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1.
Acta Virol ; 63(3): 253-260, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31507190

RESUMO

The human immunodeficiency virus (HIV) envelope, via a key extracellular amino acid sequence, may simulate the functionality of native undecapeptide substance P (SP) acting through the host's neurokinin 1 (SP preferring) receptor (NK-1R). Human monocytes and macrophages express both NK-1Rs and SP. In HIV/AIDS the NK-1R may function as a chemokine-like G-protein coupled co-receptor that: 1) fuses to the outer envelope of HIV; 2) enables intracellular entry of the envelope-capsid-NK-1R complex; 3) co-opts immune defence via its physiological interaction with the SP-like envelope; 4) may contribute to resistance of CD4/chemokine entry inhibitor type drugs; 5) relaxes the blood-brain barrier to support entry of the HIV into the central nervous system, and 6) mediates most of the common clinical sequelae of HIV/AIDS (encephalopathy and AIDS dementia complex). The data support the idea that NK-1R antagonists could be useful to treat HIV/AIDS. Keywords: human immunodeficiency virus; NK-1 receptor; NK-1 receptor antagonist; aprepitant; fusion protein; virus.


Assuntos
Infecções por HIV , Receptores da Neurocinina-1 , Substância P , Proteínas Virais de Fusão , Dipeptídeos/genética , Dipeptídeos/metabolismo , Proteína gp120 do Envelope de HIV/metabolismo , Infecções por HIV/tratamento farmacológico , Infecções por HIV/fisiopatologia , Humanos , Macrófagos/virologia , Monócitos/metabolismo , Monócitos/virologia , Antagonistas do Receptor de Neuroquinina-1/uso terapêutico , Receptores da Neurocinina-1/metabolismo , Substância P/metabolismo , Proteínas Virais de Fusão/metabolismo
2.
J Med Food ; 22(10): 1009-1021, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31536448

RESUMO

Constipation is a common gastrointestinal disorder characterized by changes in intestinal habits. Increasing evidence indicates that long-term use of irritant laxatives causes serious side effects. Meanwhile, more than 50% of patients are dissatisfied with sense of use of non-prescriptional laxatives. ß-glucans are natural polysaccharides widely found in yeast, fungus, and plants, which have been reported to exhibit various pharmacological effects. The aim of this study was to characterize the effect of ß-glucans extracted from the bread yeast cell wall on loperamide-induced constipation mice. Forty mice were fed with loperamide (10 mg/kg) to make the constipation model and a diet supplemented with 2.5, 5, and 10 mg/kg ß-glucan. We assessed the defecation frequency, intestinal transit function of mice, as well as used high-throughput sequencing to analyze the intestinal microbiota composition and functional biological profiles data. Meanwhile, we detected expression of neurotransmitters including acetylcholinesterase, substance P, and serotonin (5-HT) and expression of tight junction protein (TJP) including zonula occludens-1 and mucin-2 in distal colon to characterize the possible molecular mechanisms. ß-glucans significantly enhanced intestinal motility and provided a possibility to regulate the expression of neurotransmitters and TJP in mice. The intestinal microecological portion of the treatment group partially recovered and was closer to the normal group. This study showed that ß-glucans can influence the intestinal microbiota and restore microecological balance to regulate the express of neurotransmitters and TJP to recover intestinal epithelial mechanical barrier. We suggested that ß-glucans could be used as an active nutritional supplement to protect the damaged intestinal barrier and help patients who have constipation complications and dysbiosis.


Assuntos
Constipação Intestinal/tratamento farmacológico , Microbioma Gastrointestinal , Loperamida/efeitos adversos , Saccharomyces cerevisiae/química , beta-Glucanas/farmacologia , Acetilcolinesterase/metabolismo , Animais , Constipação Intestinal/induzido quimicamente , Defecação/efeitos dos fármacos , Trânsito Gastrointestinal/efeitos dos fármacos , Masculino , Metagenoma , Camundongos , Camundongos Endogâmicos BALB C , Mucina-2/metabolismo , Serotonina/metabolismo , Substância P/metabolismo , Proteína da Zônula de Oclusão-1/metabolismo
3.
Endocrinology ; 160(10): 2453-2463, 2019 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504389

RESUMO

The tachykinin neurokinin B (NKB, Tac2) is critical for proper GnRH release in mammals, however, the role of the other tachykinins, such as substance P (SP) and neurokinin A (NKA) in reproduction, is still not well understood. In this study, we demonstrate that NKA controls the timing of puberty onset (similar to NKB and SP) and stimulates LH release in adulthood through NKB-independent (but kisspeptin-dependent) mechanisms in the presence of sex steroids. Furthermore, this is achieved, at least in part, through the autosynaptic activation of Tac1 neurons, which express NK2R (Tacr2), the receptor for NKA. Conversely, in the absence of sex steroids, as observed in ovariectomy, NKA inhibits LH through a mechanism that requires the presence of functional receptors for NKB and dynorphin (NK3R and KOR, respectively). Moreover, the ability of NKA to modulate LH secretion is absent in Kiss1KO mice, suggesting that its action occurs upstream of Kiss1 neurons. Overall, we demonstrate that NKA signaling is a critical component in the central control of reproduction, by contributing to the indirect regulation of kisspeptin release.


Assuntos
Gonadotropinas/metabolismo , Neurocinina A/metabolismo , Animais , Feminino , Kisspeptinas , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurocinina A/genética , Neurocinina B/genética , Neurocinina B/metabolismo , Precursores de Proteínas , Receptores da Neurocinina-2/genética , Receptores da Neurocinina-2/metabolismo , Maturidade Sexual , Substância P/genética , Substância P/metabolismo , Taquicininas
4.
Int J Oral Sci ; 11(3): 24, 2019 09 10.
Artigo em Inglês | MEDLINE | ID: mdl-31501412

RESUMO

Inflammatory orofacial pain, in which substance P (SP) plays an important role, is closely related to the cross-talk between trigeminal ganglion (TG) neurons and satellite glial cells (SGCs). SGC activation is emerging as the key mechanism underlying inflammatory pain through different signalling mechanisms, including glial fibrillary acidic protein (GFAP) activation, phosphorylation of mitogen-activated protein kinase (MAPK) signalling pathways, and cytokine upregulation. However, in the TG, the mechanism underlying SP-mediated orofacial pain generated by SGCs is largely unknown. In this study, we investigated whether SP is involved in inflammatory orofacial pain by upregulating interleukin (IL)-1ß and tumour necrosis factor (TNF)-α from SGCs, and we explored whether MAPK signalling pathways mediate the pain process. In the present study, complete Freund's adjuvant (CFA) was injected into the whisker pad of rats to induce an inflammatory model in vivo. SP was administered to SGC cultures in vitro to confirm the effect of SP. Facial expression analysis showed that pre-injection of L703,606 (an NK-1 receptor antagonist), U0126 (an inhibitor of MAPK/extracellular signal-regulated kinase [ERK] kinase [MEK] 1/2), and SB203580 (an inhibitor of P38) into the TG to induce targeted prevention of the activation of the NK-1 receptor and the phosphorylation of MAPKs significantly suppressed CFA-induced inflammatory allodynia. In addition, SP promoted SGC activation, which was proven by increased GFAP, p-MAPKs, IL-1ß and TNF-α in SGCs under inflammatory conditions. Moreover, the increase in IL-1ß and TNF-α was suppressed by L703, 606, U0126 and SB203580 in vivo and in vitro. These present findings suggested that SP, released from TG neurons, activated SGCs through the ERK1/2 and P38 pathways and promoted the production of IL-1ß and TNF-α from SGCs, contributing to inflammatory orofacial pain associated with peripheral sensitization.


Assuntos
Proteínas Quinases Ativadas por Mitógeno , Neurônios/metabolismo , Substância P/metabolismo , Gânglio Trigeminal/fisiopatologia , Animais , Inflamação , Neuroglia , Ratos , Gânglio Trigeminal/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno
5.
Int J Nanomedicine ; 14: 5849-5863, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31440050

RESUMO

Background: Topical application of tacrolimus (FK506) was effective in treating atopic dermatitis (AD); however, the therapeutic efficiency is hampered by its poor penetration into the skin and local side effects of transient irritation symptoms with a burning sensation, a feeling of warmth or heat. Menthol and camphor have been widely used in topical compound formulations for adjunctive pharmacotherapy for antipruritics and analgesics owing to their cool nature, and both present skin penetration enhancing effects. Moreover, they can form a liquid eutectic oil to solubilize hydrophobic drugs. Purpose: Taking advantages of menthol/camphor eutectic (MCE), this work aims to integrate FK506 into MCE to construct a microemulsion system, i.e., FK506 MCE ME, which simultaneously enhances the percutaneous delivery and treatment efficacy, while reduces the side effects of FK506. Methods: The formulation of FK506 MCE ME was optimized and characterized. Different formulations containing FK506 were topically administered to treat 1-chloro-2, 4-dinitrobenzene (DNCB)-induced murine AD. Results: MCE solubilized FK506. FK506 in MCE ME penetrated skin in vitro more than in the commercial ointment, and MCE predominantly exerted the enhancing effects in MCE ME. FK506 MCE ME or FK506 MCE ME gel had greater effects on clinical symptoms, histological analysis, and IgE than did commercial FK506. The anti-pruritic and down-regulation of substance P effects of MCE ME vehicle mitigated the side effects of FK506 application. Conclusion: MCE ME presented the excellent properties of simultaneously enhancing the percutaneous delivery and treatment efficacy, while reducing the side effects of FK506 for AD. Therefore, MCE ME is a promising nanoscale system for FK506 to effectively treating AD with low irritation and high medication adherence. Chemical compounds studied in this article: Tacrolimus (PubChem CID: 445643); menthol (PubChem CID: 1254); camphor (PubChem CID: 2537).


Assuntos
Dermatite Atópica/tratamento farmacológico , Emulsões/química , Óleos/química , Tacrolimo/efeitos adversos , Tacrolimo/uso terapêutico , Administração Cutânea , Animais , Cânfora/química , Morte Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Dermatite Atópica/induzido quimicamente , Regulação para Baixo/efeitos dos fármacos , Orelha/patologia , Humanos , Imunoglobulina E/sangue , Imunossupressores/administração & dosagem , Masculino , Mentol/química , Camundongos , Camundongos Endogâmicos BALB C , Ratos Sprague-Dawley , Pele/efeitos dos fármacos , Pele/patologia , Absorção Cutânea/efeitos dos fármacos , Baço/efeitos dos fármacos , Substância P/metabolismo , Tacrolimo/administração & dosagem , Tacrolimo/farmacologia , Resultado do Tratamento , Perda Insensível de Água/efeitos dos fármacos
6.
Int J Mol Sci ; 20(13)2019 Jun 29.
Artigo em Inglês | MEDLINE | ID: mdl-31261857

RESUMO

Cystathionine-γ-lyase (CSE) isa hydrogen sulfide (H2S)-synthesizing enzyme that promotesinflammation by upregulating H2S in sepsis. Liver sinusoidal endothelial cells (LSECs) are fenestrated endothelial cells (liver sieve) that undergo alteration during sepsis and H2S plays a role in this process. Substance P (SP) is encoded by the preprotachykinin A (PPTA) gene, and promotes inflammation in sepsis; however, its regulation by H2S is poorly understood. Furthermore, the interaction between H2S and SP in modulating LSEC fenestrations following sepsis remains unclear. This study aimed to investigate whether CSE/H2S regulates SP and the neurokinin-1 receptor (NK-1R) andmodulates fenestrations in LSECs following caecalligation and puncture (CLP)-induced sepsis. Here we report thatthe absence of either CSE or H2S protects against liver sieve defenestration and gaps formation in LSECsin sepsis by decreased SP-NK-1R signaling. Following sepsis, there is an increased expression of liver CSE and H2S synthesis, and plasma H2S levels, which were aligned with higher SP levels in the liver, lungs and plasma and NK-1R in the liver and lungs. The genetic deletion of CSE led to decreased sepsis-induced SP and NK-1R in the liver, lungs and plasma SP suggesting H2S synthesized through CSE regulates the SP-NK-1R pathway in sepsis. Further, mice deficient in the SP-encoding gene (PPTA) preservedsepsis-induced LSEC defenestrationand gaps formation, as seen by maintenance of patent fenestrations and fewer gaps. In conclusion, CSE/H2S regulates SP-NK-1R and modulates LSEC fenestrations in sepsis.


Assuntos
Cistationina gama-Liase/metabolismo , Fígado/metabolismo , Sepse/metabolismo , Substância P/metabolismo , Sulfitos/metabolismo , Animais , Células Endoteliais/metabolismo , Células Endoteliais/patologia , Fígado/patologia , Pulmão/metabolismo , Pulmão/patologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Receptores da Neurocinina-1/metabolismo , Substância P/genética
7.
Neuropeptides ; 76: 101941, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31256921

RESUMO

Substance P (SP) is an undecapeptide encoding the tachykinin 1 (TAC1) gene and belongs to the tachykinin family. SP is widely distributed in the central nervous system and the peripheral nervous system. SP is also produced by nonneuronal cells, such as inflammatory cells and endothelial cells. The biological activities of SP are mainly regulated through the high-affinity neurokinin 1 receptor (NK-1R). The SP/NK-1R system plays an important role in the molecular bases of many human pathophysiologic processes, such as pain, infectious and inflammatory diseases, and cancer. In addition, this system has been implicated in fibrotic diseases and processes such as wound healing, myocardial fibrosis, bowel fibrosis, myelofibrosis, renal fibrosis, and lung fibrosis. Recently, studies have shown that SP plays an important role in liver fibrosis and that NK-1R antagonists can inhibit the progression of fibrosis. NK-1R receptor antagonists could provide clinical solutions for fibrotic diseases. This review summarizes the structure and function of SP and its involvement in fibrotic diseases.


Assuntos
Fibrose/metabolismo , Substância P/metabolismo , Animais , Doenças da Córnea/metabolismo , Doenças da Córnea/patologia , Cardiopatias/metabolismo , Cardiopatias/patologia , Humanos , Inflamação/metabolismo , Artropatias/metabolismo , Artropatias/patologia , Nefropatias/metabolismo , Nefropatias/patologia , Cirrose Hepática/metabolismo , Cirrose Hepática/patologia , Mielofibrose Primária/metabolismo , Mielofibrose Primária/patologia , Cicatrização
8.
Food Chem Toxicol ; 132: 110673, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31302221

RESUMO

The present study was designed to assess the influence of acrylamide supplementation, in tolerable daily intake (TDI) dose and a dose ten times higher than TDI, on the neurochemical phenotype of the ENS neurons and synthesis of proinflammatory cytokines in the wall of the porcine ileum. The study was performed on 15 juvenile female Danish Landrace pigs, divided into three groups: C group- animals receiving empty gelatine capsules, LD group- animals receiving capsules with the TDI dose (0.5 µg/kg b.w./day) of acrylamide and HD group- animals receiving acrylamide in a dose ten times higher than the TDI (5 µg/kg b.w./day) in a morning meal for 28 days. It was established that supplementation of acrylamide led to an increase in substance P (SP)-, calcitonin gene-related peptide (CGRP)-, galanin (GAL)- and vesicular acetylcholine transporter (VAChT)-like immunoreactive (LI) neurons as well as a decrease in neuronal nitric oxide synthase (nNOS) -like immunoreactivity in all types of ileum intramural plexuses. Moreover, using ELISA method, an increase in the level of proinflammatory cytokines (IL-1ß, IL-6 and TNF- α) was noted in the ileum wall. The results suggest that SP, CGRP, GAL, nNOS and VACHT participate in the regulation of inflammatory conditions induced by acrylamide supplementation.


Assuntos
Acrilamida/administração & dosagem , Íleo/efeitos dos fármacos , Neurônios/efeitos dos fármacos , Acrilamida/farmacologia , Animais , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Citocinas/biossíntese , Relação Dose-Resposta a Droga , Galanina/metabolismo , Íleo/patologia , Mediadores da Inflamação/metabolismo , Neurônios/enzimologia , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Substância P/metabolismo , Suínos , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
9.
Invest Ophthalmol Vis Sci ; 60(7): 2449-2460, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31157834

RESUMO

Purpose: To investigate changes in corneal nerves positive to substance P (SP) and transient receptor potential melastatin 8 (TRPM8) and gene expression in the trigeminal ganglia (TG) following corneal surgery to unveil peripheral nerve mechanism of induced dry eye-like pain (DELP). Methods: Surgery was performed on mice by removing the central epithelial and anterior stromal nerves. Mice were euthanized at different times up to 15 weeks. Immunostaining was performed with TRPM8, SP, or protein gene product 9.5 (PGP9.5) antibodies, and epithelial nerve densities were calculated. The origin of TRPM8- and SP-TG neurons were analyzed by retrograde tracing. Gene expression in TG was studied by real-time PCR analysis. Results: SP-positive epithelial corneal nerves were more abundant than TRPM8 and were expressed in different TG neurons. After injury, epithelial nerve regeneration occurs in two distinct stages. An early regeneration of the remaining epithelial bundles reached the highest density on day 3 and then rapidly degraded. From day 5, the epithelial nerves originated from the underlying stromal nerves were still lower than normal levels by week 15. The SP- and TRPM8-positive nerve fibers followed the same pattern as the total nerves. TRPM8-positive terminals increased slowly and reached only half of normal values by 3 months. Corneal sensitivity gradually increased and reached normal values on day 12. Corneal injury also induced significant changes in TG gene expression, decreasing trpm8 and tac1 genes. Conclusions: Abnormal SP expression, low amounts of TRPM8 terminals, and hypersensitive nerve response occur long after the injury and changes in gene expression in the TG suggest a contribution to the pathogenesis of corneal surgery-induced DELP.


Assuntos
Lesões da Córnea/metabolismo , Epitélio Anterior/inervação , Regulação da Expressão Gênica/fisiologia , Plasticidade Neuronal/fisiologia , Nervo Oftálmico/fisiologia , Substância P/genética , Canais de Cátion TRPM/genética , Animais , Temperatura Baixa , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Masculino , Camundongos , Modelos Animais , Regeneração Nervosa/fisiologia , Reação em Cadeia da Polimerase em Tempo Real , Substância P/metabolismo , Canais de Cátion TRPM/metabolismo , Lágrimas/fisiologia , Ubiquitina Tiolesterase/genética , Ubiquitina Tiolesterase/metabolismo
10.
Brain Struct Funct ; 224(6): 2079-2085, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31147779

RESUMO

Substance P is an eleven-amino acid neuropeptide (undecapeptide) with multiple effects on the gastrointestinal, cardiovascular, and urinary systems as well as complex central nervous system functions such as pain, learning, memory, and sexual homeostasis. Previous studies also revealed that substance P exhibits regulatory effects on growth possibly via influencing hypothalamic GHRH release in human. However, the morphological substrate of this phenomenon has not been elucidated yet. In the present study, we examined the putative presence of juxtapositions between the substance P- and GHRH-immunoreactive (IR) systems using double-label immunocytochemistry. High-magnification light microscopy with oil immersion was used to identify putative juxtapositions between these systems. Our studies revealed substance P-IR fiber network abutting on the surface of the majority of GHRH-immunoreactive neurons in the human hypothalamus. These fiber varicosities often cover a significant surface area on the GHRH-IR neurons, forming basket-like encasements with multiple en passant type contacts. The majority of these densely innervated GHRH-IR neurons were found in the infundibular nucleus/median eminence, while substance P-IR fibers often abut on the GHRH-IR neurons in the periventricular zone and basal perifornical area of the tuberal region and in the dorsomedial subdivision of the ventromedial nucleus. The posterior hypothalamus did not contain observable substance P-GHRH associations. The density and the morphology of these intimate associations suggest that substance P influences growth by regulating hypothalamic GHRH release by direct synaptic contacts.


Assuntos
Hormônio Liberador de Hormônio do Crescimento/metabolismo , Hipotálamo/metabolismo , Neurônios/metabolismo , Substância P/metabolismo , Idoso , Idoso de 80 Anos ou mais , Diencéfalo/metabolismo , Feminino , Humanos , Imuno-Histoquímica/métodos , Masculino , Eminência Mediana/metabolismo
11.
Neuron ; 103(3): 432-444.e3, 2019 08 07.
Artigo em Inglês | MEDLINE | ID: mdl-31221559

RESUMO

Subtypes of nucleus accumbens medium spiny neurons (MSNs) promote dichotomous outcomes in motivated behaviors. However, recent reports indicate enhancing activity of either nucleus accumbens (NAc) core MSN subtype augments reward, suggesting coincident MSN activity may underlie this outcome. Here, we report a collateral excitation mechanism in which high-frequency, NAc core dopamine 1 (D1)-MSN activation causes long-lasting potentiation of excitatory transmission (LLP) on dopamine receptor 2 (D2)-MSNs. Our mechanistic investigation demonstrates that this form of plasticity requires release of the excitatory peptide substance P from D1-MSNs and robust cholinergic interneuron activation through neurokinin receptor stimulation. We also reveal that D2-MSN LLP requires muscarinic 1 receptor activation, intracellular calcium signaling, and GluR2-lacking AMPAR insertion. This study uncovers a mechanism for shaping NAc core activity through the transfer of excitatory information from D1-MSNs to D2-MSNs and may provide a means for altering goal-directed behavior through coordinated MSN activity.


Assuntos
Neurônios Dopaminérgicos/fisiologia , Potenciação de Longa Duração/fisiologia , Núcleo Accumbens/fisiologia , Substância P/metabolismo , Potenciais de Ação/fisiologia , Animais , Aprepitanto/farmacologia , Sinalização do Cálcio/fisiologia , Neurônios Colinérgicos/fisiologia , Neurônios Dopaminérgicos/efeitos da radiação , Potenciais Pós-Sinápticos Excitadores/efeitos dos fármacos , Potenciais Pós-Sinápticos Excitadores/fisiologia , Interneurônios/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Motivação , Antagonistas do Receptor de Neuroquinina-1/farmacologia , Núcleo Accumbens/citologia , Estimulação Luminosa , Piperidinas/farmacologia , Receptor Muscarínico M1/fisiologia , Receptores de AMPA/fisiologia , Receptores de Dopamina D1/análise , Receptores de Dopamina D2/análise , Receptores da Neurocinina-1/fisiologia
12.
Int J Mol Sci ; 20(8)2019 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31010055

RESUMO

Hyperbaric oxygen treatment (HBOT) has been used to reduce neuropathic pain. Melatonin and opioid receptors are involved in neuropathic pain, but it is not known if HBOT works through these pathways to achieve its antinociceptive effect. We divided anesthetized rats into two treatment and three sham groups. The two treatment groups received third-degree burns on their right hind paws, one treated in a hyperbaric chamber for a week and the other for two weeks. We evaluated the mechanical paw-withdrawal threshold (MWT) and expression of melatonin receptor 1 (MT1), melatonin receptor 2 (MT2), µ (MOR) and κ (KOR) opioid receptor, brain-derived neurotrophic factor (BDNF), Substance P, and calcitonin gene-related peptide (CGRP) in cuneate nucleus, dorsal horn, and hind paw skin by immunohistochemical, immunofluorescence assays and real-time quantitative polymerase chain reaction (RT-PCR). The group receiving one-week HBOT had increased expressions of MT1, MT2, MOR and KOR and decreased expressions of BDNF, Substance P, and CGRP. Their mechanically measured pain levels returned to normal within a week and lasted three weeks. This anti-allodynia effect lasted twice as long in those treated for two weeks. Our findings suggest that increasing the duration of HBOT can reduce burn-induced mechanical allodynia for an extended period of time in rats. The upregulation of melatonin and opioid receptors observed after one week of HBOT suggests they may be partly involved in attenuation of the mechanical allodynia. Downregulation of BDNF, substance P and CGRP may have also contributed to the overall beneficial effect of HBOT.


Assuntos
Queimaduras/complicações , Oxigenação Hiperbárica , Neuralgia/etiologia , Neuralgia/terapia , Animais , Astrócitos/metabolismo , Astrócitos/patologia , Comportamento Animal , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Proteína Glial Fibrilar Ácida/metabolismo , Masculino , Bulbo/metabolismo , Nociceptividade , Ratos Sprague-Dawley , Receptores de Melatonina/metabolismo , Receptores Opioides/metabolismo , Pele/patologia , Corno Dorsal da Medula Espinal/metabolismo , Substância P/metabolismo
13.
Int J Mol Sci ; 20(7)2019 Apr 04.
Artigo em Inglês | MEDLINE | ID: mdl-30987291

RESUMO

Diabetic autonomic peripheral neuropathy (PN) involves a broad spectrum of organs. One of them is the gastrointestinal (GI) tract. The molecular mechanisms underlying the pathogenesis of digestive complications are not yet fully understood. Digestion is controlled by the central nervous system (CNS) and the enteric nervous system (ENS) within the wall of the GI tract. Enteric neurons exert regulatory effects due to the many biologically active substances secreted and released by enteric nervous system (ENS) structures. These include nitric oxide (NO), produced by the neural nitric oxide synthase enzyme (nNOS). It is a very important inhibitory factor, necessary for smooth muscle relaxation. Moreover, it was noted that nitrergic innervation can undergo adaptive changes during pathological processes. Additionally, nitrergic neurons function may be regulated through the synthesis of other active neuropeptides. Therefore, in the present study, using the immunofluorescence technique, we first examined the influence of hyperglycemia on the NOS- containing neurons in the porcine small intestine and secondly the co-localization of nNOS with vasoactive intestinal polypeptide (VIP), galanin (GAL) and substance P (SP) in all plexuses studied. Following chronic hyperglycaemia, we observed a reduction in the number of the NOS-positive neurons in all intestinal segments studied, as well as an increased in investigated substances in nNOS positive neurons. This observation confirmed that diabetic hyperglycaemia can cause changes in the neurochemical characteristics of enteric neurons, which can lead to numerous disturbances in gastrointestinal tract functions. Moreover, can be the basis of an elaboration of these peptides analogues utilized as therapeutic agents in the treatment of GI complications.


Assuntos
Intestino Delgado/citologia , Intestino Delgado/metabolismo , Neurônios/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Animais , Sistema Nervoso Central/citologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Entérico/citologia , Sistema Nervoso Entérico/metabolismo , Feminino , Galanina/metabolismo , Hiperglicemia/metabolismo , Substância P/metabolismo , Suínos , Peptídeo Intestinal Vasoativo/metabolismo
14.
BMC Neurosci ; 20(1): 18, 2019 04 25.
Artigo em Inglês | MEDLINE | ID: mdl-31023212

RESUMO

BACKGROUND: Despite increasing evidence that lipopolysaccharide (LPS) affects the biological active substances of dorsal root ganglia (DRG) we have limited knowledge of the influence of a single low dose of LPS, which does not result in any clinical symptoms of disease (subclinical LPS) on neuropeptides connected with the sensory pathway. Accordingly, in this work, we investigated the influence of subclinical LPS from Salmonella Enteritidis on selected neuropeptides: substance P (SP), galanin (GAL), neuropeptide Y (NPY), vasoactive intestinal peptide (VIP) and somatostatin (SOM) in the cervical, thoracic, lumbar and sacral regions of the DRG and spinal cord. METHODS: This study was performed on immature female pigs of the Pietrain × Duroc breed. Seven days after the intravenous injection of saline solution for control animals (n = 5) and 5 µg/kg b.w. LPS from S. Enteritidis for the experimental group (n = 5), the DRG and the spinal cord were collected to extract the neuropeptides using solid-phase extraction technology. RESULTS: Our results demonstrated that subclinical LPS in DRG was able to change the levels of all studied neuropeptides except SOM, whereas in the spinal cord it down-regulated all studied neuropeptides in the sacral spinal cord, maintaining the concentration of all studied neuropeptides in other regions similar to that observed in the control animals. The significant differences in the intensity and character of observed changes between particular regions of the DRG suggest that the exact functions of the studied neuropeptides and mechanisms of responses to subclinical LPS action depend on specific characteristics and functions of each examination region of DRG. CONCLUSIONS: The mechanisms of observed changes are not fully understood and require further study of the molecular interactions between subclinical LPS from S. Enteritidis and neuronal and non-neuronal cells of DRG and spinal cord. The peripheral and central pain pathways must be analysed with the aspect of unknown long-term consequences of the influence of subclinical LPS from S. Enteritidis on neuropeptides in the spinal cord and the dorsal root ganglia.


Assuntos
Galanina/metabolismo , Gânglios Espinais/metabolismo , Lipopolissacarídeos/farmacologia , Salmonella enteritidis , Somatostatina/metabolismo , Medula Espinal/metabolismo , Substância P/metabolismo , Peptídeo Intestinal Vasoativo/metabolismo , Animais , Feminino , Suínos , Peptídeo Intestinal Vasoativo/farmacologia
15.
J Am Soc Mass Spectrom ; 30(6): 919-931, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30980380

RESUMO

We report ion mobility spectrometry and mass spectrometry studies of the non-enzymatic step-by-step degradation of substance P (subP), an 11-residue neuropeptide, with the sequence Arg1-Pro2-Lys3-Pro4-Gln5-Gln6-Phe7-Phe8-Gly9-Leu10-Met11-NH2, in ethanol. At elevated solution temperatures (55 to 75 °C), several reactions are observed, including a protonation event, i.e., [subP+2H]2+ + H+ → [subP+3H]3+, that appears to be regulated by a configurational change and two sequential bond cleavages (the Pro2-Lys3 peptide bond is cleaved to form the smaller nonapeptide Lys3-Met11-NH2 [subP(3-11)], and subsequently, subP(3-11) is cleaved at the Pro4-Gln5 peptide bond to yield the heptapeptide Gln5-Met11-NH2 [subP(5-11)]). Each of the product peptides [subP(3-11) and subP(5-11)] is accompanied by a complementary diketopiperazine (DKP): cyclo-Arg1-Pro2 (cRP) for the first cleavage, and cyclo-Lys3-Pro4 (cKP) for the second. Insight about the mechanism of degradation is obtained by comparing kinetics calculations of trial model mechanisms with experimental data. The best model of our experimental data indicates that the initial cleavage of subP is regulated by a conformational change, likely a trans→cis isomerization of the Arg1-Pro2 peptide bond. The subP(3-11) product has a long lifetime (t1/2 ~ 30 h at 55 °C) and appears to transition through several structural intermediates prior to dissociation, suggesting that subP(3-11) is initially formed with a Lys3-trans-Pro4 peptide bond configuration and that slow trans→cis isomerization regulates the second bond cleavage event as well. From these data and our model mechanisms, we obtain transition state thermochemistry ranging from ΔH‡ = 41 to 85 kJ mol-1 and ΔS‡ = - 43 to - 157 J mol-1 K-1 for each step in the reaction. Graphical Abstract.


Assuntos
Etanol/metabolismo , Prolina/metabolismo , Substância P/metabolismo , Sequência de Aminoácidos , Temperatura Alta , Hidrólise , Isomerismo , Cinética , Prolina/química , Proteólise , Substância P/química , Termodinâmica
16.
Int J Mol Sci ; 20(7)2019 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-30935032

RESUMO

Substance P (SP), an 11-amino-acid neuropeptide, has long been considered an effector of pain. However, accumulating studies have proposed a paradoxical role of SP in anti-nociception. Here, we review studies of SP-mediated nociception and anti-nociception in terms of peptide features, SP-modulated ion channels, and differential effector systems underlying neurokinin 1 receptors (NK1Rs) in differential cell types to elucidate the effect of SP and further our understanding of SP in anti-nociception. Most importantly, understanding the anti-nociceptive SP-NK1R pathway would provide new insights for analgesic drug development.


Assuntos
Canais de Cálcio/metabolismo , Nociceptividade , Canais de Potássio/metabolismo , Substância P/metabolismo , Animais , Humanos
17.
J Diabetes Res ; 2019: 9426014, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30918901

RESUMO

Objective: Diabetic polyneuropathy (DPN) is one of the most prevalent diabetic complications. We previously demonstrated that exendin-4 (Ex4), a glucagon-like peptide-1 receptor agonist (GLP-1RA), has beneficial effects in animal models of DPN. We hypothesized that GLP-1 signaling would protect neurons of the peripheral nervous system from oxidative insult in DPN. Here, the therapeutic potential of GLP-1RAs on DPN was investigated in depth using the cellular oxidative insult model applied to the dorsal root ganglion (DRG) neuronal cell line. Research Design and Methods: Immortalized DRG neuronal 50B11 cells were cultured with and without hydrogen peroxide in the presence or absence of Ex4 or GLP-1(7-37). Cytotoxicity and viability were determined using a lactate dehydrogenase assay and MTS (3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium inner salt), respectively. Antioxidant enzyme activity was evaluated using a superoxide dismutase assay. Alteration of neuronal characteristics of 50B11 cells induced by GLP-1RAs was evaluated with immunocytochemistry utilizing antibodies for transient receptor potential vanilloid subfamily member 1, substance P, and calcitonin gene-related peptide. Cell proliferation and apoptosis were also examined by ethynyl deoxyuridine incorporation assay and APOPercentage dye, respectively. The neurite projection ratio induced by treatment with GLP-1RAs was counted. Intracellular activation of adenylate cyclase/cyclic adenosine monophosphate (cAMP) signaling was also quantified after treatment with GLP-1RAs. Results: Neither Ex4 nor GLP-1(7-37) demonstrated cytotoxicity in the cells. An MTS assay revealed that GLP-1RAs amended impaired cell viability induced by oxidative insult in 50B11 cells. GLP-1RAs activated superoxide dismutase. GLP-1RAs induced no alteration of the distribution pattern in neuronal markers. Ex4 rescued the cells from oxidative insult-induced apoptosis. GLP-1RAs suppressed proliferation and promoted neurite projections. No GLP-1RAs induced an accumulation of cAMP. Conclusions: Our findings indicate that GLP-1RAs have neuroprotective potential which is achieved by their direct actions on DRG neurons. Beneficial effects of GLP-1RAs on DPN could be related to these direct actions on DRG neurons.


Assuntos
Apoptose , Gânglios Espinais/citologia , Gânglios Espinais/efeitos dos fármacos , Receptor do Peptídeo Semelhante ao Glucagon 1/agonistas , Estresse Oxidativo , Animais , Antioxidantes/metabolismo , Calcitonina/metabolismo , Linhagem Celular , Proliferação de Células , Sobrevivência Celular , AMP Cíclico/metabolismo , Neuropatias Diabéticas/tratamento farmacológico , Hipoglicemiantes/uso terapêutico , Neurônios/efeitos dos fármacos , Fármacos Neuroprotetores/uso terapêutico , Ratos , Substância P/metabolismo , Superóxido Dismutase/metabolismo
18.
Int J Mol Sci ; 20(5)2019 Feb 27.
Artigo em Inglês | MEDLINE | ID: mdl-30818742

RESUMO

Neurons of the enteric nervous system (ENS) may undergo changes during maturation and aging, but knowledge of physiological stimuli-dependent changes in the ENS is still fragmentary. On the other hand, the frequency of many ENS-related intestinal illnesses depends on age and/or sex. The double immunofluorescence technique was used to study the influence of both of these factors on calcitonin gene-related peptide (CGRP)-positive enteric nervous structures-in the descending colon in young and adult female and castrated male pigs. The influence of age and gender on the number and neurochemical characterization (i.e., co-localization of CGRP with substance P, nitric oxide synthase, galanin, cocaine- and amphetamine-regulated transcript peptide and vesicular acetylcholine transporter) of CGRP-positive nerve structures in the colonic wall has been shown. These observations strongly suggest the participation of CGRP in adaptive processes in the ENS during GI tract maturation. Moreover, although the castration of males may mask some aspects of sex-dependent influences on the ENS, the sex-specific differences in CGRP-positive nervous structures were mainly visible in adult animals. This may suggest that the distribution and exact role of this substance in the ENS depend on the sex hormones.


Assuntos
Envelhecimento/metabolismo , Peptídeo Relacionado com Gene de Calcitonina/metabolismo , Colo Descendente/metabolismo , Neurônios/metabolismo , Caracteres Sexuais , Animais , Feminino , Galanina/metabolismo , Masculino , Proteínas do Tecido Nervoso/metabolismo , Óxido Nítrico Sintase Tipo I/metabolismo , Substância P/metabolismo , Suínos , Proteínas Vesiculares de Transporte de Acetilcolina/metabolismo
19.
EBioMedicine ; 41: 649-658, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30819512

RESUMO

BACKGROUND: The most prevalent inherited form of generalized dystonia is caused by a mutation in torsinA (DYT1, ∆GAG) with incomplete penetrance. Rodent models with mutated torsinA do not develop dystonic symptoms, but previous ex vivo studies indicated abnormal excitation of cholinergic interneurons (ChI) and increased striatal acetylcholine. METHODS: We used in vivo optogenetics to exacerbate this endophenotype in order to determine its capacity to trigger dystonic symptoms in freely behaving mice. Tor1a+/Δgag DYT1 mice and wildtype littermates expressing channelrhodopsin2 under the Chat promotor were implanted bilaterally with optical LED cannulae and stimulated with blue light pulses of varied durations. FINDINGS: Six months old DYT1 KI mice but not wildtype controls responded with hyperactivity to blue light specifically at 25 ms pulse duration, 10 Hz frequency. Neuronal activity (c-Fos) in cholinergic interneurons was increased immediately after light stimulation and persisted only in DYT1 KI over 15 min. Substance P was increased specifically in striosome compartments in naïve DYT1 KI mice compared to wildtype. Under optogenetic stimulation substance P increased in wildtype to match levels in Dyt1 KI, and acetylcholinesterase was elevated in the striatum of stimulated DYT1 KI. No signs of dystonic movements were observed under stimulation of up to one hour in both genotypes and age groups, and the sensorimotor deficit previously observed in 6 months old DYT1 KI mice persisted under stimulation. INTERPRETATION: Overall this supports an endophenotype of dysregulated cholinergic activity in DYT1 dystonia, but depolarizing cholinergic interneurons was not sufficient to induce overt dystonia in DYT1 KI mice.


Assuntos
Neurônios Colinérgicos/metabolismo , Chaperonas Moleculares/genética , Optogenética , Acetilcolinesterase/genética , Acetilcolinesterase/metabolismo , Animais , Comportamento Animal/efeitos da radiação , Channelrhodopsins/metabolismo , Endofenótipos , Feminino , Técnicas de Introdução de Genes , Luz , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Proteínas Proto-Oncogênicas c-fos/metabolismo , Substância P/genética , Substância P/metabolismo
20.
Parasitol Res ; 118(4): 1193-1203, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30725179

RESUMO

The development of metacercariae of Diplostomum pseudospathaceum Niewiadomska, 1984 is accompanied by profound morphological transformations often characterized as metamorphosis, which makes these metacercariae an interesting case for studying the morphogenesis of the digenean nervous system. Although the nervous system of D. pseudospathaceum is one of the most extensively studied among digeneans, there are still gaps in our knowledge regarding the distribution patterns of some neuroactive substances, most notably neuropeptides. The present study addresses these gaps by studying pre-infective metacercariae of D. pseudospathaceum using immunochemical staining and confocal microscopy to characterize the distribution patterns of serotonin (5-HT) and two major groups of flatworm neuropeptides, FMRFamide-related (FaRPs) and substance P-related (SP) peptides. The general morphology of the nervous system was examined with antibodies to alpha-tubulin. The nervous system of the metacercariae was shown to conform to the most common morphology of the nervous system in the hermaphroditic generation, with three pairs of posterior nerve cords and four pairs of anterior nerves. The patterns of FaRP- and 5-HT immunoreactivity (IR) were similar to those revealed in earlier studies by cholinesterase activity, which is in accordance with the known role of these neurotransmitters in controlling muscle activity in flatworms. The SP-IR nervous system was significantly different and consisted of mostly bipolar cells presumably acting as mechanoreceptors. The architecture of the nervous system in D. pseudospathaceum metacercariae is discussed in comparison to that in cercariae of D. pseudospathaceum and metacercariae of related digenean species.


Assuntos
FMRFamida/metabolismo , Metacercárias/anatomia & histologia , Sistema Nervoso/anatomia & histologia , Substância P/metabolismo , Trematódeos/anatomia & histologia , Animais , Metacercárias/fisiologia , Metamorfose Biológica , Microscopia Confocal , Fenômenos Fisiológicos do Sistema Nervoso , Serotonina/metabolismo , Coloração e Rotulagem , Trematódeos/fisiologia , Tubulina (Proteína)/imunologia
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