The Influence of Kynurenine Metabolites on Neurodegenerative Pathologies

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 853 - 853

Published: Jan. 10, 2024

As the kynurenine pathway’s links to inflammation, immune system, and neurological disorders became more apparent, it attracted attention. It is main pathway through which liver breaks down Tryptophan initial step in creation of nicotinamide adenine dinucleotide (NAD+) mammals. Immune system activation buildup potentially neurotoxic substances can result from dysregulation or overactivation this pathway. Therefore, not shocking that kynurenines have been linked conditions (Depression, Parkinson’s, Alzheimer’s, Huntington’s Disease, Schizophrenia, cognitive deficits) relation inflammation. Nevertheless, preclinical research has demonstrated are essential components behavioral analogs depression schizophrenia-like deficits addition mediators associated with pathologies due their neuromodulatory qualities. Neurodegenerative diseases extensively neuroactive metabolites (KP) tryptophan breakdown. In being a necessary amino acid for protein synthesis, also transformed into important neurotransmitters tryptamine serotonin higher eukaryotes. article, summary KP, its function neurodegeneration, approaches used currently target route therapeutically discussed.

Language: Английский

---

The Impact of C-3 Side Chain Modifications on Kynurenic Acid: A Behavioral Analysis of Its Analogs in the Motor Domain

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(6), P. 3394 - 3394

Published: March 16, 2024

The central nervous system (CNS) is the final frontier in drug delivery because of blood–brain barrier (BBB), which poses significant barriers to access most drugs their targets. Kynurenic acid (KYNA), a tryptophan (Trp) metabolite, plays an important role behavioral functions, and abnormal KYNA levels have been observed neuropsychiatric conditions. current challenge lies delivering CNS owing its polar side chain. Recently, C-3 chain-modified analogs shown cross BBB; however, it unclear whether they retain biological functions parent molecule. This study examined impact analogs, specifically, SZR-72, SZR-104, newly developed SZRG-21, on behavior. were administered intracerebroventricularly (i.c.v.), effects motor domain compared with those KYNA. Specifically, open-field (OF) rotarod (RR) tests employed assess activity skills. SZR-104 increased horizontal exploratory OF test at dose 0.04 μmol/4 μL, while SZR-72 decreased vertical doses 0.1 μL. In RR test, neither nor showed any differences skills either dose. Side chain modification affects affective performance behavior, as results show for first time. this study, we that alter emotional components such motor-associated curiosity emotions. Consequently, design necessitates development precise strategies traverse BBB paying close attention modifications

Language: Английский

---

Cerebrospinal fluid quinolinic acid is strongly associated with delirium and mortality in hip-fracture patients

Journal of Clinical Investigation, Journal Year: 2022, Volume and Issue: 133(2)

Published: Nov. 30, 2022

BACKGROUND. The kynurenine pathway (KP) has been identified as a potential mediator linking acute illness to cognitive dysfunction by generating neuroactive metabolites in response inflammation. Delirium (acute confusion) is common complication of and associated with increased risk dementia mortality. However, the molecular mechanisms underlying delirium, particularly relation KP, remain elusive.

Language: Английский

---

An Emerging Cross-Species Marker for Organismal Health: Tryptophan-Kynurenine Pathway

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(11), P. 6300 - 6300

Published: June 4, 2022

Tryptophan (TRP) is an essential dietary amino acid that, unless otherwise committed to protein synthesis, undergoes metabolism via the Tryptophan-Kynurenine (TRP-KYN) pathway in vertebrate organisms. TRP and its metabolites have key roles diverse physiological processes including cell growth maintenance, immunity, disease states coordination of adaptive responses environmental cues. Changes can alter availability for serotonin biosynthesis as well levels immune-active KYN metabolites. There now considerable evidence which has shown that TRP-KYN be influenced by various stressors glucocorticoids (marker chronic stress), infection, inflammation oxidative stress, toxicants. While there little known regarding role following exposure contaminants, linkages between chemically induced metabolic perturbations altered enzymes Moreover, conserved across species xenobiotics, therefore, understanding how this regulated may broader implications wildlife toxicology. The goal narrative review (1) identify pathways affecting Trp-Kyn vertebrates (2) highlight consequences tryptophan mammals, birds, amphibians, fish. We discuss current literature available species, gaps state knowledge, further postulate kynurenine ratio used a novel biomarker assessing organismal and, more broadly, ecosystem health.

Language: Английский

---

Higher concentrations of kynurenic acid in CSF are associated with the slower clinical progression of Alzheimer's disease

Alzheimer s & Dementia, Journal Year: 2023, Volume and Issue: 19(12), P. 5573 - 5582

Published: June 2, 2023

Abstract INTRODUCTION The kynurenine pathway's (KP) malfunction is closely related to Alzheimer's disease (AD), for antagonistic kynurenic acid (KA) and agonistic quinolinic act on the N ‐methyl‐D‐aspartate receptor, a possible therapeutic target in treating AD. METHODS In our longitudinal case–control study, KP metabolites cerebrospinal fluid were analyzed 311 patients with AD 105 cognitively unimpaired controls. RESULTS Patients exhibited higher concentrations of KA (β = 0.18, P < 0.01) picolinic 0.20, than was positively associated tau pathology 0.29, 0.01), concentration slower progression dementia. DISCUSSION neuroprotective suggest that activation KP's branch an adaptive response may be promising intervention treatment. Highlights (AD) Higher Potential neurotoxic kynurenines not increased among Activation

Language: Английский

---

Dementia and depression: Biological connections with amyloid β protein

Basic & Clinical Pharmacology & Toxicology, Journal Year: 2024, Volume and Issue: 134(5), P. 563 - 573

Published: March 8, 2024

Dementia is an umbrella term for a broad group of age-associated neurodegenerative diseases. It estimated that dementia affects 50 million people worldwide and Alzheimer's disease (AD) responsible up to 75% cases. Small extracellular senile plaques composed filamentous aggregates amyloid β (Aβ) protein tend bind neuronal receptors, affecting cholinergic, serotonergic, dopaminergic noradrenergic neurotransmission, leading neuroinflammation, among other pathophysiologic processes subsequent death, followed by dementia. The cascade hypothesis points pathological process in the cleavage precursor (APP), resulting Aβ. There close relationship between pathologies lead depression. depression prevalent 90% individuals diagnosed with Parkinson's disease, varying severity, 20 30% cases disease. hypothalamic pituitary adrenal (HPA) axis great intermediary pathophysiological mechanisms diseases This review discusses role Aβ depression, considering HPA axis, oxidative stress, signalling pathways neurotransmission.

Language: Английский

---

Aquaporin proteins: A promising frontier for therapeutic intervention in cerebral ischemic injury

Cellular Signalling, Journal Year: 2024, Volume and Issue: 124, P. 111452 - 111452

Published: Oct. 5, 2024

Language: Английский

---

Mechanism and Therapeutic Prospect of miRNAs in Neurodegenerative Diseases

Behavioural Neurology, Journal Year: 2023, Volume and Issue: 2023, P. 1 - 24

Published: Nov. 23, 2023

MicroRNAs (miRNAs) are the smallest class of noncoding RNAs, which widely exist in animals and plants. They can inhibit translation or overexpression by combining with mRNA participate posttranscriptional regulation genes, resulting reduced expression target proteins, affecting development, growth, aging, metabolism, other physiological pathological processes It is a powerful negative regulator gene expression. mediates information exchange between different cellular pathways homeostasis stress response regulates differentiation, plasticity, neurotransmission neurons. In neurodegenerative diseases, addition to complex interactions genetic susceptibility environmental factors, miRNAs serve as promising diagnostic tool for diseases. also increase reduce neuronal damage regulating body's signaling pathways, immune system, stem cells, gut microbiota, etc. not only affect occurrence diseases exacerbate disease progression but promote repair apoptosis, prevent slow down development This article reviews research progress on mechanism treatment nervous system. trial registered NCT01819545, NCT02129452, NCT04120493, NCT04840823, NCT02253732, NCT02045056, NCT03388242, NCT01992029, NCT04961450, NCT03088839, NCT04137926, NCT02283073, NCT04509271, NCT02859428, NCT05243017.

Language: Английский

---

Structural-Activity Relationship of Rare Ginsenosides from Red Ginseng in the Treatment of Alzheimer’s Disease

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(10), P. 8625 - 8625

Published: May 11, 2023

Rare ginsenosides are the major components of red ginseng. However, there has been little research into relationship between structure and their anti-inflammatory activity. In this work, BV-2 cells induced by lipopolysaccharide (LPS) or nigericin, activity eight rare ginsenosides, target proteins expression AD were compared. addition, Morris water maze test, HE staining, thioflavins urine metabonomics used to evaluate effect Rh4 on mice. Our results showed that configuration influences ginsenosides. Ginsenosides Rk1, Rg5, Rk3, have significant compared S-Rh1, R-Rh1, S-Rg3, R-Rg3. S-Rh1 S-Rg3 more pronounced than R-Rh1 R-Rg3, respectively. Furthermore, two pairs stereoisomeric can significantly reduce level NLRP3, caspase-1, ASC in cells. Interestingly, improve learning ability mice, cognitive impairment, hippocampal neuronal apoptosis Aβ deposition, regulate AD-related pathways such as tricarboxylic acid cycle sphingolipid metabolism. findings conclude with a double bond those without, 20(S)-ginsenosides excellent 20(R)-ginsenosides.

Language: Английский

---

Sex-specific associations of kynurenic acid with neopterin in Alzheimer’s disease

Alzheimer s Research & Therapy, Journal Year: 2024, Volume and Issue: 16(1)

Published: July 27, 2024

Abstract Background Sex differences in neuroinflammation could contribute to women’s increased risk of Alzheimer’s disease (AD), providing rationale for exploring sex-specific AD biomarkers. In AD, dysregulation the kynurenine pathway (KP) contributes and there is some evidence sex KP metabolism. However, associations between metabolism biomarkers need be explored further. Methods Here we investigate cerebrospinal fluid concentrations seven metabolites with established neopterin, an indicator neuroinflammation. This study included 311 patients symptomatic 105 age-matched cognitively unimpaired (CU) controls, followed up 5 years. Results We found group, higher levels most men, while were no CU group. line this, more significantly altered men compared was a trend same direction women. Furthermore, kynurenic acid acid/quinolinic ratio but clinical progression. Discussion our cohort, restricted patients. Our results suggest that due inflammation

Language: Английский

---