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1.
J Allergy Clin Immunol ; 152(1): 11-23, 2023 07.
Artigo em Inglês | MEDLINE | ID: mdl-37201903

RESUMO

Pruritus (or itch) is an unpleasant sensation leading to a desire to scratch. In the epidermis, there are selective C or Aδ epidermal nerve endings that are pruriceptors. At their other ends, peripheral neurons form synapses with spinal neurons and interneurons. Many areas in the central nervous system are involved in itch processing. Although itch does not occur solely because of parasitic, allergic, or immunologic diseases, it is usually the consequence of neuroimmune interactions. Histamine is involved in a minority of itchy conditions, and many other mediators play a role: cytokines (eg, IL-4, IL-13, IL-31, IL-33, and thymic stromal lymphopoietin), neurotransmitters (eg, substance P, calcitonin gene-related peptide, vasoactive intestinal peptide, neuropeptide Y, NBNP, endothelin 1, and gastrin-releasing peptide), and neurotrophins (eg, nerve growth factor and brain-derived neurotrophic factor). Moreover, ion channels such as voltage-gated sodium channels, transient receptor potential vanilloid 1, transient receptor ankyrin, and transient receptor potential cation channel subfamily M (melastatin) member 8 play a crucial role. The main markers of nonhistaminergic pruriceptors are PAR-2 and MrgprX2. A notable phenomenon is the sensitization to pruritus, in which regardless of the initial cause of pruritus, there is an increased responsiveness of peripheral and central pruriceptive neurons to their normal or subthreshold afferent input in the context of chronic itch.


Assuntos
Neurônios , Prurido , Humanos , Prurido/metabolismo , Neurônios/metabolismo , Sistema Nervoso Central , Citocinas/metabolismo , Epiderme/metabolismo
2.
Pain ; 164(3): e144-e156, 2023 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-35916738

RESUMO

ABSTRACT: The pathophysiology of primary burning mouth syndrome (BMS) remains controversial. Targeted analyses or "omics" approach of saliva provide diagnostic or pathophysiological biomarkers. This pilot study's primary objective was to explore the pathophysiology of BMS through a comparative analysis of the salivary metabolome among 26 BMS female cases and 25 age- and sex-matched control subjects. Secondary objectives included comparative analyses of inflammatory cytokines, neuroinflammatory markers, and steroid hormones among cases and control subjects, and among BMS patients according to their clinical characteristics. Salivary metabolome, neuroinflammatory markers, cytokines, and steroids were, respectively, analysed by liquid chromatography coupled with mass spectrometry, ELISA and protease activity assay, and multiparametric Luminex method. Among the 166 detected metabolites, univariate analysis did not find any discriminant metabolite between groups. Supervised multivariate analysis divided patients into 2 groups with an accuracy of 60% but did not allow significant discrimination (permutation test, P = 0.35). Among the metabolites contributing to the model, 3 belonging to the tyrosine pathway ( l -dopa, l -tyrosine, and tyramine) were involved in the discrimination between cases and control subjects, and among BMS patients according to their levels of pain. Among the detectable molecules, levels of cytokines, steroid hormones, and neuroinflammatory markers did not differ between cases and control subjects and were not associated with characteristics of BMS patients. These results do not support the involvement of steroid hormones, inflammatory cytokines, or inflammatory neurogenic mediators in the pathophysiology of pain in BMS, whereas the observed shift in tyrosine metabolism may indicate an adaptative response to chronic pain or an impaired dopaminergic transmission.


Assuntos
Síndrome da Ardência Bucal , Dor Crônica , Humanos , Feminino , Estudos de Casos e Controles , Projetos Piloto , Saliva/química , Citocinas/metabolismo , Dor Crônica/metabolismo , Metaboloma , Hormônios
3.
Food Chem Toxicol ; 159: 112757, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34915065

RESUMO

Seaweeds accumulate toxic contaminants present in the surrounding waters such as trace elements, ammonium, dioxins and pesticides. Seaweed consumption data are scarce in France as in Europe. Given that seaweed consumption data are essential to assess exposure and the risks for human health linked to toxic substances, it would appear essential to generate these data. The aim of the study was to assess the current consumption of seaweed foodstuffs by the French population via an online survey conducted on 780 adults (seaweed foodstuffs consumed, percentage of consumers and frequency of consumption). The daily consumption of seaweeds was assessed. Enquiries at points of purchase were also performed to reference the type of foodstuffs found on the French market, the seaweed species present, and the percentage of seaweed in the product. These new data generated in this work will be useful for safety assessors and for safety agencies.


Assuntos
Dieta/estatística & dados numéricos , Alga Marinha , Adolescente , Adulto , Inquéritos sobre Dietas , Feminino , França , Humanos , Iodo , Masculino , Metais Pesados , Agricultura Orgânica , Medição de Risco , Alga Marinha/química , Alga Marinha/classificação , Adulto Jovem
4.
Mar Drugs ; 19(9)2021 Sep 15.
Artigo em Inglês | MEDLINE | ID: mdl-34564182

RESUMO

Brevetoxins (BTXs) are marine biotoxins responsible for neurotoxic shellfish poisoning (NSP) after ingestion of contaminated shellfish. NSP is characterized by neurological, gastrointestinal and/or cardiovascular symptoms. The main known producer of BTXs is the dinoflagellate Karenia brevis, but other microalgae are also suspected to synthesize BTX-like compounds. BTXs are currently not regulated in France and in Europe. In November 2018, they have been detected for the first time in France in mussels from a lagoon in the Corsica Island (Mediterranean Sea), as part of the network for monitoring the emergence of marine biotoxins in shellfish. To prevent health risks associated with the consumption of shellfish contaminated with BTXs in France, a working group was set up by the French Agency for Food, Environmental and Occupational Health & Safety (Anses). One of the aims of this working group was to propose a guidance level for the presence of BTXs in shellfish. Toxicological data were too limited to derive an acute oral reference dose (ARfD). Based on human case reports, we identified two lowest-observed-adverse-effect levels (LOAELs). A guidance level of 180 µg BTX-3 eq./kg shellfish meat is proposed, considering a protective default portion size of 400 g shellfish meat.


Assuntos
Dinoflagellida , Toxinas Marinhas/análise , Oxocinas/análise , Intoxicação por Frutos do Mar/prevenção & controle , Frutos do Mar , Animais , Monitoramento Ambiental , França , Humanos , Mar Mediterrâneo
5.
Mar Drugs ; 19(7)2021 Jul 06.
Artigo em Inglês | MEDLINE | ID: mdl-34356812

RESUMO

Ciguatera fish poisoning (CFP) and neurotoxic shellfish poisoning syndromes are induced by the consumption of seafood contaminated by ciguatoxins and brevetoxins. Both toxins cause sensory symptoms such as paresthesia, cold dysesthesia and painful disorders. An intense pruritus, which may become chronic, occurs also in CFP. No curative treatment is available and the pathophysiology is not fully elucidated. Here we conducted single-cell calcium video-imaging experiments in sensory neurons from newborn rats to study in vitro the ability of Pacific-ciguatoxin-2 (P-CTX-2) and brevetoxin-1 (PbTx-1) to sensitize receptors and ion channels, (i.e., to increase the percentage of responding cells and/or the response amplitude to their pharmacological agonists). In addition, we studied the neurotrophin release in sensory neurons co-cultured with keratinocytes after exposure to P-CTX-2. Our results show that P-CTX-2 induced the sensitization of TRPA1, TRPV4, PAR2, MrgprC, MrgprA and TTX-r NaV channels in sensory neurons. P-CTX-2 increased the release of nerve growth factor and brain-derived neurotrophic factor in the co-culture supernatant, suggesting that those neurotrophins could contribute to the sensitization of the aforementioned receptors and channels. Our results suggest the potential role of sensitization of sensory receptors/ion channels in the induction or persistence of sensory disturbances in CFP syndrome.


Assuntos
Ciguatera , Ciguatoxinas/farmacologia , Toxinas Marinhas/farmacologia , Oxocinas/farmacologia , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Animais Recém-Nascidos , Organismos Aquáticos , Modelos Animais , Oceano Pacífico , Dor/metabolismo , Prurido/metabolismo , Ratos , Ratos Wistar
6.
Br J Pharmacol ; 178(24): 4775-4791, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34463358

RESUMO

Until recently, itch pathophysiology was poorly understood and treatments were poorly effective in relieving itch. Current progress in our knowledge of the itch processing, the numerous mediators and receptors involved has led to a large variety of possible therapeutic pathways. Currently, inhibitors of IL-31, IL-4/13, NK1 receptors, opioids and cannabinoids, JAK, PDE4 or TRP are the main compounds involved in clinical trials. However, many new targets, such as Mas-related GPCRs and unexpected new pathways need to be also explored.


Assuntos
Prurido , Receptores da Neurocinina-1 , Humanos , Terapia de Alvo Molecular , Prurido/tratamento farmacológico
7.
J Invest Dermatol ; 141(3): 648-658.e3, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-32800876

RESUMO

Ciguatera fish poisoning is caused by the consumption of fish contaminated with ciguatoxins (CTXs). The most distressing symptoms are cutaneous sensory disturbances, including cold dysesthesia and itch. CTXs are neurotoxins known to activate voltage-gated sodium channels, but no specific treatment exists. Peptidergic neurons have been critically involved in ciguatera fish poisoning sensory disturbances. Protease-activated receptor-2 (PAR2) is an itch- and pain-related G protein‒coupled receptor whose activation leads to a calcium-dependent neuropeptide release. In this study, we studied the role of voltage-gated sodium channels, PAR2, and the PAR2 agonist cathepsin S in the cytosolic calcium increase and subsequent release of the neuropeptide substance P elicited by Pacific CTX-2 (P-CTX-2) in rat sensory neurons and human epidermal keratinocytes. In sensory neurons, the P-CTX-2‒evoked calcium response was driven by voltage-gated sodium channels and PAR2-dependent mechanisms. In keratinocytes, P-CTX-2 also induced voltage-gated sodium channels and PAR2-dependent marked calcium response. In the cocultured cells, P-CTX-2 significantly increased cathepsin S activity, and cathepsin S and PAR2 antagonists almost abolished P-CTX-2‒elicited substance P release. Keratinocytes synergistically favored the induced substance P release. Our results demonstrate that the sensory effects of CTXs involve the cathepsin S-PAR2 pathway and are potentiated by their direct action on nonexcitable keratinocytes through the same pathway.


Assuntos
Ciguatera/patologia , Ciguatoxinas/toxicidade , Epiderme/patologia , Queratinócitos/metabolismo , Células Receptoras Sensoriais/metabolismo , Animais , Cálcio/metabolismo , Catepsinas/metabolismo , Ciguatera/complicações , Técnicas de Cocultura , Citosol/metabolismo , Modelos Animais de Doenças , Epiderme/inervação , Humanos , Microscopia Intravital , Queratinócitos/efeitos dos fármacos , Queratinócitos/patologia , Parestesia/etiologia , Parestesia/patologia , Cultura Primária de Células , Prurido/etiologia , Prurido/patologia , Ratos , Receptor PAR-2/agonistas , Receptor PAR-2/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Análise de Célula Única , Substância P/metabolismo
8.
Cells ; 9(12)2020 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-33348659

RESUMO

Red tides involving Karenia brevis expose humans to brevetoxins (PbTxs). Oral exposition triggers neurotoxic shellfish poisoning, whereas inhalation induces a respiratory syndrome and sensory disturbances. No curative treatment is available and the pathophysiology is not fully elucidated. Protease-activated receptor 2 (PAR2), cathepsin S (Cat-S) and substance P (SP) release are crucial mediators of the sensory effects of ciguatoxins (CTXs) which are PbTx analogs. This work explored the role of PAR2 and Cat-S in PbTx-1-induced sensory effects and deciphered the signaling pathway involved. We performed calcium imaging, PAR2 immunolocalization and SP release experiments in monocultured sensory neurons or co-cultured with keratinocytes treated with PbTx-1 or P-CTX-2. We demonstrated that PbTx-1-induced calcium increase and SP release involved Cat-S, PAR2 and transient receptor potential vanilloid 4 (TRPV4). The PbTx-1-induced signaling pathway included protein kinase A (PKA) and TRPV4, which are compatible with the PAR2 biased signaling induced by Cat-S. Internalization of PAR2 and protein kinase C (PKC), inositol triphosphate receptor and TRPV4 activation evoked by PbTx-1 are compatible with the PAR2 canonical signaling. Our results suggest that PbTx-1-induced sensory disturbances involve the PAR2-TRPV4 pathway. We identified PAR2, Cat-S, PKA, and PKC that are involved in TRPV4 sensitization induced by PbTx-1 in sensory neurons.


Assuntos
Cálcio/metabolismo , Toxinas Marinhas/farmacologia , Oxocinas/farmacologia , Receptor PAR-2/metabolismo , Transdução de Sinais/efeitos dos fármacos , Substância P/metabolismo , Animais , Catepsinas/genética , Catepsinas/metabolismo , Catepsinas/farmacologia , Células Cultivadas , Dipeptídeos/farmacologia , Potenciais Evocados/efeitos dos fármacos , Humanos , Isoxazóis/farmacologia , Queratinócitos/citologia , Queratinócitos/efeitos dos fármacos , Queratinócitos/metabolismo , Proteína Quinase C/antagonistas & inibidores , Proteína Quinase C/metabolismo , Ratos , Ratos Wistar , Receptor PAR-2/genética , Proteínas Recombinantes/biossíntese , Proteínas Recombinantes/farmacologia , Células Receptoras Sensoriais/citologia , Células Receptoras Sensoriais/efeitos dos fármacos , Células Receptoras Sensoriais/metabolismo , Canais de Cátion TRPV/antagonistas & inibidores , Canais de Cátion TRPV/metabolismo
9.
Cells ; 9(10)2020 10 14.
Artigo em Inglês | MEDLINE | ID: mdl-33066435

RESUMO

Ciguatera fish poisoning (CFP), the most prevalent seafood poisoning worldwide, is caused by the consumption of tropical and subtropical fish contaminated with potent neurotoxins called ciguatoxins (CTXs). Ciguatera is a complex clinical syndrome in which peripheral neurological signs predominate in the acute phase of the intoxication but also persist or reoccur long afterward. Their recognition is of particular importance in establishing the diagnosis, which is clinically-based and can be a challenge for physicians unfamiliar with CFP. To date, no specific treatment exists. Physiopathologically, the primary targets of CTXs are well identified, as are the secondary events that may contribute to CFP symptomatology. This review describes the clinical features, focusing on the sensory disturbances, and then reports on the neuronal targets and effects of CTXs, as well as the neurophysiological and histological studies that have contributed to existing knowledge of CFP neuropathophysiology at the molecular, neurocellular and nerve levels.


Assuntos
Ciguatera/fisiopatologia , Doenças do Sistema Nervoso/etiologia , Doenças do Sistema Nervoso/fisiopatologia , Potenciais de Ação , Animais , Ciguatera/diagnóstico , Ciguatera/prevenção & controle , Ciguatera/terapia , Ciguatoxinas/química , Erros de Diagnóstico , Humanos , Doenças do Sistema Nervoso/epidemiologia , Prevalência
10.
Ann Neurol ; 88(6): 1205-1219, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-32951274

RESUMO

OBJECTIVE: Pain, temperature, and itch are conventionally thought to be exclusively transduced by the intraepidermal nerve endings. Although recent studies have shown that epidermal keratinocytes also participate in sensory transduction, the mechanism underlying keratinocyte communication with intraepidermal nerve endings remains poorly understood. We sought to demonstrate the synaptic character of the contacts between keratinocytes and sensory neurons and their involvement in sensory communication between keratinocytes and sensory neurons. METHODS: Contacts were explored by morphological, molecular, and functional approaches in cocultures of epidermal keratinocytes and sensory neurons. To interrogate whether structures observed in vitro were also present in the human epidermis, in situ correlative light electron microscopy was performed on human skin biopsies. RESULTS: Epidermal keratinocytes dialogue with sensory neurons through en passant synaptic-like contacts. These contacts have the ultrastructural features and molecular hallmarks of chemical synaptic-like contacts: narrow intercellular cleft, keratinocyte synaptic vesicles expressing synaptophysin and synaptotagmin 1, and sensory information transmitted from keratinocytes to sensory neurons through SNARE-mediated (syntaxin1) vesicle release. INTERPRETATION: By providing selective communication between keratinocytes and sensory neurons, synaptic-like contacts are the hubs of a 2-site receptor. The permanent epidermal turnover, implying a specific en passant structure and high plasticity, may have delayed their identification, thereby contributing to the long-held concept of nerve endings passing freely between keratinocytes. The discovery of keratinocyte-sensory neuron synaptic-like contacts may call for a reassessment of basic assumptions in cutaneous sensory perception and sheds new light on the pathophysiology of pain and itch as well as the physiology of touch. ANN NEUROL 2020;88:1205-1219.


Assuntos
Queratinócitos/ultraestrutura , Células Receptoras Sensoriais/ultraestrutura , Sinapses/ultraestrutura , Adulto , Idoso , Animais , Técnicas de Cocultura , Epiderme/inervação , Feminino , Humanos , Queratinócitos/metabolismo , Masculino , Microscopia Eletrônica , Pessoa de Meia-Idade , Proteínas Qa-SNARE/metabolismo , Ratos , Vesículas Sinápticas/metabolismo , Sinaptofisina/metabolismo , Sinaptotagmina I/metabolismo
11.
Front Physiol ; 10: 862, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31333501

RESUMO

Skin is constantly subjected to pressure at different levels. Pressure-induced vasodilation (PIV) is one of the response mechanisms to low pressure that maintains the homeostasis of the skin. PIV results from the interaction of primary afferent nerves and vascular endothelium of skin vessels. Thanks to this cutaneous neuro-vascular interaction, the cutaneous blood flow increase allows the maintenance of an optimal level of oxygenation and minimizes the lack of vascularization of the skin tissue under low pressure. It seems to be associated with the cutaneous protection mechanisms to prevent pressure ulcers. In some contexts, where microangiopathy and neuropathy can occur, such as aging and diabetes, PIV is impaired, leading to a dramatic early decrease in local skin blood flow when low pressure is applied. In aging, PIV alteration is due to endothelial dysfunction, essentially from an alteration of the nitric oxide pathway. In the inflamm-aging context, oxidative stress increases leading to endothelial cell and nerve damages. An age-related sensory neuropathy will exacerbate the alteration of PIV during the aging process. In diabetes, non-controlled hyperglycaemia leads to an increase in several pathological biochemical pathways that involve oxidative stress and can affect PIV. Sorbinil, alagebrium and alpha-lipoic acid are able individually to restore PIV through a possible oxidative stress reduction. Candesartan, an angiotensin II type 1 receptor blocker, is also able to restore PIV and prevent pressure ulcer formation. The possibility of preventing pressure ulcer associated to diabetes and/or aging with the restoration of PIV seems to be a promising research path.

12.
J Invest Dermatol ; 138(7): 1564-1572, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29458120

RESUMO

PAR2 activation in basal keratinocytes stimulates inflammation via the Ca2+-dependent production of mediators such as IL-1ß, TNF-α, and TSLP. In this study, we investigated PAR2 calcium signaling and the consequent production of inflammatory mediators in differentiated human primary keratinocytes (DhPKs). Stimulation with the PAR2-activating peptide SLIGKV promoted Ca2+ store depletion in both undifferentiated human primary keratinocytes and DhPKs. SLIGKV-evoked Ca2+ store depletion did not trigger the store-operated Ca2+ entry (i.e., SOCE) through ORAI1 in DhPKs compared with undifferentiated human primary keratinocytes. The inhibition of phospholipase C and the concomitant inhibition of TRPV1 and inositol triphosphate receptor in DhPKs abrogated the SLIGKV-evoked Ca2+ store depletion; NF-κB activity; and the production of inflammatory mediators such as IL-1ß, TNF-α, and TSLP. Taken together, these results indicate a key role for both InsP3R and TRPV1 in Ca2+ internal stores in the PAR2-evoked Ca2+ release and consequent skin inflammation in DhPKs. These findings may provide clues to understanding the pathological role of DhPKs in skin disorders in which PAR2 is known to be involved, such as atopic dermatitis, Netherton syndrome, and psoriasis.


Assuntos
Mediadores da Inflamação/imunologia , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Queratinócitos/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Canais de Cátion TRPV/metabolismo , Sinalização do Cálcio/imunologia , Diferenciação Celular , Dermatite/imunologia , Humanos , Mediadores da Inflamação/metabolismo , Receptores de Inositol 1,4,5-Trifosfato/imunologia , Queratinócitos/efeitos dos fármacos , Proteína ORAI1/genética , Proteína ORAI1/imunologia , Proteína ORAI1/metabolismo , Oligopeptídeos/farmacologia , Cultura Primária de Células , RNA Interferente Pequeno/metabolismo , Receptor PAR-2 , Receptores Acoplados a Proteínas G/imunologia , Canais de Cátion TRPV/genética , Canais de Cátion TRPV/imunologia
13.
Toxicon ; 149: 6-19, 2018 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-29360534

RESUMO

Ciguatoxins (CTXs) and brevetoxins (PbTxs) are phycotoxins that can accumulate along the marine food chain and thus cause seafood poisoning in humans, namely "ciguatera fish poisoning" (CFP) and "neurotoxic shellfish poisoning" (NSP), respectively. CFP is characterized by early gastrointestinal symptoms and typical sensory disorders (paraesthesia, pain, pruritus and cold dysaesthesia), which can persist several weeks and, in some cases, several months or years. NSP is considered a mild form of CFP with similar but less severe symptoms. After inhaled exposure, PbTxs can also cause respiratory tract irritation in healthy subjects and asthma exacerbations in predisposed subjects, whose respiratory functions may be disrupted for several days following PbTx inhalation. Mechanistically, it is well established that CTX- or PbTx-induced disturbances are primarily mainly due to voltage-gated sodium channel activation in sensory and motor peripheral nervous system. However, little is known about the pathophysiology or a potential individual susceptibility to long lasting effects of CFP/NSP. In addition to their action on the nervous system, PbTxs and CTXs were also shown to exert effects on the immune system. However, their role in the pathophysiology of syndromes induced by CTX or PbTx exposure is poorly documented. The aim of this review is to inventory the literature thus far on the inflammatory and immune effects of PbTxs and CTXs.


Assuntos
Ciguatoxinas/toxicidade , Sistema Imunitário/efeitos dos fármacos , Toxinas Marinhas/toxicidade , Oxocinas/toxicidade , Humanos , Imunidade Inata/efeitos dos fármacos , Modelos Imunológicos , Canais de Sódio Disparados por Voltagem/efeitos dos fármacos
14.
Protein Cell ; 8(9): 644-661, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28364279

RESUMO

Cutaneous neurogenic inflammation (CNI) is inflammation that is induced (or enhanced) in the skin by the release of neuropeptides from sensory nerve endings. Clinical manifestations are mainly sensory and vascular disorders such as pruritus and erythema. Transient receptor potential vanilloid 1 and ankyrin 1 (TRPV1 and TRPA1, respectively) are non-selective cation channels known to specifically participate in pain and CNI. Both TRPV1 and TRPA1 are co-expressed in a large subset of sensory nerves, where they integrate numerous noxious stimuli. It is now clear that the expression of both channels also extends far beyond the sensory nerves in the skin, occuring also in keratinocytes, mast cells, dendritic cells, and endothelial cells. In these non-neuronal cells, TRPV1 and TRPA1 also act as nociceptive sensors and potentiate the inflammatory process. This review discusses the role of TRPV1 and TRPA1 in the modulation of inflammatory genes that leads to or maintains CNI in sensory neurons and non-neuronal skin cells. In addition, this review provides a summary of current research on the intracellular sensitization pathways of both TRP channels by other endogenous inflammatory mediators that promote the self-maintenance of CNI.


Assuntos
Dermatite/metabolismo , Regulação da Expressão Gênica , Células Receptoras Sensoriais/metabolismo , Canal de Cátion TRPA1/biossíntese , Canais de Cátion TRPV/biossíntese , Animais , Doença Crônica , Células Dendríticas/metabolismo , Células Dendríticas/patologia , Dermatite/patologia , Humanos , Inflamação/metabolismo , Inflamação/patologia , Queratinócitos/metabolismo , Queratinócitos/patologia , Mastócitos/metabolismo , Mastócitos/patologia , Células Receptoras Sensoriais/patologia
15.
Toxicon ; 116: 4-10, 2016 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-26562445

RESUMO

Ciguatoxins are the major toxins responsible for ciguatera fish poisoning, a disease dominated by muco-cutaneous sensory disorders including paresthesiae, cold dysesthesia and pruritus. While the ciguatoxins are well known to target voltage-gated sodium channels (VGSCs), the ensuing molecular mechanisms underlying these sensory disorders remain poorly understood. In this study, we propose a primary sensory neuron-keratinocyte co-culture as an appropriate model to study the neuro-cutaneous effects of ciguatoxins. Using this model, we show for the first time that nanomolar concentrations of Pacific ciguatoxin-2 (P-CTX-2) induced a VGSC-dependent release of substance P (SP) and calcitonin gene-related peptide (CGRP). As these neuropeptides are known mediators of pain and itch sensations, the ciguatoxin-induced sensory disturbances in ciguatera fish poisoning may involve the release of these neuropeptides. We further determined time- and P-CTX-2 concentration-dependence of the release of SP and CGRP from the co-culture model. Moreover, we highlighted the influence of extracellular calcium on the release of neuropeptides elicited by P-CTX-2. These findings underline the usefulness of this novel in vitro model for studying the cellular and molecular mechanisms of the neuro-cutaneous effects of ciguatoxins, which may assist with identifying potential therapeutics for ciguatera fish poisoning.


Assuntos
Ciguatoxinas/farmacologia , Queratinócitos/efeitos dos fármacos , Modelos Biológicos , Neuropeptídeos/metabolismo , Células Receptoras Sensoriais/efeitos dos fármacos , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Cálcio/metabolismo , Ciguatera , Ciguatoxinas/química , Técnicas de Cocultura , Humanos , Imuno-Histoquímica , Queratinócitos/citologia , Ratos , Células Receptoras Sensoriais/citologia
16.
Nat Rev Neurol ; 10(7): 408-16, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24912513

RESUMO

Pruritus, also known as itch, is a very common, unpleasant sensation that elicits an urge to scratch. Its origin is not always in the skin, and neuropathic itch that is caused by neuronal or glial damage is common, but poorly understood by both dermatologists and neurologists. Although pruritus has not been considered as serious a symptom as pain, it is difficult to treat and--if chronic--can severely impair quality of life. Neuropathic itch is often associated with other clinical symptoms, most commonly neuropathic pain, and hypersensitization to stimuli is present in both pruritus and pain of neuropathic origin. The shared aetiology can aid in finding suitable treatment for itch in some cases, but more detailed knowledge of the mechanisms of itch, along with standardized, well-controlled trials, is needed. Pruritus research is an emerging but currently very active field, and our understanding of this sensation is rapidly increasing. Here, we review new discoveries regarding the role of the nervous system and the contribution of different pathways in pruritus, discuss the different aetiologies of neuropathic itch, and outline currently available and potential strategies for managing neuropathic pruritus.


Assuntos
Sistema Nervoso Central/patologia , Doenças do Sistema Nervoso/complicações , Prurido/tratamento farmacológico , Prurido/etiologia , Humanos , Imageamento por Ressonância Magnética , Prurido/diagnóstico
17.
J Ethnopharmacol ; 142(2): 516-22, 2012 Jul 13.
Artigo em Inglês | MEDLINE | ID: mdl-22633967

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Trigonella foenum-graecum L. (TFG) is traditionally used to treat diabetes in North Africa. we therefore tested the effects of the hydro-alcoholic extract of TFG seeds in a C57/BL6J mouse model of diabetes induced by a standardised high-fat diet (HFD). MATERIALS AND METHODS: Plant extracts (2 g/kg daily) were administered orally by gavage at the start of HFD, or after confirmation of established diabetes (17th week), for 20 or 18 weeks, respectively, to male C57BL/6J mice. Animals were weighed; food intake and plasma glucose, lipid profile, insulin and insulin resistance were measured. RESULTS: TFG extracts opposed the development of diabetes: compared with untreated HFD mice, TFG-treated HFD mice had lower mean (± SD) plasma glucose (129.3 ± 39.4 vs. 183.1 ± 19.1mg/dL, p<0.05), plasma insulin (1.3 ± 0.8 vs. 3.1 ± 1.8 ng/mL, p<0.05) and triglycerides (18.9 ± 12.9 vs. 48.9 ± 12.1mg/dL, p<0.05), and less insulin resistance as estimated by the homeostasis model assessment (HOMA: 9.7 ± 11.1 vs. 38.3 ± 26.6, p<0.05). In mice with established diabetes, TFG reduced fasting plasma glucose (170.4 ± 24.1 vs. 229.0 ± 20.8 mg/dL, p<0.05), plasma insulin (1.7 ± 1.3 vs. 3.3 ± 14.3 ng/mL, p<0.05) and insulin resistance (HOMA: TFG: 19.2 ± 15.7 vs. HFD control: 38.5 ± 30.3, p<0.05). In addition, administration of TFG extract also caused significant reduction in triglycerides (17.9 ± 9.7 vs. 62.8 ± 18.3 mg/dL, p<0.05) and total cholesterol (1.30 ± 0.20 vs. 1.80 ± 1.10 g/L, p<0.05), and an increase in HDL-cholesterol (1.6 ± 0.2 vs. 1.2 ± 0.1 g/L). The plant extract had no effect on calorie intake or body weight. CONCLUSION: TFG extract opposed the development of experimental HFD diabetes in mice, and had an anti-diabetic effect in mice with established diabetes.


Assuntos
Glicemia/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Dieta Hiperlipídica/efeitos adversos , Hipoglicemiantes/uso terapêutico , Insulina/sangue , Fitoterapia , Trigonella , Animais , Colesterol/sangue , HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Diabetes Mellitus Tipo 2/prevenção & controle , Modelos Animais de Doenças , Hipoglicemiantes/farmacologia , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Sementes , Triglicerídeos/sangue
18.
J Ethnopharmacol ; 133(2): 931-3, 2011 Jan 27.
Artigo em Inglês | MEDLINE | ID: mdl-21094236

RESUMO

AIM OF THE STUDY: Hydro-alcoholic extracts of Centaurium erythraea Rafn (CE), Gentianaceae and Artemisia herba-alba Asso (AHA), Asteraceae, medicinal plants used in traditional treatment of diabetes in north-eastern Algeria, were tested in established type 2 diabetes induced with a standardized high fat diet (HFD) in mice. MATERIALS AND METHODS: After confirmation of diabetes (17th week), plant extracts were administered orally by gavage at a dose of 2 g/kg daily for 18 weeks to male C57BL/6J mice fed HFD. Animals were weighed, food intake and plasma glucose measured weekly, insulin and lipid profile at study end. RESULTS: At 35 weeks, groups treated with AHA or CE vs. HFD control had a significant reduction in mean (±SD) fasting blood glucose concentrations (143.8±23.9 and 139.5±14.2 vs. 229.0±20.8 mg/dL, p<0.05, respectively), triglyceride (18.9±11.1 and 16.0±6.5 vs. 62.8±18.3 mg/dL, p<0.05), total cholesterol (1.2±0.1 and 1.2±0.3 vs. 1.8±1.1 g/L, p<0.05) and serum insulin concentrations (1.7±0.7 and 0.9±0.7 vs. 3.3±14.3 ng/mL, p<0.05). Plant extracts also markedly reduced insulin resistance as compared to HFD controls (AHA: 15.6±9.1, CE: 9.0±7.7 vs. HFD control 38.5±30.3, p<0.05). The plant extracts decreased calorie intake and had little effect on body weight or HDL-cholesterol. CONCLUSION: AHA has already been shown to have a antihyperglycaemic and antihyperlipidemic effect but this is the first demonstration of an effect of AHA and CE on established HFD-induced diabetes.


Assuntos
Artemisia , Centaurium , Diabetes Mellitus Tipo 2/tratamento farmacológico , Hipoglicemiantes/farmacologia , Fitoterapia , Argélia , Animais , Glicemia/metabolismo , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/etiologia , Gorduras na Dieta/administração & dosagem , Etnofarmacologia , Hipoglicemiantes/isolamento & purificação , Insulina/sangue , Lipídeos/sangue , Masculino , Medicinas Tradicionais Africanas , Camundongos , Camundongos Endogâmicos C57BL , Extratos Vegetais/farmacologia , Plantas Medicinais
19.
Blood Cells Mol Dis ; 36(1): 1-9, 2006.
Artigo em Inglês | MEDLINE | ID: mdl-16364667

RESUMO

The mechanisms underlying the swelling of frog red blood cells (RBC), induced by Pacific (P-CTX-1) and Caribbean (C-CTX-1) ciguatoxins (CTXs), were investigated by measuring the length, width and surface of their elliptic shape. P-CTX-1 (0.5 to 5 nM) and C-CTX-1 (1 nM) induced RBC swelling within 60 min. The CTXs-induced RBC swelling was blocked by apamin (1 microM) and by Sr(2+) (1 mM). P-CTX-1-induced RBC swelling was prevented and inhibited by H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (27 microM), an inhibitor of soluble guanylate cyclase (sGC), and NOS blockade by NG methyl-l-arginine (l-NMA; 10 microM). Cytochalasin D (cytD, 10 microM) increased RBC surface and mimicked CTX effect but did not prevent the P-CTX-1-induced l-NMA-sensitive extra increase. Calculations revealed that P-CTX-1 and cytD increase RBC total surface envelop and volume. These data strongly suggest that the molecular mechanisms underlying CTXs-induced RBC swelling involve the NO pathway by an activation of the inducible NOS, leading to sGC activation which modulates intracellular cGMP and regulates L-type Ca(2+) channels. The resulting increase in intracellular Ca(2+) content, in turn, disrupts the actin cytoskeleton, which causes a water influx and triggers a Ca(2+)-activated K(+) current through SK2 isoform channels.


Assuntos
Permeabilidade da Membrana Celular/efeitos dos fármacos , Tamanho Celular/efeitos dos fármacos , Ciguatoxinas/toxicidade , Membrana Eritrocítica/enzimologia , Guanilato Ciclase/metabolismo , Óxido Nítrico Sintase Tipo II/metabolismo , Actinas/metabolismo , Animais , Cálcio/metabolismo , Canais de Cálcio Tipo L/metabolismo , GMP Cíclico/metabolismo , Citoesqueleto/metabolismo , Inibidores Enzimáticos/farmacologia , Membrana Eritrocítica/efeitos dos fármacos , Membrana Eritrocítica/patologia , Guanilato Ciclase/antagonistas & inibidores , Óxido Nítrico Sintase Tipo II/antagonistas & inibidores , Rana esculenta , Água/metabolismo
20.
Toxicon ; 46(6): 625-34, 2005 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-16165180

RESUMO

The effects of 31 plant extracts, which most are traditionally used to treat ciguatera fish poisoning in the Pacific area, were studied on the cytotoxicity of mouse neuroblastoma cells produced by ouabain, veratridine and/or brevetoxin-3 or Pacific ciguatoxin-1. The cell viability was determined using a quantitative colorimetric method. A marked cytotoxicity of seven of the 31 plant extracts studied, was observed. Despite this, these plant extracts were suspected to contain active compound(s) against the cytotoxicity produced by brevetoxin (2 extracts), brevetoxin, ouabain and/or veratridine (3 extracts), or only against that of ouabain and/or veratridine (2 extracts). Among the 24 plant extracts that exhibited by themselves no cytotoxicity, 22 were active against the effect of brevetoxin or against that of both veratridine and brevetoxin. Similar results were obtained when the seven most active plant extracts were reassayed using ciguatoxin instead of brevetoxin. In conclusion, the present work reports the first activity assessment of some plant extracts, achieved in vitro on a quite large scale. The fact that 27 plant extracts were found to exert, in vitro, a protective effect against the action of ciguatoxin and/or brevetoxin, paves the way for finding new active compounds to treat ciguatera fish poisoning, provided these compounds also reverse the effects of sodium channel activators.


Assuntos
Ciguatoxinas/antagonistas & inibidores , Toxinas Marinhas/antagonistas & inibidores , Ouabaína/antagonistas & inibidores , Oxocinas/antagonistas & inibidores , Extratos Vegetais/farmacologia , Agonistas de Canais de Sódio , Veratridina/antagonistas & inibidores , Animais , Bioensaio , Linhagem Celular Tumoral , Ciguatoxinas/toxicidade , Colorimetria , Testes Imunológicos de Citotoxicidade , Toxinas Marinhas/toxicidade , Camundongos , Ouabaína/toxicidade , Oxocinas/toxicidade , Canais de Sódio/metabolismo , Especificidade da Espécie , Veratridina/toxicidade
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