Kynurenine Pathway in Diabetes Mellitus—Novel Pharmacological Target?

Cells, Journal Year: 2023, Volume and Issue: 12(3), P. 460 - 460

Published: Jan. 31, 2023

The tryptophan–kynurenine pathway (Trp–KYN) is the major route for tryptophan conversion in brain and periphery. Kynurenines display a wide range of biological actions (which are often contrasting) such as cytotoxic/cytoprotective, oxidant/antioxidant or pro-/anti-inflammatory. net effect depends on their local concentration, cellular environment, well complex positive negative feedback loops. imbalance between beneficial harmful kynurenines was implicated pathogenesis various neurodegenerative disorders, psychiatric illnesses metabolic including diabetes mellitus (DM). Despite available therapies, DM may lead to serious macro- microvascular complications cardio- cerebrovascular disease, peripheral vascular chronic renal diabetic retinopathy, autonomic neuropathy cognitive impairment. It established that low-grade inflammation, which coincides with DM, can affect function KP and, conversely, modulate immune response. This review provides detailed summary findings concerning status Trp–KYN based animal, human microbiome studies. We highlight importance molecular interplay deranged (functionally qualitatively) Trp development insulin resistance. emerges novel target search preventive therapeutic interventions DM.

Language: 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, Journal Year: 2023, Volume and Issue: 24(6), P. 5926 - 5926

Published: March 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.

Language: Английский

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

Molecules, Journal Year: 2023, Volume and Issue: 28(4), P. 1889 - 1889

Published: Feb. 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.

Language: Английский

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

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(4), P. 4114 - 4114

Published: Feb. 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.

Language: Английский

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Investigating the Neuroprotective and Cognitive-Enhancing Effects of Bacopa monnieri: A Systematic Review Focused on Inflammation, Oxidative Stress, Mitochondrial Dysfunction, and Apoptosis

Antioxidants, Journal Year: 2024, Volume and Issue: 13(4), P. 393 - 393

Published: March 25, 2024

The aging of the global population has increased prevalence neurodegenerative conditions. Bacopa monnieri (BM), an herb with active compounds, such as bacosides A and B, betulinic acid, loliolide, asiatic quercetin, demonstrates potential for brain health. Limited research been conducted on therapeutic applications BM in This systematic review aims to project BM’s beneficial role disorders. anti-apoptotic antioxidant actions can repair damaged neurons, stimulate kinase activity, restore synaptic function, improve nerve transmission, increase neuroprotection. included twenty-two clinical trials demonstrated that reduce Nuclear Factor-κB phosphorylation, emotional cognitive functions, anhedonia, hyperactivity, sleep routine, depression, attention deficit, learning problems, memory retention, impulsivity, psychiatric problems. Moreover, levels pro-inflammatory biomarkers oxidative stress. Here, we highlight provides notable benefits serve a complementary approach care patients conditions associated adds growing interest natural products their by improving our understanding mechanisms underlying function neurodegeneration informing development new strategies diseases.

Language: Английский

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Targeting Human Glucocorticoid Receptors in Fear Learning: A Multiscale Integrated Approach to Study Functional Connectivity

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(2), P. 864 - 864

Published: Jan. 10, 2024

Fear extinction is a phenomenon that involves gradual reduction in conditioned fear responses through repeated exposure to fear-inducing cues. Functional brain connectivity assessments, such as functional magnetic resonance imaging (fMRI), provide valuable insights into how regions communicate during these processes. Stress, ubiquitous aspect of life, influences learning and by changing the activity amygdala, prefrontal cortex, hippocampus, leading enhanced and/or impaired extinction. Glucocorticoid receptors (GRs) are key stress response show dual function regulation: while they enhance consolidation memories, also facilitate Accordingly, GR dysregulation associated with anxiety mood disorders. Recent advancements cognitive neuroscience underscore need for comprehensive understanding integrates perspectives from molecular, cellular, systems levels. In particular, neuropharmacology provides neurotransmitter receptor systems, aiding investigation mechanisms underlying regulation potential therapeutic targets. A notable player this context cortisol, hormone, which significantly both memory reconsolidation Gaining thorough intricate interactions has implications terms addressing psychiatric disorders related stress. This review sheds light on complex between processes, emotions, their neural bases. endeavor, our aim reshape comprehension fear, stress, emotional well-being, ultimately development interventions.

Language: Английский

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Polyphenols, Alkaloids, and Terpenoids Against Neurodegeneration: Evaluating the Neuroprotective Effects of Phytocompounds Through a Comprehensive Review of the Current Evidence

Metabolites, Journal Year: 2025, Volume and Issue: 15(2), P. 124 - 124

Published: Feb. 13, 2025

Neurodegenerative diseases comprise a group of chronic, usually age-related, disorders characterized by progressive neuronal loss, deformation structure, or loss function, leading to substantially reduced quality life. They remain significant focus scientific and clinical interest due their increasing medical social importance. Most neurodegenerative present intracellular protein aggregation extracellular deposition (plaques), such as α-synuclein in Parkinson's disease amyloid beta (Aβ)/tau aggregates Alzheimer's. Conventional treatments for conditions incur high costs are related the development several adverse effects. In addition, many patients irresponsive them. For these reasons, there is growing tendency find new therapeutic approaches help patients. This review intends investigate some phytocompounds' effects on diseases. These generally increased oxidative stress inflammation, so phytocompounds can prevent treat To achieve our aim provide critical assessment current literature about phytochemicals targeting neurodegeneration, we reviewed reputable databases, including PubMed, EMBASE, COCHRANE, seeking trials that utilized against conditions. A few investigated humans, after screening, 13 were ultimately included following PRISMA guidelines. compounds include polyphenols (flavonoids luteolin quercetin, phenolic acids rosmarinic acid, ferulic caffeic other like resveratrol), alkaloids (such berberine, huperzine A, caffeine), terpenoids ginkgolides limonene). The gathered evidence underscores caffeine, ginkgolides, primarily anti-inflammatory, antioxidant, neuroprotective, counteracting neuroinflammation, oxidation, synaptic dysfunctions, which crucial aspects intervention various conditions, Alzheimer's dementias, depression, neuropsychiatric disorders. summary, they show use improvements cognition, memory, disinhibition, irritability/lability, aberrant behavior, hallucinations, mood

Language: Английский

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Integrating Armchair, Bench, and Bedside Research for Behavioral Neurology and Neuropsychiatry: Editorial

Biomedicines, Journal Year: 2022, Volume and Issue: 10(12), P. 2999 - 2999

Published: Nov. 22, 2022

"To learning much inclined, who went to see the Elephant (though all of them were blind) that each by observation might satisfy mind" [...].

Language: Английский

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

Published: July 8, 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 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 other. Mitochondrial observed be compromised become less resilient under continuous stress. Meanwhile, inflammation have linked activation tryptophan (Trp)-kynurenine (KYN) system, observably contributes development pathological conditions disorders. This narrative review discusses mitochondria Trp-KYN interaction system mitochondria, current understanding involvement clinical

Language: Английский

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From CGRP to PACAP, VIP, and Beyond: Unraveling the Next Chapters in Migraine Treatment

Cells, Journal Year: 2023, Volume and Issue: 12(22), P. 2649 - 2649

Published: Nov. 17, 2023

Migraine is a neurovascular disorder that can be debilitating for individuals and society. Current research focuses on finding effective analgesics management strategies migraines by targeting specific receptors neuropeptides. Nonetheless, newly approved calcitonin gene-related peptide (CGRP) monoclonal antibodies (mAbs) have 50% responder rate ranging from 27 to 71.0%, whereas CGRP receptor inhibitors 56 71%. To address the need novel therapeutic targets, researchers are exploring potential of another secretin family peptide, pituitary adenylate cyclase-activating polypeptide (PACAP), as ground-breaking treatment avenue migraine. Preclinical models revealed how PACAP affects trigeminal system, which implicated in headache disorders. Clinical studies demonstrated significance migraine pathophysiology; however, few clinical trials remain inconclusive: 1 mAb, AMG 301 showed no benefit prevention, while ligand Lu AG09222 significantly reduced number monthly days over placebo phase 2 trial. Meanwhile, vasoactive intestinal (VIP) gaining interest new target. In light recent advances research, we emphasize promising target treatment, highlighting member antimigraine armamentarium, especially patients who do not respond or contraindicated anti-CGRP therapies. By updating our knowledge its unique contribution pathophysiology, pave way reinforcing other peptides, including VIP, option migraines.

Language: Английский

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