scholarly journals The Kynurenine Pathway as a Potential Target for Neuropathic Pain Therapy Design: From Basic Research to Clinical Perspectives

2021 ◽  
Vol 22 (20) ◽  
pp. 11055
Author(s):  
Katarzyna Ciapała ◽  
Joanna Mika ◽  
Ewelina Rojewska
Keyword(s):  
Neuropathic Pain ◽  
Pain Therapy ◽  
Basic Research ◽  
Kynurenine Pathway ◽  
Response To Therapy ◽  
Therapeutic Monitoring ◽  
The Central Nervous System ◽  
New Research ◽  
Research Initiatives ◽  
Chronic Pain Therapy

Accumulating evidence suggests the key role of the kynurenine pathway (KP) of the tryptophan metabolism in the pathogenesis of several diseases. Despite extensive research aimed at clarifying the mechanisms underlying the development and maintenance of neuropathic pain, the roles of KP metabolites in this process are still not fully known. Although the function of the peripheral KP has been known for several years, it has only recently been acknowledged that its metabolites within the central nervous system have remarkable consequences related to physiology and behavior. Both the products and metabolites of the KP are involved in the pathogenesis of pain conditions. Apart from the neuroactive properties of kynurenines, the KP regulates several neurotransmitter systems in direct or indirect ways. Some neuroactive metabolites are known to have neuroprotective properties (kynurenic acid, nicotinamide adenine dinucleotide cofactor), while others are toxic (3-hydroxykynurenine, quinolinic acid). Numerous animal models show that modulation of the KP may turn out to be a viable target for the treatment of diseases. Importantly, some compounds that affect KP enzymes are currently described to possess analgesic properties. Additionally, kynurenine metabolites may be useful for assessing response to therapy or as biomarkers in therapeutic monitoring. The following review describes the molecular site of action and changes in the levels of metabolites of the kynurenine pathway in the pathogenesis of various conditions, with a particular emphasis on their involvement in neuropathy. Moreover, the potential clinical implications of KP modulation in chronic pain therapy as well as the directions of new research initiatives are discussed.

Management of Chronic Facial Head and Neck Pain: A Rational Approach

1995 ◽  
Vol 112 (5) ◽  
pp. P98-P98
Author(s):  
John S. McDonald
Keyword(s):  
Chronic Pain ◽  
Neuropathic Pain ◽  
Neck Pain ◽  
Head And Neck ◽  
Nerve Block ◽  
Pain Therapy ◽  
Diagnostic Group ◽  
Rational Approach ◽  
Chronic Pain Therapy ◽  
Interdisciplinary Course

Educational objectives: To plan treatment and coordinate an interdisciplinary course of chronic pain therapy and to tailor and adjust an appropriate pharmacotherapeutic regimen to a particular diagnostic group such as myofascial or neuropathic pain and effectively use nerve block therapy.

Spinal cord stimulator for neuropathic pain in a patient with severe disability due to transverse myelitis

2021 ◽  
Vol 14 (5) ◽  
pp. e242522
Author(s):  
Hector Xavier Martinez Villegas ◽  
Alejandro Hallo ◽  
Soraya Cruz-Loor ◽  
Karen Jacome-Calderon
Keyword(s):  
Neuropathic Pain ◽  
Pain Therapy ◽  
Pain Perception ◽  
Treatment Success ◽  
Transverse Myelitis ◽  
Lower Limbs ◽  
Chronic Neuropathic Pain ◽  
Conventional Medical Treatment ◽  
The Central Nervous System

Transverse myelitis is an inflammatory disease of the central nervous system that disrupts nerve signals’ conduction. The illness is characterised by weakness in the lower limbs accompanied by paresthesia and urinary and bowel incontinence. The most disabling sequel is the onset of chronic neuropathic pain, which can severely limit the patient’s independence and negatively affect her quality of life. We present the case of a patient who received a spinal neurostimulator after a failure of conventional medical treatment. Masking pain through paresthesia, a mechanism provided by the device significantly reduces pain perception. The treatment success in our patient represents an advance in pain therapy.

Kinurenines in Central Nervous System under neuropathic pain – clinical implications from basic research

Ból ◽  
2020 ◽  
Vol 20 (3) ◽  
pp. 32-39
Author(s):  
Katarzyna Ciapała ◽  
Ewelina Rojewska
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Neuronal Excitability ◽  
Wide Spectrum ◽  
Basic Research ◽  
Kynurenine Pathway ◽  
Pharmacological Therapy ◽  
Clinical Implications ◽  
Promising Target

Central nervous system disorders are often accompanied by changes in tryptophan metabolism. Kynurenine pathway is known to be the main route by which this essential amino acid is catabolized to a plenty of metabolites. Intermediates of this cascade are responsible for a wide spectrum of effects, including endogenous regulation of neuronal excitability and immune cells response. Excessive or disrupted activation of the pathway can lead to the accumulation of neurotoxic compounds, and in consequence, contributes to the development of various type of pathologies. These aspects shed new light on the kynurenine pathway as a promising target for development of new therapeutic strategies. Following work briefly characterizes the kynurenine pathway and discusses the neurobiological functions of kynurenines, with particular focus on their role in the development and persistence of neuropathic pain. It is also presenting the potential clinical implications of modulation of the kynurenine pathway in pharmacological therapy of chronic pain.

scholarly journals Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1548
Author(s):  
Mustafa N. Mithaiwala ◽  
Danielle Santana-Coelho ◽  
Grace A. Porter ◽  
Jason C. O’Connor
Keyword(s):  
Molecular Mechanisms ◽  
Treatment Options ◽  
Treatment Strategies ◽  
Kynurenine Pathway ◽  
Economic Problem ◽  
Cns Disease ◽  
Therapeutic Implications ◽  
Efficacious Treatment ◽  
The Central Nervous System ◽  
Significant Health

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around the globe. The development of therapeutic strategies for CNS conditions has suffered due to a poor understanding of the underlying pathologies that manifest them. Understanding common etiological origins at the cellular and molecular level is essential to enhance the development of efficacious and targeted treatment options. Over the years, neuroinflammation has been posited as a common link between multiple neurological, neurodegenerative and neuropsychiatric disorders. Processes that precipitate neuroinflammatory conditions including genetics, infections, physical injury and psychosocial factors, like stress and trauma, closely link dysregulation in kynurenine pathway (KP) of tryptophan metabolism as a possible pathophysiological factor that ‘fuel the fire’ in CNS diseases. In this study, we aim to review emerging evidence that provide mechanistic insights between different CNS disorders, neuroinflammation and the KP. We provide a thorough overview of the different branches of the KP pertinent to CNS disease pathology that have therapeutic implications for the development of selected and efficacious treatment strategies.

scholarly journals Ketamine’s effect on inflammation and kynurenine pathway in depression: A systematic review

2021 ◽  
pp. 026988112110264
Author(s):  
Emma Kopra ◽  
Valeria Mondelli ◽  
Carmine Pariante ◽  
Naghmeh Nikkheslat
Keyword(s):  
Systematic Review ◽  
Animal Studies ◽  
Bipolar Depression ◽  
Strong Support ◽  
Kynurenine Pathway ◽  
Future Research ◽  
Downstream Effects ◽  
Tnf Α ◽  
The Central Nervous System ◽  
Anti Inflammatory

Background: Ketamine is a novel rapid-acting antidepressant with high efficacy in treatment-resistant patients. Its exact therapeutic mechanisms of action are unclear; however, in recent years its anti-inflammatory properties and subsequent downstream effects on tryptophan (TRP) metabolism have sparked research interest. Aim: This systematic review examined the effect of ketamine on inflammatory markers and TRP–kynurenine (KYN) pathway metabolites in patients with unipolar and bipolar depression and in animal models of depression. Methods: MEDLINE, Embase, and PsycINFO databases were searched on October 2020 (1806 to 2020). Results: Out of 807 initial results, nine human studies and 22 animal studies on rodents met the inclusion criteria. Rodent studies provided strong support for ketamine-induced decreases in pro-inflammatory cytokines, namely in interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α and indicated anti-inflammatory effects on TRP metabolism, including decreases in the enzyme indoleamine 2,3-dioxygenase (IDO). Clinical evidence was less robust with high heterogeneity between sample characteristics, but most experiments demonstrated decreases in peripheral inflammation including in IL-1β, IL-6, and TNF-α. Preliminary support was also found for reduced activation of the neurotoxic arm of the KYN pathway. Conclusion: Ketamine appears to induce anti-inflammatory effects in at least a proportion of depressed patients. Suggestions for future research include investigation of markers in the central nervous system and examination of clinical relevance of inflammatory changes.

Understanding Neuropathic Pain

CNS Spectrums ◽  
2005 ◽  
Vol 10 (4) ◽  
pp. 298-308 ◽  
Author(s):  
Walter Zieglgänsberger ◽  
Achim Berthele ◽  
Thomas R. Tölle
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Neuropathic Pain ◽  
Neuronal Excitability ◽  
Traumatic Injury ◽  
Nerve Fibers ◽  
Cellular Events ◽  
Excitatory Neurotransmitters ◽  
The Central Nervous System ◽  
Activity Dependent

AbstractNeuropathic pain is defined as a chronic pain condition that occurs or persists after a primary lesion or dysfunction of the peripheral or central nervous system. Traumatic injury of peripheral nerves also increases the excitability of nociceptors in and around nerve trunks and involves components released from nerve terminals (neurogenic inflammation) and immunological and vascular components from cells resident within or recruited into the affected area. Action potentials generated in nociceptors and injured nerve fibers release excitatory neurotransmitters at their synaptic terminals such as L-glutamate and substance P and trigger cellular events in the central nervous system that extend over different time frames. Short-term alterations of neuronal excitability, reflected for example in rapid changes of neuronal discharge activity, are sensitive to conventional analgesics, and do not commonly involve alterations in activity-dependent gene expression. Novel compounds and new regimens for drug treatment to influence activity-dependent long-term changes in pain transducing and suppressive systems (pain matrix) are emerging.

A hybrid for pain, i.e. bifunctional analgesics in neuropathy

Ból ◽  
2021 ◽  
Vol 21 (4) ◽  
pp. 17-24
Author(s):  
Joanna Starnowska-Sokół
Keyword(s):  
Neuropathic Pain ◽  
Side Effects ◽  
Pain Therapy ◽  
Analgesic Efficacy ◽  
Hybrid Structure ◽  
Multimodal Approach ◽  
Pharmacological Profile ◽  
Hybrid Compounds ◽  
Therapeutic Outcomes ◽  
Promising Perspective

The need of developing new neuropathic pain therapies results from limited potency of currently available treatments, which is underlain by low efficacy of conventional analgesics, complex etiology and pathogenesis of neuropathy, diversity of its symptoms, as well as heightened side effects risk that accompanies the polypharmaceutical strategy, employed commonly to improve the therapeutic outcomes. Designing hybrid compounds, i.e. multimodal molecules that present the affinity to more than one receptor target, offers a promising perspective in this context. The multimodal approach allows to increase the analgesic efficacy of a given compound thanks to aiming at the very pathomechanisms specific for neuropathic pain, and to optimize the pharmacological profile of the drug. Thanks to the hybrid structure, analgesic properties of its moieties can be maximized, even if their action as separate pharmacophores tends to be limited or inconsistent under nerve injury conditions, such as in the case of opioid agonists. The present review discusses selected targets of hybrid compounds in the view of potential neuropathic pain therapy, along with the gains, limitations and challenges related to the use of hybrid compounds.

Epigenetics In Autoimmune Disease

2018 ◽  
Author(s):  
Matlock A Jeffries
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Autoimmune Disease ◽  
Noncoding Rna ◽  
Specific Treatment ◽  
Cell Types ◽  
Response To Therapy ◽  
Human Immune System ◽  
Treatment Regimens ◽  
New Research

Autoimmunity refers to a pathologic state of immunologic dysregulation in which the human immune system turns inward, attacking healthy tissues. The key step in this process is a break of self-immune tolerance. Recent studies have implicated dysregulation of gene expression via altered epigenetic control as a key mechanism in the development and promotion of autoimmunity. Epigenetics is defined as heritable changes in gene expression as a result of modification of DNA methylation, histone side chains, and noncoding RNA. Studies examining identical twins discordant for lupus, for example, were among the first to identify alterations in DNA methylation leading to lupus. Histone side-chain changes have been studied extensively in rheumatoid arthritis (RA), and many pathogenic cell types in RA exhibit a hyperacetylation phenotype. Finally, new research in the noncoding RNA field has not only uncovered potentially targetable pathways (e.g., miR-155) but may lead to the development of new diagnostic and prognostic biomarkers, helping physicians better tailor specific treatment regimens to improve response to therapy in autoimmune disease.   This review contains 4 figures, 1 table and 47 references Key Words: autoimmunity, big data, biomarkers, computational biology, DNA methylation, epigenetics, histone acetylation, histone methylation, microRNA, noncoding RNA

scholarly journals Antihyperalgesic Activity of Atomoxetine on Diabetes-Induced Neuropathic Pain: Contribution of Noradrenergic and Dopaminergic Systems

Molecules ◽  
2018 ◽  
Vol 23 (8) ◽  
pp. 2072 ◽  
Author(s):  
Mustafa Barbaros ◽  
Özgür Can ◽  
Umut Üçel ◽  
Nazlı Turan Yücel ◽  
Ümide Demir Özkay
Keyword(s):  
Neuropathic Pain ◽  
Therapeutic Potential ◽  
Sch 23390 ◽  
Withdrawal Threshold ◽  
Dopaminergic Systems ◽  
Noradrenaline Reuptake ◽  
The Central Nervous System ◽  
Streptozotocin Induced Diabetes ◽  
Noxious Stimuli ◽  
Inhibitor Drug

Atomoxetine is a selective noradrenaline reuptake inhibitor drug. Based on the knowledge that agents increasing monoamine levels in the central nervous system have therapeutic potential for neuropathic pain, it is planned to investigate the possible efficacy of atomoxetine on diabetes-induced hyperalgesia, in this study. Randall-Selitto (mechanical noxious stimuli) and Hargreaves (thermal noxious stimuli) tests were used to evaluate nociceptive perception of rats. Obtained data indicated that streptozotocin-induced diabetes causes significant decreases in the paw withdrawal threshold and paw withdrawal latency values of the animals, respectively. However, atomoxetine administered at 3 mg/kg/day for 7 and 14 days improved these diabetes-induced hyperalgesia responses. Furthermore, antihyperalgesic activity was antagonized with α-methyl-para-tyrosine methyl ester, phentolamine, propranolol, and sulpiride pre-treatments. The same effect was not reversed, however, by SCH 23390. These findings demonstrated, for the first time, that atomoxetine possesses significant antihyperalgesic activity on diabetes-induced neuropathic pain and this effect seems to be mediated by α- and β-adrenergic and D2/D3 dopaminergic receptors. Results of this present study seem to offer a new indication for an old drug; atomoxetine, but these preclinical data should first be confirmed with further well-designed clinical trials.

scholarly journals Fungal colonization of the brain: anatomopathological aspects of neurological cryptococcosis

2015 ◽  
Vol 87 (2 suppl) ◽  
pp. 1293-1309 ◽  
Author(s):  
ANA CAROLINE COLOMBO ◽  
MARCIO L. RODRIGUES
Keyword(s):  
Basic Research ◽  
Fungal Colonization ◽  
Brain Cells ◽  
Research Activity ◽  
Brain Infection ◽  
Clinical Syndromes ◽  
The Central Nervous System ◽  
Therapeutic Tools ◽  
Near Future ◽  
The Brain

Brain infection by the fungus Cryptococcus neoformans results in an estimated 500,000 human deaths per annum. Colonization of the central nervous system (CNS) by C. neoformans causes different clinical syndromes that involve interaction of a number of fungal components with distinct brain cells. In this manuscript, our literature review confirmed the notion that the Cryptococcus field is expanding rapidly, but also suggested that studies on neuropathogenesis still represent a small fraction of basic research activity in the field. We therefore discussed anatomical and physiological aspects of the brain during infection by C. neoformans, in addition to mechanisms by which brain resident cells interact with the fungus. This review suggests that multiple efforts are necessary to improve the knowledge on how C. neoformans affects brain cells, in order to enable the generation of new therapeutic tools in a near future.

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