Mitochondrial Impairment: A Common Motif in Neuropsychiatric Presentation? The Link to the Tryptophan–Kynurenine Metabolic System

Cells, Год журнала: 2022, Номер 11(16), С. 2607 - 2607

Опубликована: Авг. 21, 2022

Nearly half a century has passed since the discovery of cytoplasmic inheritance human chloramphenicol resistance. The was then revealed to take place maternally by mitochondrial DNA (mtDNA). Later, number mutations in mtDNA were identified as cause severe inheritable metabolic diseases with neurological manifestation, and impairment functions been probed pathogenesis wide range illnesses including neurodegenerative diseases. Recently, growing preclinical studies have that animal behaviors are influenced possibly loss stress resilience. Indeed, high 54% patients one most common primary diseases, encephalomyopathy lactic acidosis stroke-like episodes (MELAS) syndrome, present psychiatric symptoms cognitive impairment, mood disorder, anxiety, psychosis. Mitochondria multifunctional organelles which produce cellular energy play major role other homeostasis, signaling, gene expression, among others. Mitochondrial observed be compromised become less resilient under continuous stress. Meanwhile, inflammation linked activation tryptophan (Trp)-kynurenine (KYN) system, observably contributes development pathological conditions disorders. This review discusses mitochondria Trp-KYN interaction system mitochondria, current understanding involvement clinical

Язык: Английский

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The Role of Tryptophan Dysmetabolism and Quinolinic Acid in Depressive and Neurodegenerative Diseases

Biomolecules, Год журнала: 2022, Номер 12(7), С. 998 - 998

Опубликована: Июль 18, 2022

Emerging evidence suggests that neuroinflammation is involved in both depression and neurodegenerative diseases. The kynurenine pathway, generating metabolites which may play a role pathogenesis, one of several competing pathways tryptophan metabolism. present article narrative review metabolism, neuroinflammation, depression, neurodegeneration. A disturbed metabolism with increased activity the pathway production quinolinic acid result deficiencies derived neurotransmitters. Quinolinic an N-methyl-D-aspartate receptor agonist, raised levels CSF, together inflammatory cytokines, have been reported mood disorders. Increased has also observed diseases, including Parkinson's disease, Alzheimer's amyotrophic lateral sclerosis, HIV-related cognitive decline. Oxidative stress connection indole-dioxygenase (IDO) formation contribute to responses cytokines. occur at expense kynurenic neuroprotective picolinic acid. While awaiting ongoing research on potential pharmacological interventions adequate protein intake appropriate amounts antioxidants offer protection against oxidative provide balanced set physiological ligands.

Язык: Английский

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Neuropharmacological Modulation of N-methyl-D-aspartate, Noradrenaline and Endocannabinoid Receptors in Fear Extinction Learning: Synaptic Transmission and Plasticity

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(6), С. 5926 - 5926

Опубликована: Март 21, 2023

Learning to recognize and respond potential threats is crucial for survival. Pavlovian threat conditioning represents a key paradigm investigating the neurobiological mechanisms of fear learning. In this review, we address role specific neuropharmacological adjuvants that act on neurochemical synaptic transmission, as well brain plasticity processes implicated in memory. We focus novel manipulations targeting glutamatergic, noradrenergic, endocannabinoid systems, how modulation these systems affects extinction learning humans. show administration N-methyl-D-aspartate (NMDA) agonists system by fatty acid amide hydrolase (FAAH) inhibition can boost through stabilization regulation receptor concentration. On other hand, elevated noradrenaline levels dynamically modulate learning, hindering long-term processes. These pharmacological interventions could provide targeted treatments prevention strategies fear-based anxiety-related disorders.

Язык: Английский

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Exploring Novel Therapeutic Targets in the Common Pathogenic Factors in Migraine and Neuropathic Pain

International Journal of Molecular Sciences, Год журнала: 2023, Номер 24(4), С. 4114 - 4114

Опубликована: Фев. 18, 2023

Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as target for migraine management; nevertheless, the efficacy applicability of CGRP modifiers warrant search more effective therapeutic targets management. This scoping review focuses on human studies pathogenic factors in NP, with reference available preclinical evidence explore potential novel targets. inhibitors monoclonal antibodies alleviate inflammation meninges; targeting transient receptor (TRP) ion channels may help prevent release nociceptive substances, modifying endocannabinoid system open path toward discovery analgesics. There exist tryptophan-kynurenine (KYN) metabolic system, is closely linked glutamate-induced hyperexcitability; alleviating neuroinflammation complement pain-relieving armamentarium, microglial excitation, observed conditions, be possible approach. Those several analgesic deserve explored analgesics; however, much remains missing. highlights need subtypes, TRP modulators, knowledge status KYN metabolites, consensus cytokines sampling, biomarkers function, innovative management methods NP.

Язык: Английский

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mTOR Signaling Disruption and Its Association with the Development of Autism Spectrum Disorder

Molecules, Год журнала: 2023, Номер 28(4), С. 1889 - 1889

Опубликована: Фев. 16, 2023

Autism spectrum disorder (ASD) is a complex neurodevelopmental characterized by impairments in social interaction and communication along with repetitive stereotypic behaviors. Currently, there are no specific biomarkers for diagnostic screening or treatments available autistic patients. Numerous genetic disorders associated high prevalence of ASD, including tuberous sclerosis complex, phosphatase tensin homolog, fragile X syndrome. Preclinical investigations animal models these diseases have revealed irregularities the PI3K/Akt/mTOR signaling pathway as well ASD-related behavioral defects. Reversal downstream molecular irregularities, mTOR hyperactivation, improved deficits observed preclinical investigations. Plant bioactive molecules shown beneficial pre-clinical evidence ASD treatment modulating pathway. In this review, we summarize involvement alterations components its critical impact on development autism disorder. Mutations negative regulators mTORC1, such TSC1, TSC2, PTEN, result ASD-like phenotypes through disruption mTORC1-mediated signaling. We further discuss various naturally occurring phytoconstituents that been identified to be modulate prevent contribute therapeutic effects ASD.

Язык: Английский

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The Tryptophan-Kynurenine Metabolic System Is Suppressed in Cuprizone-Induced Model of Demyelination Simulating Progressive Multiple Sclerosis

Biomedicines, Год журнала: 2023, Номер 11(3), С. 945 - 945

Опубликована: Март 20, 2023

Progressive multiple sclerosis (MS) is a chronic disease with unique pattern, which histologically classified into the subpial type 3 lesions in autopsy. The lesion also homologous to that of cuprizone (CPZ) toxin-induced animal models demyelination. Aberration tryptophan (TRP)-kynurenine (KYN) metabolic system has been observed patients MS; nevertheless, KYN metabolite profile progressive MS remains inconclusive. In this study, C57Bl/6J male mice were treated 0.2% CPZ toxin for 5 weeks and then underwent 4 recovery. We measured levels serotonin, TRP, metabolites plasma brain samples at 1, 3, demyelination, 7 9 remyelination periods by ultra-high-performance liquid chromatography tandem mass spectrometry (UHPLC-MS/MS) after body weight measurement immunohistochemical analysis confirm development UHPLC-MS/MS measurements demonstrated significant reduction kynurenic acid, 3-hydoxykynurenine (3-HK), xanthurenic acid 3-HK, anthranilic week 5. Here, we show CPZ-induced mouse model Thus, potentially serves as biomarker thus opens new path toward planning personalized treatment, frequently obscured immunologic components deterioration.

Язык: Английский

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Preclinical modeling in depression and anxiety: Current challenges and future research directions

Advances in Clinical and Experimental Medicine, Год журнала: 2023, Номер 32(5), С. 505 - 509

Опубликована: Май 22, 2023

This editorial highlights the limitations of preclinical models in accurately reflecting complexity anxiety and depression, which leads to a lack effective treatments for these disorders. Inconsistencies experimental designs methodologies can entail conflicting or inconclusive findings, while an overreliance on medication mask underlying problems. Researchers are exploring new approaches modeling negative emotional disorders, including using patient-derived cells, developing more complex animal models, integrating genetic environmental factors. Advanced technologies, such as optogenetics, chemogenetics neuroimaging, also being employed improve specificity selectivity models. Collaboration innovation across different disciplines sectors needed address societal challenges, requires funding support that prioritize cooperation multidisciplinary research. By harnessing power technology ways working, researchers collaborate effectively bring about transformative change.

Язык: Английский

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Oxidative and Excitatory Neurotoxic Stresses in CRISPR/Cas9-Induced Kynurenine Aminotransferase Knockout Mice: A Novel Model for Despair-Based Depression and Post-Traumatic Stress Disorder

Frontiers in Bioscience-Landmark, Год журнала: 2025, Номер 30(1)

Опубликована: Янв. 20, 2025

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

Язык: Английский

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Stopping in (e)motion: Reactive action inhibition when facing valence-independent emotional stimuli

Frontiers in Behavioral Neuroscience, Год журнала: 2022, Номер 16

Опубликована: Сен. 30, 2022

Emotions are able to impact our ability control behaviors. However, it is not clear whether emotions play a detrimental or an advantageous effect on action and the valence of emotional stimuli differently affects such motor abilities. One way measure reactive inhibitory stop-signal task (SST), which estimates cancel outright response presentation stop signal by means reaction times (SSRT). Impaired as well facilitated has been found when faced with signals in SSTs mixed results were observed for positive versus negative stimuli. Here, we aimed investigate these unresolved issues more deeply. Action capabilities tested 60 participants SST, represented fearful happy body posture together their neutral counterpart. Results showed that both postures enhanced suppress ongoing compared postures. These demonstrate valence-independent facilitate suggest may trigger increased sensory representation and/or attentional processing have promote hence improved performance.

Язык: Английский

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Editorial of Special Issue ‘Dissecting Neurological and Neuropsychiatric Diseases: Neurodegeneration and Neuroprotection’

International Journal of Molecular Sciences, Год журнала: 2022, Номер 23(13), С. 6991 - 6991

Опубликована: Июнь 23, 2022

This Special Issue has focused on dissecting the neuroprotective and neurodegenerative components of neurological neuropsychiatric diseases, highlighting latest advance in understanding etiology, pathomechanism, biomarkers, imaging techniques, novel therapeutic targets diseases (NDDs) [...].

Язык: Английский

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