratification, and support biomarker-enriched translational psychiatry. More broadly, it offers a practical model for linking immune biology to symptom dimensions across heterogeneous brain disorders. See also the graphical abstract(Fig. 1).

Background and purpose:In migraine prophylaxis, specific therapeutic options are provided by monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) and its receptor, CGRP receptor antagonists (gepants), and 5-hydroxytryptamine 1F receptor agonist ditans. mAbs acting on the pituitary adenylate cyclase-activating polypeptide (PACAP) or its receptor (PAC1) represent a new therapeutic target. Methods:A literature review based on a PubMed search. Results:Results from a Phase 2a randomized clinical trial using a human mAb against the PAC1 receptor (subcutaneous AMG 301) showed no difference between placebo and the active drug in reducing the number of monthly migraine days (MMD). The HOPE study (Phase 2) targeted PACAP as a ligand used low (100 mg) and high (750 mg) doses of an intravenous humanized mAb, Lu AG09222, in patients with episodic and chronic migraine. After 4 weeks of treatment, the reduction in MMDs from baseline was -6.2 days in the high-dose active group, compared to -4.2 days in the placebo group. A recently published Phase 2 clinical trial investigating a human mAb targeting PACAP (a single 1500 mg intravenous dose of LY3451838) showed no difference in the reduction of MMDs in patients with episodic and chronic migraine. The results of the ongoing PROCEED study, which evaluates the efficacy of four different doses of Lu AG09222 in migraine prevention, are expected to be published soon. Conclusion:Based on the findings from early-phase observations with mAbs against PACAP and its receptor, further high-phase clinical studies are required.

Migraine is one of the most common types of primary headaches, and its pathomecha nism is not yet fully understood. Our know ledge of its pathophysiology has previously focused primarily on the serotonin system; however, in recent years, increa sing attention has been given to tryptophan metabolism, particularly the Kynurenine pathway (KP). The KP, which is involved in the regulation of glutamatergic neurotransmission, is responsible for the synthesis of several neuroprotective and neurotoxic metabolites. Kynurenic acid (KYNA) is endogenous glutamate NMDA receptor antagonist in the body. Experimental data indicate that KYNA plays an important role in the pathophysiology of migraine attacks. Preclinical studies support that KYNA and its synthetic analogs are able to inhibit the pathological processes occur ring during migraine. Our previous clinical studies have confirmed that in patients with migraine, the balance maintained by neuroprotective and neurotoxic KP metabolites is disrupted, affecting both the protective and the toxic side. It is important to note, however, that various molecules of KP metabolism can exert both positive and negative effects depending on their concentration at multiple sites of the body, and therefore there is no international consensus regarding the spectrum of protective and toxic molecules. Recently, "migraine associated" neuropeptides have emerged as another promising target for migraine therapy. Calcitonin gene related peptide (CGRP) and pituitary adenylate cyclase activating polypeptide (PACAP) are involved, among other process es, in nociception and neurogenic inflammation, and their expression is altered duringmigraine attacks. Monoclonal antibody therapies targeting these neuropeptides are currently considered the most promising treatment for migraine. Our experimental data have demonstrated a close correla tion between the kynurenine pathway (KP), PACAP, and CGRP signaling, which suggests that investigation of these systems together may offer a new approach to understanding the pathological processes underlying migraine.

Neurodegenerative diseases are a growing global health burden associated with aging and characterized by progressive neuronal dysfunction, metabolic failure, mitochondrial impairment, oxidative stress, and chronic neuroinflammation. Among the metabolic pathways implicated in these disorders, coenzyme A (CoA)-linked biology has emerged as a potentially important but still underexplored contributor to neuronal resilience and vulnerability. Pantethine, a disulfide derivative of pantetheine and a CoA-related metabolic precursor, has attracted attention because of its reported effects on cellular metabolism, redox balance, and inflammatory signaling. However, its relevance across neurodegenerative diseases remains unevenly defined, with direct support strongest in pantothenate kinase-associated neurodegeneration (PKAN) and more limited evidence in common disorders such as Alzheimer’s disease (AD) and Parkinson’s disease (PD). This narrative review critically examines the mechanistic and translational evidence linking pantethine to neurodegeneration. PKAN represents the most logical disease context for pantethine investigation because impaired CoA biosynthesis is proximal to disease pathogenesis, although pantethine remains investigational and its clinical efficacy has not been established. By contrast, proposed applications in AD and PD remain highly theoretical and hypothesis-generating. Nevertheless, research on pantethine and related CoA-restoring strategies may identify new intervention targets across neurodegenerative diseases and other disorders characterized by impaired cellular bioenergetics, including selected neuropsychiatric disorders. These possibilities require biomarker-informed, disease-specific studies that establish active-species exposure, target engagement, and clinically meaningful effects.

Mitochondria govern energy transfer, redox balance, and cell fate. Tryptophan catabolism generates kynurenines (KYNs) that can tune mitochondrial function, with growing evidence that G protein coupled receptor 35 (GPR35), aryl hydrocarbon receptor (AhR), and N-methyl-D-aspartate receptors (NMDA receptors) link extracellular cues to adenosine 5 prime triphosphate (ATP) maintenance, calcium (Ca2+) handling, mitophagy, and inflammasome control. In parallel, quinolinic acid (QA)-driven de novo nicotinamide adenine dinucleotide (NAD+) synthesis connects KYN flux to tricarboxylic acid (TCA) cycle activity and sirtuin programs across tissues. Key gaps remain: receptor pharmacology is rarely integrated with NAD+ economics and respiration, and clinical workflows still lack single run assays that quantify both kynurenine and TCA nodes. We therefore integrate receptor proximal signaling, QA-driven NAD+ supply, and unified liquid chromatography mass spectrometry (LC-MS) measurement into one translational framework spanning kynurenic acid (KYNA), KYN, 3-hydroxykynurenine (3-HK), and QA, using mitochondrial endpoints as the common readout. We synthesize evidence for mitochondrial GPR35 signaling that preserves ATP, AhR programs that tune oxidative defenses and mitophagy, and NMDA receptor antagonism that limits excitotoxic stress. These mechanisms are linked to QA-dependent NAD+ biogenesis and alpha-ketoglutarate control points, then aligned with chromatography and ionization choices suited to routine LC-MS workflows. This receptor-to-organelle framework couples KYN flux to respiratory control and provides a practical roadmap for standardized single-run LC-MS panels. It can strengthen target validation in ischemia, neurodegeneration, psychiatry, and oncology while improving biomarker qualification through harmonized analytics and decision-grade readouts.

Migraine is one of the most common forms of primary headaches, affecting a significant portion of the population. In addition to reducing the quality of life for those affected, the disease causes serious economic problems worldwide due to decreased productivity and lost work hours. The exact pathophysiology of migraine remains unclear to this day, and available therapeutic options are not satisfactory. The increasing prevalence and therapy-resistant cases call for precise mapping of the disease’s pathomechanism and the development of new therapeutic alternatives as soon as possible. Although our knowledge of the pathomechanism has long been centered primarily around serotonin, the kynurenine metabolic pathway has gained increasing attention in recent years. The kynurenine pathway of tryptophan metabolism plays a significant role in the pathophysiology of migraine due to its important function in regulating glutamatergic mechanisms. This metabolic pathway is responsible for the synthesis of numerous neuroprotective and neurotoxic metabolites. One of the end-products of the pathway is kynurenic acid, an endogenous ionotropic glutamate receptor antagonist. Experimental data supports that kynurenic acid plays an important role in the pathomechanism of migraine. Preclinical studies have demonstrated that kynurenic acid and its synthetic analogs are capable of inhibiting pathological processes occurring during migraine, making them potential targets for future drug research. Our human clinical studies have confirmed that the delicate balance maintained by neuroprotective and neurotoxic kynurenine metabolites is disrupted in migraine patients. This imbalance manifests in a significant decrease in the concentration of neuroprotective molecules and a significant increase in the concentration of neurotoxic molecules. Exploring the relationship between primary headache disorders and the kynurenine pathway of tryptophan metabolism may improve understanding of pathophysiology. Depressed kynurenine metabolism in migraine patients suggests a link with the gastrointestinal system, while synthetic analogs with better pharmacokinetics than kynurenic acid may offer new treatment perspectives. Orv Hetil. 2025; 166(23): 879–886.

Backgrounds: Memory and emotion are especially vulnerable to psychiatric disorders such as post-traumatic stress disorder (PTSD), which is linked to disruptions in serotonin (5-HT) metabolism. Over 90% of the 5-HT precursor tryptophan (Trp) is metabolized via the Trp-kynurenine (KYN) metabolic pathway, which generates a variety of bioactive molecules. Dysregulation of KYN metabolism, particularly low levels of kynurenic acid (KYNA), appears to be linked to neuropsychiatric disorders. The majority of KYNA is produced by the aadat (kat2) gene-encoded mitochondrial kynurenine aminotransferase (KAT) isotype 2. Little is known about the consequences of deleting the KYN enzyme gene. Methods: In CRISPR/Cas9-induced aadat knockout (kat2-/-) mice, we examined the effects on emotion, memory, motor function, Trp and its metabolite levels, enzyme activities in the plasma and urine of 8-week-old males compared to wild-type mice. Results: Transgenic mice showed more depressive-like behaviors in the forced swim test, but not in the tail suspension, anxiety, or memory tests. They also had fewer center field and corner entries, shorter walking distances, and fewer jumping counts in the open field test. Plasma metabolite levels are generally consistent with those of urine: antioxidant KYNs, 5-hydroxyindoleacetic acid, and indole-3-acetic acid levels were lower; enzyme activities in KATs, kynureninase, and monoamine oxidase/aldehyde dehydrogenase were lower, but kynurenine 3-monooxygenase was higher; and oxidative stress and excitotoxicity indices were higher. Transgenic mice displayed depression-like behavior in a learned helplessness model, emotional indifference, and motor deficits, coupled with a decrease in KYNA, a shift of Trp metabolism toward the KYN-3-hydroxykynurenine pathway, and a partial decrease in the gut microbial Trp-indole pathway metabolite. Conclusions: This is the first evidence that deleting the aadat gene induces depression-like behaviors uniquely linked to experiences of despair, which appear to be associated with excitatory neurotoxic and oxidative stresses. This may lead to the development of a double-hit preclinical model in despair-based depression, a better understanding of these complex conditions, and more effective therapeutic strategies by elucidating the relationship between Trp metabolism and PTSD pathogenesis.

Kynurenic acid (KYNA) is one of the main neuroprotective substances of the kynurenine pathway. KYNA plays an important role in various neurodegenerative and psychiatric diseases. Although KYNA has been shown to have neuroprotective effects, it cannot be used as a peripherally administered drug due to its poor ability to cross the blood-brain barrier. To address this limitation, chemically modified KYNA analogues are being developed: SZR72 is one such analogue and has been shown to be protective in various animal models. Glutamate-induced excitotoxicity is a key factor in many neurodegenerative diseases. Therefore, we used the N-methyl-D-aspartate (NMDA)-induced excitotoxicity model to investigate the neuromodulatory agents. Using acute hippocampal slices from mouse brains, we investigated the potential neuroprotective effect of KYNA and its analogue, SZR72 on NMDA-induced excitotoxicity across different age groups of mice. The degree of tissue damage was assessed using biochemical and histological methods. In young animals (1- and 4-week-old), NMDA treatment caused no significant changes, and the cells were found to be resistant. However, in older animals (8-week-old and 1-year-old), NMDA caused significant damage in cells and tissue structure, which was reduced by KYNA and SZR72 treatment. To our knowledge, this is the first study to compare the neuroprotective effects of KYNA and SZR72 in animals of different ages using an in vitro NMDA excitotoxicity model.

The kynurenine pathway is the principal route of tryptophan metabolism in the brain, generating several neuroactive metabolites, including kynurenic acid (KYNA). KYNA functions as both a neuromodulator and a neuroprotective compound, and its dysregulation has been associated with numerous neurological and psychiatric disorders. Kynurenine aminotransferase-2 (KAT-2) is the key enzyme responsible for KYNA synthesis, yet its precise cellular localization in the mouse brain remains insufficiently characterized. In this study, we systematically compared KAT-2 expression in primary astrocytic, microglial, and neuronal cultures derived from mouse brain, complemented by in situ immunolabeling of brain sections. Immunocytochemistry combined with quantitative colocalization analysis revealed that KAT-2 is expressed in all three major brain cell types, with significant overlap with cell type-specific markers. Furthermore, KAT-2 immunoreactivity was largely restricted to the soma, showing a perinuclear distribution in glial cells and partial extension into dendritic compartments in neurons. These findings provide the first parallel characterization of KAT-2 distribution across astrocytes, microglia, and neurons in the mouse brain. Overall, our results indicate that KAT-2 is widely expressed in neural cells, a finding that supports the hypothesis that KAT-2 contributes broadly to kynurenine metabolism. Taken together, our findings provide a foundation for future studies aimed at defining the cell type-specific functional roles of KAT-2.

The kynurenine (KYN) metabolic pathway sits at the crossroads of immunity, metabolism, and neurobiology, yet its clinical translation remains fragmented. Emerging spatial omics, wearable chronobiology, and synthetic microbiota studies reveal that tryptophan (Trp) metabolism is regulated by distinct cellular “checkpoints” along the gut–brain axis, finely modulated by sex differences, circadian rhythms, and microbiome composition. However, current interventions tackle single levers in isolation, leaving a key gap in the precision control of Trp’s fate. To address this, we drew upon an extensive body of the primary literature and databases, mapping enzyme expression across tissues at single-cell resolution and linking these profiles to clinical trials investigating dual indoleamine 2,3-dioxygenase 1 (IDO1)/tryptophan 2,3-dioxygenase (TDO) inhibitors, engineered probiotics, and chrono-modulated dosing strategies. We then developed decision-tree algorithms that rank therapeutic combinations against biomarker feedback loops derived from real-time saliva, plasma, and stool metabolomics. This synthesis pinpoints microglial and endothelial KYN hotspots, quantifies sex-specific chronotherapeutic windows, and identifies engineered Bifidobacterium consortia and dual inhibitors as synergistic nodes capable of reducing immunosuppressive KYN while preserving neuroprotective kynurenic acid. Here, we highlight a framework that couples lifestyle levers, bio-engineered microbes, and adaptive pharmaco-regimens into closed-loop “smart protocols.” By charting these intersections, this study offers a roadmap for biomarker-guided, multidisciplinary interventions that could recalibrate KYN metabolic activity across cancer, mood, neurodegeneration, and metabolic disorders, appealing to clinicians, bioengineers, and systems biologists alike.

A Magyar Tudományos Akadémia, a területi akadémiai bizottságok sorában elsőként hozta létre a Szegedi Akadémiai Bizottságot azzal a céllal, hogy Szeged és a környező vidék akadémiai tagjainak, tudósainak munkáját támogassa, a tudományosság ismérveit és szempontjait megossza és érvényesítse a társadalomszervezés mindennapjaiban, valamint hozzájáruljon a tudomány művelői és az Akadémia közötti kapcsolat fejlesztéséhez. Jelen írásunkban célunk, hogy felidézzünk pillanatokat az elmúlt 65 évből. A természettudományok, az élettudományok, az orvostudományok, a társadalomtudományok és a bölcsészettudományok területén emelünk ki fordulópontokat, személyeket, egyéniségeket, sorsfordító momentumokat, amelyek a dél-alföldi tudományosság letéteményesei, a dél-alföldi tudományosság formálói.

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide. Recently long non-coding RNAs (lncRNAs) have emerged as possible molecular hubs in the diverse pathomechanisms of the disease. Among them, NEAT1 gained particular interest due to findings suggesting both protective and deleterious effects of this lncRNA in PD models.The aim of this study was to clarify some of the contradictions among data that appeared in recent publications concerning NEAT1 effects. For this, we determined whether pharmacological increase of NEAT1 levels worsened the detrimental effect of MPP + in the SH-SY5Y cell model, and whether the levels of the short and long isoform of the lncRNA changed differently upon short and extended MPTP treatment in an MPTP-induced mouse model of PD. Our findings suggest differential expression of NEAT1/Neat1 isoforms in MPP + /MPTP-induced PD models, which is in accord with the proposed role of the lncRNA in the general stress response. We propose that first an early up-regulation of Neat1_2 is dominant. The level of Neat1_2 then decreases as pathology progresses, resulting in a shift in the ratio of the two isoforms towards a higher level of Neat1_1 accompanied by damage of the central nervous system.

Millions of individuals around the world are afflicted with Parkinson’s disease (PD), a prevalent and incapacitating neurodegenerative disorder. Dr. Reichmann, a distinguished professor and neurologist, has made substantial advancements in the domain of PD research, encompassing both fundamental scientific investigations and practical applications. His research has illuminated the etiology and treatment of PD, as well as the function of energy metabolism and premotor symptoms. As a precursor to a number of neurotransmitters and neuromodulators that are implicated in the pathophysiology of PD, he has also investigated the application of tryptophan (Trp) derivatives in the disease. His principal findings and insights are summarized and synthesized in this narrative review article, which also emphasizes the challenges and implications for future PD research. This narrative review aims to identify and analyze the key contributions of Reichmann to the field of PD research, with the ultimate goal of informing future research directions in the domain. By examining Reichmann’s work, the study seeks to provide a comprehensive understanding of his major contributions and how they can be applied to advance the diagnosis and treatment of PD. This paper also explores the potential intersection of Reichmann’s findings with emerging avenues, such as the investigation of Trp and its metabolites, particularly kynurenines, which could lead to new insights and potential therapeutic strategies for managing neurodegenerative disorders like PD.

A multicenter molecular biomarker survey was conducted in Multiple Sclerosis (MS) centers across Central-Eastern European countries, encompassing a population of 107 million. Our aim was to provide a “snapshot” for future studies investigating the use of molecular biomarkers in MS. A self-report questionnaire was distributed via email to MS centers in seven Central-Eastern European countries (Croatia, Czech Republic, Poland, Romania, Serbia, Slovakia, and Slovenia) and to four reference centers (two in Austria, one in Germany, and one in Denmark), focusing on cerebrospinal fluid (CSF) analysis and molecular biomarkers in MS. Responding centers routinely request CSF oligoclonal band (OCB) testing in suspected MS cases, although no consensus exists on the number of CSF-restricted bands required to define OCB positivity, either within or between countries. More than half of the surveyed centers in the Czech Republic, Slovakia, Slovenia, and the reference centers request kappa free light chain (κFLC) testing in patients with suspected MS. Neurofilament light chain (NfL) is frequently used as a molecular biomarker for MS in Romania, Slovakia, and the reference centers. In summary, besides the use of CSF-specific OCB there is no consensus among the surveyed countries regarding the use of molecular biomarkers in MS.

Numerous illnesses, including neurological and mental disorders, have been associated with mitochondrial dysfunction. Disruptions in mitochondrial respiration and energy production have been linked to dysmetabolism of the tryptophan (Trp)-kynurenine (KYN) pathway, which produces a diverse array of bioactive metabolites. Kynurenic acid (KYNA) is a putative neuroprotectant. The exact mechanisms through which Trp-KYN metabolic dysregulation affects mitochondrial function remain largely unclear. This study investigates the impact of the genetic deletion of kynurenine aminotransferase (KAT) enzymes, which are responsible for KYNA synthesis, on mitochondrial function, specifically mitochondrial respiration and ATP synthesis, and its potential role in neuropsychiatric pathology. CRISPR/Cas9-induced knockout mouse strains kat1-/-, kat2-/-, and kat3-/- were generated. Eight-to-ten-week-old male mice were used, and cerebral and hepatic respiration, complex I- and II-linked oxidative phosphorylation (CI and CII OXPHOS), and complex IV (CIV) activity were measured using high-resolution respirometry. Mitochondrial membrane potential changes were measured with Fluorescence-Sensor Blue and safranin dye. KAT knockout mice exhibited significantly lower cerebellar respiration (CI OXPHOS, CII OXPHOS, and CIV activity) compared to wild-type mice. Lower baseline respiration and attenuated OXPHOS activities were observed in the hippocampus and striatum, particularly in kat2-/- and kat3-/- mice. Non-neuronal tissues showed reduced CIV activity, while ADP-stimulated CI and CII OXPHOS remained unchanged. The deletion of the KAT genes significantly impairs mitochondrial respiration and ATP synthesis, potentially contributing to pathogenesis. This study highlights the importance of KYNA in mitochondrial function, offering new insights into potential therapeutic targets for various disorders. Targeting the KYN pathway could mitigate mitochondrial dysfunction in a variety of diseased conditions.

Multiple sclerosis (MS) is a chronic autoimmune disease characterised by inflammation, demyelination, and neurodegeneration within the central nervous system. The pathogenesis of MS involves an immune-mediated attack on myelin and neurons, accompanied by blood–brain barrier dysfunction and chronic CNS inflammation. Central to MS pathology is dysregulation of the kynurenine pathway, which metabolises tryptophan into neuroactive compounds. Kynurenine pathway (KP) activation, driven by inflammatory cytokines, leads to the production of both neuroprotective (e.g., kynurenic acid, KYNA) and neurotoxic (e.g., quinolinic acid, QUIN) metabolites. Imbalance between these metabolites, particularly increased QUIN production, exacerbates glutamate excitotoxicity, oxidative stress, and mitochondrial dysfunction, contributing to neuronal and oligodendrocyte damage. Mitochondrial dysfunction plays a critical role in the pathophysiology of MS, exacerbating neurodegeneration through impaired energy metabolism and oxidative stress. This review integrates the current understanding of KP dysregulation in multiple sclerosis across disease stages. In RRMS, heightened KP activity correlates with inflammation and neuroprotection attempts through increased KYNA production. In contrast, SPMS and PPMS are associated with a shift towards a more neurotoxic KP profile, marked by elevated QUIN levels and reduced KYNA, exacerbating neurodegeneration and disability progression. Understanding these mechanisms offers insights into potential biomarkers and therapeutic targets for MS, emphasising the need for strategies to rebalance KP metabolism and mitigate neurotoxicity in progressive disease stages.