RESUMEN
Pharmacological investigations have substantiated the potential of bifunctional opioid/cannabinoid agonists in delivering potent analgesia while minimizing adverse reactions. Peptide modulators of cannabinoid receptors, known as pepcans, have been investigated before. In this study, we designed a series of chimeric peptides based on pepcans and morphiceptin (YPFP-NH2). Here, we combined injections of pepcans and morphiceptin to investigate the combination treatment of opioids and cannabis and compared the analgesic effect with chimeric compounds. Subsequently, we employed computational docking to screen the compounds against opioid and cannabinoid receptors, along with an acute pain model, to identify the most promising peptide. Among these peptides, MP-13, a morphiceptin and pepcan-9 (PVNFKLLSH) construct, exhibited superior supraspinal analgesic efficacy in the tail-flick test, with an ED50 value at 1.43 nmol/mouse, outperforming its parent peptides and other chimeric analogs. Additionally, MP-13 displayed potent analgesic activity mediated by mu-opioid receptor (MOR), delta-opioid receptor (DOR), and cannabinoid type 1 (CB1) receptor pathways. Furthermore, MP-13 did not induce psychological dependence and gastrointestinal motility inhibition at the effective analgesic doses, and it maintained non-tolerance-forming antinociception throughout a 7-day treatment regimen, with an unaltered count of microglial cells in the periaqueductal gray region, supporting this observation. Moreover, intracerebroventricular administration of MP-13 demonstrated dose-dependent antinociception in murine models of neuropathic, inflammatory, and visceral pain. Our findings provide promising insights for the development of opioid/cannabinoid peptide agonists, addressing a crucial gap in the field and holding significant potential for future research and development. PERSPECTIVE: This article offers insights into the combination treatment of pepcans with morphiceptin. Among the chimeric peptides, MP-13 exhibited potent analgesic effects in a series of preclinical pain models with a favorable side-effect profile.
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Analgésicos , Animales , Ratones , Masculino , Analgésicos/farmacología , Analgésicos/administración & dosificación , Neuropéptidos/farmacología , Neuropéptidos/administración & dosificación , Analgésicos Opioides/farmacología , Analgésicos Opioides/administración & dosificación , Dolor/tratamiento farmacológico , Péptidos/farmacología , Péptidos/administración & dosificación , Péptidos/química , Simulación del Acoplamiento Molecular , EndorfinasRESUMEN
AIM: The hypothesis of this study is to determine the effects of intracerebroventricular (icv) prokineticin 2 infusion on food consumption and body weight and to elucidate whether it has effects on energy expenditure via the hypothalamus-pituitary-thyroid (HPT) axis in adipose tissue. MATERIAL AND METHODS: A total of 40 rats were used in the study and 4 groups were established: Control, Sham, Prokineticin 1.5 and Prokineticin 4.5 (n=10). Except for the Control group, rats were treated intracerebroventricularly via osmotic minipumps, the Sham group was infused with aCSF (vehicle), and the Prokineticin 1.5 and Prokineticin 4.5 groups were infused with 1.5 nMol and 4.5 nMol prokineticin 2, respectively. Food and water consumption and body weight were monitored during 7-day infusion in all groups. At the end of the infusion, the rats were decapitated and serum TSH, fT4 and fT3 levels were determined by ELISA. In addition, PGC-1α and UCP1 gene expression levels in white adipose tissue (WAT) and brown adipose tissue (BAT), TRH from rat hypothalamic tissue were determined by real-time PCR. RESULTS: Icv prokineticin 2 (4.5 nMol) infusion had no effect on water consumption but reduced daily food consumption and body weight (p<0.05). Icv prokineticin 2 (4.5 nMol) infusion significantly increased serum TSH, fT4 and fT3 levels when compared to Control and Sham groups (p<0.05). Also, icv prokineticin 2 (4.5 nMol) infusion increased the expression of TRH in the hypothalamus tissue and expression of PGC-1α UCP1 in the WAT and BAT (p<0.05). CONCLUSION: Icv prokineticin 2 (4.5 nMol) infusion may suppress food consumption via its receptors in the hypothalamus and reduce body weight by stimulating energy expenditure and thermogenesis in adipose tissue through the HPT axis.
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Peso Corporal , Ingestión de Alimentos , Metabolismo Energético , Hormonas Gastrointestinales , Infusiones Intraventriculares , Glándula Tiroides , Animales , Metabolismo Energético/efectos de los fármacos , Metabolismo Energético/fisiología , Masculino , Peso Corporal/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Glándula Tiroides/efectos de los fármacos , Glándula Tiroides/metabolismo , Ratas , Hormonas Gastrointestinales/metabolismo , Hormonas Gastrointestinales/administración & dosificación , Proteína Desacopladora 1/metabolismo , Sistema Hipotálamo-Hipofisario/efectos de los fármacos , Sistema Hipotálamo-Hipofisario/metabolismo , Neuropéptidos/metabolismo , Neuropéptidos/administración & dosificación , Tirotropina/sangre , Tirotropina/metabolismo , Tejido Adiposo Pardo/metabolismo , Tejido Adiposo Pardo/efectos de los fármacos , Tiroxina/sangre , Tiroxina/administración & dosificación , Ingestión de Líquidos/efectos de los fármacos , Triyodotironina/administración & dosificación , Triyodotironina/sangre , Triyodotironina/farmacología , Ratas Wistar , Hipotálamo/metabolismo , Hipotálamo/efectos de los fármacos , Tejido Adiposo Blanco/metabolismo , Tejido Adiposo Blanco/efectos de los fármacosRESUMEN
Transient global cerebral ischemia (GCI) results in delayed neuronal death, primarily apoptosis, in the hippocampal CA1 subregion, which leads to severe cognitive deficits. While therapeutic hypothermia is an approved treatment for patients following cardiac arrest, it is associated with various adverse effects. Secretoneurin (SN) is an evolutionarily conserved neuropeptide generated in the brain, adrenal medulla and other endocrine tissues. In this study, SN was infused into the rat brain by intracerebroventricular injection 1 day after GCI, and we demonstrated that SN could significantly preserve spatial learning and memory in the Barnes maze tasks examined on days 14-17 after GCI. To further investigate underlying pathways involved, we demonstrated that, on day 5 after GCI, SN could significantly inhibit GCI-induced expression levels of Apoptosis Inducing Factor (AIF) and cleaved-PARP1, as well as neuronal apoptosis and synaptic loss in the hippocampal CA1 region. Additionally, SN could attenuate GCI-induced activation of both caspase-1 and caspase-3, and the levels of pro-inflammatory cytokines IL-1ß and IL-18 in the CA1 region. Mechanically, we observed that treatment with SN effectively inhibited NLRP3 protein elevation and the bindings of NLRP3-ASC and ASC-caspase-1 in hippocampal neurons after GCI. In summary, our data indicate that SN could effectively attenuate NLRP3 inflammasome formation, as well as the activation of caspase-1 and -3, the production of pro-inflammatory cytokines, and ultimately the neuronal apoptotic loss induced by GCI. Potential neuronal pyroptosis, or caspase-1-dependent cell death, could also be involved in ischemic neuronal death, which needs further investigation.
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Apoptosis , Isquemia Encefálica , Memoria , Proteína con Dominio Pirina 3 de la Familia NLR , Neuronas , Neuropéptidos , Ratas Sprague-Dawley , Animales , Apoptosis/efectos de los fármacos , Masculino , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Isquemia Encefálica/metabolismo , Isquemia Encefálica/tratamiento farmacológico , Isquemia Encefálica/patología , Neuropéptidos/administración & dosificación , Neuropéptidos/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Ratas , Memoria/efectos de los fármacos , Secretogranina II/administración & dosificación , Secretogranina II/metabolismo , Infusiones Intraventriculares , Aprendizaje por Laberinto/efectos de los fármacos , Aprendizaje por Laberinto/fisiología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Dysfunctions of the neuronal-glial crosstalk and/or impaired signaling of neurotrophic factors represent key features of the maladaptive changes in the central nervous system (CNS) in neuroinflammatory as neurodegenerative disorders. Tissue plasminogen activator (tPA)/plasminogen (PA)/plasmin system has been involved in either process of maturation and degradation of nerve growth factor (NGF), highlighting multiple potential targets for new therapeutic strategies. We here investigated the role of intrathecal (i.t.) delivery of neuroserpin (NS), an endogenous inhibitor of plasminogen activators, on neuropathic behavior and maladaptive synaptic plasticity in the rat spinal cord following spared nerve injury (SNI) of the sciatic nerve. We demonstrated that SNI reduced spinal NGF expression, induced spinal reactive gliosis, altering the expression of glial and neuronal glutamate and GABA transporters, reduced glutathione (GSH) levels and is associated to neuropathic behavior. Beside the increase of NGF expression, i.t. NS administration reduced reactive gliosis, restored synaptic homeostasis, GSH levels and reduced neuropathic behavior. Our results hereby highlight the essential role of tPA/PA system in the synaptic homeostasis and mechanisms of maladaptive plasticity, sustaining the beneficial effects of NGF-based approach in neurological disorders.
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Fibrinolisina/antagonistas & inhibidores , Factores de Crecimiento Nervioso/metabolismo , Plasticidad Neuronal , Traumatismos de los Nervios Periféricos/metabolismo , Traumatismos de los Nervios Periféricos/fisiopatología , Plasminógeno/antagonistas & inhibidores , Médula Espinal/fisiopatología , Animales , Conducta Animal , Gliosis , Inyecciones Espinales , Masculino , Neuralgia/psicología , Neuropéptidos/administración & dosificación , Neuropéptidos/uso terapéutico , Traumatismos de los Nervios Periféricos/psicología , Ratas , Ratas Sprague-Dawley , Recuperación de la Función , Nervio Ciático/lesiones , Serpinas/administración & dosificación , Serpinas/uso terapéutico , NeuroserpinaRESUMEN
This study aims to explore the effect of chronic central neuropeptide-S (NPS) treatment on gastrointestinal dysmotility and the changes of cholinergic neurons in the dorsal motor nucleus of the vagus (DMV) of a Parkinson's disease (PD) rat model. The PD model was induced through a unilateral medial forebrain bundle (MFB) administration of the 6-hydroxydopamine (6-OHDA). Locomotor activity (LMA), solid gastric emptying (GE), and gastrointestinal transit (GIT) were measured 7 days after the surgery. NPS was daily administered (1 nmol, icv, 7 days). In substantia nigra (SN), dorsal motor nucleus of the vagus (DMV), and gastric whole-mount samples, changes in tyrosine hydroxylase (TH), choline acetyltransferase (ChAT), neuronal nitric oxide synthase (nNOS), glial fibrillary acidic protein (GFAP), NPS receptor (NPSR), and alpha-synuclein (Ser129) were examined by immunohistochemistry. Cuprolinic blue staining was used to evaluate the number of neuronal cells in myenteric ganglia. The GIT rate, the total number of myenteric neurons, and the expressions of ChAT, nNOS, TH, and GFAP in the myenteric plexus were not changed in rats that received the 6-OHDA. Chronic NPS treatment reversed 6-OHDA-induced impairment of the motor performance, and GE, while preventing the loss of dopaminergic and cholinergic neurons in SN and DMV, respectively. NPS attenuated 6-OHDA-induced α-syn (Ser129) pathology both in SN and DMV. Additionally, expression of NPSR protein was detected in gastro-projecting cells in DMV. Taken together, centrally applied NPS seems to prevent 6-OHDA-induced gastric dysmotility through a neuroprotective action on central vagal circuitry.
Asunto(s)
Vaciamiento Gástrico/efectos de los fármacos , Motilidad Gastrointestinal/efectos de los fármacos , Neuropéptidos/administración & dosificación , Oxidopamina/toxicidad , Animales , Colina O-Acetiltransferasa/metabolismo , Vaciamiento Gástrico/fisiología , Motilidad Gastrointestinal/fisiología , Inyecciones Intraventriculares , Locomoción/efectos de los fármacos , Locomoción/fisiología , Masculino , Ratas , Ratas Wistar , Receptores de Neuropéptido/metabolismo , Tirosina 3-Monooxigenasa/metabolismo , Nervio Vago/efectos de los fármacos , Nervio Vago/metabolismoRESUMEN
Neuropeptide W (NPW) messenger ribonucleic acid (mRNA) and NPBW1 and/or NPBW2 mRNA are expressed in the descending pain inhibitory system. In the present study, we examined whether NPW microinjected into the descending pain inhibitory system, such as the periaqueductal gray (PAG), locus coeruleus (LC), and rostral ventromedial medulla (RVM), produces an analgesic effect using a rat formalin test. Microinjections of NPW into the PAG ipsilateral and contralateral to the formalin-injected side, LC ipsilateral and contralateral to the formalin-injected side, and RVM produced an analgesic effect. In the RVM study, the analgesic effect was antagonized by WAY100135, a 5-HT1A antagonist, and enhanced by prazosin, an α1 antagonist, and SB269970, a 5-HT7 antagonist. Naloxone, an opioid antagonist, also antagonized the effect of NPW in the RVM study. In the ipsilateral LC study, the analgesic effect was antagonized by WAY100135, idazoxan, an α2 antagonist, and naloxone and was enhanced by prazosin and SB269970. In the contralateral LC study, the analgesic effect was antagonized by prazosin, idazoxan, SB269970, and naloxone. The analgesic effect was antagonized by WAY100135, SB269970, idazoxan, and naloxone in the ipsilateral and contralateral PAG studies. These findings strongly suggest that NPBW1/W2 activation by NPW microinjection into the RVM, LC, and PAG affect the descending pain modulatory system and produce anti-nociceptive and pro-nociceptive effects in the rat formalin test.
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Analgésicos/farmacología , Neuropéptidos/farmacología , Dolor/patología , Receptores de Neuropéptido/metabolismo , Analgésicos/administración & dosificación , Animales , Formaldehído , Inyecciones , Ligandos , Locus Coeruleus/efectos de los fármacos , Masculino , Bulbo Raquídeo/efectos de los fármacos , Neuropéptidos/administración & dosificación , Sustancia Gris Periacueductal/efectos de los fármacos , Ratas Sprague-DawleyRESUMEN
AIM: Besides motor impairment, non-motor symptoms including cognitive decline, anxiety, and depression are observed in Parkinson's Disease (PD). The aim of this study was to investigate whether chronic administration of central neuropeptide-S (NPS) improves non-motor symptoms in 6-hydroxydopamine (6-OHDA)-induced parkinsonian rats. MATERIAL AND METHODS: Experimental PD was utilized by unilateral stereotaxic injection of the 6-OHDA into the medial forebrain bundle (MFB), while the sham-operated animals underwent the same surgical procedures. NPS (1 nmol) or vehicle was daily administered through an intracerebroventricular (icv) cannula for 7 days. Radial arm maze (RAM) test was used to evaluate the working memory; whereas, elevated plus maze (EPM) test and sucrose preference test were used to monitor the anxiety and depression status, respectively. The levels of dopamine, glutamic acid, and glutamine was determined in harvested striatal and hippocampal tissue samples. The immunoreactivities for tyrosine hydroxylase (TH) was determined using immunohistochemistry. RESULTS: In the RAM test, the 6-OHDA-induced increases in the reference and working memory errors were reduced by the central NPS administration. The decreased sucrose preference in the parkinsonian rats was increased by centrally administered NPS. The levels of dopamine levels in striatum and hippocampus were decreased in the parkinsonian rats, however, they were not altered by the centrally administered NPS. Additionally, NPS treatment significantly attenuated the 6-OHDA-induced loss of TH neuronal number. CONCLUSION: Consequently, NPS appears to be a therapeutic candidate for the treatment of non-motor complications of PD.
Asunto(s)
Conducta Animal/efectos de los fármacos , Neuropéptidos/administración & dosificación , Trastornos Parkinsonianos/psicología , Sustancias Protectoras/administración & dosificación , Animales , Ansiedad , Depresión , Modelos Animales de Enfermedad , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratas WistarRESUMEN
Two novel peptides, neuromedin U precursor-related peptide (NURP) and neuromedin S precursor-related peptide (NSRP), are produced from neuromedin U (NMU) and neuromedin S (NMS) precursors, respectively, as these precursors have multiple consensus sequences for proteolytic processing. Our group has shown previously that one of these two novel peptides, NURP, stimulates body temperature and locomotor activity, but not food intake. However, the physiological function of the other peptide, NSRP, has remained unclear. Therefore, the aim of this study was to characterize differences in the regions of the rat brain targeted by the NMU/NMS peptide family, including NURP and NSRP, and their physiological functions. First, we explored the regions of c-Fos expression after intracerebroventricular (i.c.v.) injection of NURP and NSRP and found that these were fewer than after i.c.v. injection of NMU and NMS in the hypothalamus, possibly because NURP and NSRP cannot activate NMU/NMS receptors. In the ventral subiculum, which is one region of the hippocampus, c-Fos expression was evident only after i.c.v. injection of NURP. We also examined the effects of NSRP on food intake, body temperature and locomotor activity. Like NURP, NSRP increased both body temperature and locomotor activity, but not food intake, indicating that NSRP is also a functional peptide. However, these effects of NSRP were distinctly weaker than those of NURP. These findings suggest differences in the affinity of NURP and/or NSRP for specific receptors, or in their respective biological activities.
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Sistema Nervioso Central/fisiología , Neuropéptidos/fisiología , Precursores de Proteínas/fisiología , Secuencia de Aminoácidos , Animales , Temperatura Corporal/efectos de los fármacos , Temperatura Corporal/fisiología , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Sistema Nervioso Central/efectos de los fármacos , Ingestión de Alimentos/efectos de los fármacos , Ingestión de Alimentos/fisiología , Inyecciones Intraventriculares , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Neuropéptidos/administración & dosificación , Neuropéptidos/genética , Precursores de Proteínas/administración & dosificación , Precursores de Proteínas/genética , Proteínas Proto-Oncogénicas c-fos/metabolismo , Ratas , Ratas Wistar , Receptores de Neurotransmisores/fisiología , Homología de Secuencia de AminoácidoRESUMEN
Fibromyalgia is characterized by the amplification of central nervous system pain with concomitant fatigue, sleep, mood disorders, depression, and anxiety. It needs extensive pharmacological therapy. In the present study, Swiss mice were treated with reserpine (0.25 mg/kg, s.c.) over three consecutive days, in order to reproduce the pathogenic process of fibromyalgia. On day 4, the administrations of the Tx3-3 toxin produced significant antinociception in the mechanical allodynia (87.16% ±12.7%) and thermal hyperalgesia (49.46% ± 10.6%) tests when compared with the PBS group. The effects produced by the classical analgesics (duloxetine 30 mg/kg, pramipexole 1 mg/kg, and pregabalin 30 mg/kg, p.o., respectively) in both of the tests also demonstrated antinociception. The administrations were able to increase the levels of the biogenic amines (5-HTP and DE) in the brain. The treatments with pramipexole and pregabalin, but not duloxetine, decreased the immobility time in the FM-induced animals that were submitted to the forced swimming test; however, the Tx3-3 toxin (87.45% ± 4.3%) showed better results. Taken together, the data has provided novel evidence of the ability of the Tx3-3 toxin to reduce painful and depressive symptoms, indicating that it may have significant potential in the treatment of FM.
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Analgésicos/administración & dosificación , Fibromialgia/tratamiento farmacológico , Neuropéptidos/administración & dosificación , Anestésicos/administración & dosificación , Animales , Modelos Animales de Enfermedad , Fibromialgia/inducido químicamente , Hiperalgesia/tratamiento farmacológico , Masculino , Ratones , Reserpina/administración & dosificaciónRESUMEN
BACKGROUND: Ischemia-reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) and increases the risk of subsequently developing chronic kidney disease. Angiogenesis has been shown to play an important role in reducing renal injury after ischemia reperfusion. In this study, we investigated whether IMD could reduce renal IRI by promoting angiogenesis. METHODS: The kidneys of Wistar rats were subjected to 45 min of warm ischemia followed by 24 h of reperfusion. IMD was overexpressed in vivo using the vector pcDNA3.1-IMD transfected by an ultrasound-mediated system. The renal injury after ischemia reperfusion was assessed by detection of the serum creatinine concentration and histologic examinations of renal tissues stained by PAS and H&E. Real-time PCR and Western blotting were used to determine the mRNA and protein levels, respectively. Histological examinations were used to assess the expression of CD31, MMP2, MMP9, ET-1, VEGF and VEGFR2 in tissues. RESULTS: Renal function and renal histological damage were significantly ameliorated in IMD-transfected rats after ischemia reperfusion. Compared to the IRI, IMD significantly promoted angiogenesis. IMD also upregulated the protein and mRNA expression levels of VEGF and VEGFR2 and downregulated the expression level of MMP2, MMP9 and ET-1. CONCLUSION: IMD could protect the kidney after renal ischemia-reperfusion injury by promoting angiogenesis and reducing the destruction of the perivascular matrix.
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Adrenomedulina/metabolismo , Endotelina-1/metabolismo , Metaloproteinasa 2 de la Matriz/metabolismo , Metaloproteinasa 9 de la Matriz/metabolismo , Neovascularización Patológica/metabolismo , Neuropéptidos/metabolismo , Daño por Reperfusión/metabolismo , Adrenomedulina/administración & dosificación , Adrenomedulina/genética , Animales , Masculino , Neuropéptidos/administración & dosificación , Neuropéptidos/genética , Ratas , Ratas Wistar , Ondas UltrasónicasRESUMEN
Octadecaneuropeptide (ODN) and its precursor diazepam-binding inhibitor (DBI) are peptides belonging to the family of endozepines. Endozepines are exclusively produced by astroglial cells in the central nervous system of mammals, and their release is regulated by stress signals and neuroactive compounds. There is now compelling evidence that the gliopeptide ODN protects cultured neurons and astrocytes from apoptotic cell death induced by various neurotoxic agents. In vivo, ODN causes a very strong neuroprotective action against neuronal degeneration in a mouse model of Parkinson's disease. The neuroprotective activity of ODN is based on its capacity to reduce inflammation, apoptosis, and oxidative stress. The protective effects of ODN are mediated through its metabotropic receptor. This receptor activates a transduction cascade of second messengers to stimulate protein kinase A (PKA), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK)-extracellular signal-regulated kinase (ERK) signaling pathways, which in turn inhibits the expression of proapoptotic factor Bax and the mitochondrial apoptotic pathway. In N2a cells, ODN also promotes survival and stimulates neurite outgrowth. During the ODN-induced neuronal differentiation process, numerous mitochondria and peroxisomes are identified in the neurites and an increase in the amount of cholesterol and fatty acids is observed. The antiapoptotic and neurotrophic properties of ODN, including its antioxidant, antiapoptotic, and pro-differentiating effects, suggest that this gliopeptide and some of its selective and stable derivatives may have therapeutic value for the treatment of some neurodegenerative diseases.
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Citoprotección/efectos de los fármacos , Inhibidor de la Unión a Diazepam/administración & dosificación , Modelos Animales de Enfermedad , Enfermedades Neurodegenerativas/prevención & control , Neuropéptidos/administración & dosificación , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Animales , Citoprotección/fisiología , Humanos , Ratones , Factores de Crecimiento Nervioso/administración & dosificación , Enfermedades Neurodegenerativas/metabolismo , Enfermedades Neurodegenerativas/patología , Neuroprotección/fisiología , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiologíaRESUMEN
BACKGROUND: Despite the health benefits of breastfeeding, initiation and duration rates continue to fall short of international guidelines. Many factors influence a woman's decision to wean; the main reason cited for weaning is associated with lactation complications, such as mastitis. Mastitis is an inflammation of the breast, with or without infection. It can be viewed as a continuum of disease, from non-infective inflammation of the breast to infection that may lead to abscess formation. OBJECTIVES: To assess the effectiveness of preventive strategies (for example, breastfeeding education, pharmacological treatments and alternative therapies) on the occurrence or recurrence of non-infective or infective mastitis in breastfeeding women post-childbirth. SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register, ClinicalTrials.gov, the WHO International Clinical Trials Registry Platform (ICTRP) (3 October 2019), and reference lists of retrieved studies. SELECTION CRITERIA: We included randomised controlled trials of interventions for preventing mastitis in postpartum breastfeeding women. Quasi-randomised controlled trials and trials reported only in abstract form were eligible. We attempted to contact the authors to obtain any unpublished results, wherever possible. Interventions for preventing mastitis may include: probiotics, specialist breastfeeding advice and holistic approaches. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trials for inclusion and risk of bias, extracted data and assessed the certainty of the evidence using GRADE. MAIN RESULTS: We included 10 trials (3034 women). Nine trials (2395 women) contributed data. Generally, the trials were at low risk of bias in most domains but some were high risk for blinding, attrition bias, and selective reporting. Selection bias (allocation concealment) was generally unclear. The certainty of evidence was downgraded due to risk of bias and to imprecision (low numbers of women participating in the trials). Conflicts of interest on the part of trial authors, and the involvement of industry funders may also have had an impact on the certainty of the evidence. Most trials reported our primary outcome of incidence of mastitis but there were almost no data relating to adverse effects, breast pain, duration of breastfeeding, nipple damage, breast abscess or recurrence of mastitis. Probiotics versus placebo Probiotics may reduce the risk of mastitis more than placebo (risk ratio (RR) 0.51, 95% confidence interval (CI) 0.35 to 0.75; 2 trials; 399 women; low-certainty evidence). It is uncertain if probiotics reduce the risk of breast pain or nipple damage because the certainty of evidence is very low. Results for the biggest of these trials (639 women) are currently unavailable due to a contractual agreement between the probiotics supplier and the trialists. Adverse effects were reported in one trial, where no woman in either group experienced any adverse effects. Antibiotics versus placebo or usual care The risk of mastitis may be similar between antibiotics and usual care or placebo (RR 0.37, 95% CI 0.10 to 1.34; 3 trials; 429 women; low-certainty evidence). The risk of mastitis may be similar between antibiotics and fusidic acid ointment (RR 0.22, 95% CI 0.03 to 1.81; 1 trial; 36 women; low-certainty evidence) or mupirocin ointment (RR 0.44, 95% CI 0.05 to 3.89; 1 trial; 44 women; low-certainty evidence) but we are uncertain due to the wide CIs. None of the trials reported adverse effects. Topical treatments versus breastfeeding advice The risk of mastitis may be similar between fusidic acid ointment and breastfeeding advice (RR 0.77, 95% CI 0.27 to 2.22; 1 trial; 40 women; low-certainty evidence) and mupirocin ointment and breastfeeding advice (RR 0.39, 95% CI 0.12 to 1.35; 1 trial; 48 women; low-certainty evidence) but we are uncertain due to the wide CIs. One trial (42 women) compared topical treatments to each other. The risk of mastitis may be similar between fusidic acid and mupirocin (RR 0.51, 95% CI 0.13 to 2.00; low-certainty evidence) but we are uncertain due to the wide CIs. Adverse events were not reported. Specialist breastfeeding education versus usual care The risk of mastitis (RR 0.93, 95% CI 0.17 to 4.95; 1 trial; 203 women; low-certainty evidence) and breast pain (RR 0.93, 95% CI 0.36 to 2.37; 1 trial; 203 women; low-certainty evidence) may be similar but we are uncertain due to the wide CIs. Adverse events were not reported. Anti-secretory factor-inducing cereal versus standard cereal The risk of mastitis (RR 0.24, 95% CI 0.03 to 1.72; 1 trial; 29 women; low-certainty evidence) and recurrence of mastitis (RR 0.39, 95% CI 0.03 to 4.57; 1 trial; 7 women; low-certainty evidence) may be similar but we are uncertain due to the wide CIs. Adverse events were not reported. Acupoint massage versus routine care Acupoint massage probably reduces the risk of mastitis compared to routine care (RR 0.38, 95% CI 0.19 to 0.78;1 trial; 400 women; moderate-certainty evidence) and breast pain (RR 0.13, 95% CI 0.07 to 0.23; 1 trial; 400 women; moderate-certainty evidence). Adverse events were not reported. Breast massage and low frequency pulse treatment versus routine care Breast massage and low frequency pulse treatment may reduce risk of mastitis (RR 0.03, 95% CI 0.00 to 0.21; 1 trial; 300 women; low-certainty evidence). Adverse events were not reported. AUTHORS' CONCLUSIONS: There is some evidence that acupoint massage is probably better than routine care, probiotics may be better than placebo, and breast massage and low frequency pulse treatment may be better than routine care for preventing mastitis. However, it is important to note that we are aware of at least one large trial investigating probiotics whose results have not been made public, therefore, the evidence presented here is incomplete. The available evidence regarding other interventions, including breastfeeding education, pharmacological treatments and alternative therapies, suggests these may be little better than routine care for preventing mastitis but our conclusions are uncertain due to the low certainty of the evidence. Future trials should recruit sufficiently large numbers of women in order to detect clinically important differences between interventions and results of future trials should be made publicly available.
Asunto(s)
Antibacterianos/administración & dosificación , Lactancia Materna/efectos adversos , Mastitis/prevención & control , Educación del Paciente como Asunto , Sesgo , Grano Comestible/química , Femenino , Ácido Fusídico/administración & dosificación , Humanos , Masaje/métodos , Mupirocina/administración & dosificación , Neuropéptidos/administración & dosificación , Pomadas/administración & dosificación , Placebos/uso terapéutico , Probióticos/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
Molting enables growth and development across ecdysozoa. The molting process is strictly controlled by hormones - ecdysteroids. Ecdysteroidogenesis occurs in theprothoracic glands and stimulated by prothoracicotropic hormone in insects, while it ensues in the Y-organ and regulated by the molt inhibiting hormone in crustaceans. A peak in ecdysteroids in the hemolymph induces a cascade of multiple neuropeptides including Ecdysis Triggering Hormone (ETH) and Corazonin. The role of ETH is well defined in controlling the molt process in insects, but it is yet to be defined in crustaceans. In this study, we investigated the behavioral response of intermolt crayfish to ETH and Corazonin injections as well as the impact of ETH on the molt period using in vivo assays. Injection of Corazonin and ETH resulted in a clear and immediate eye twitching response to these two neuropeptides. The Corazonin injection induced eye twitching in slow and asynchronous manner, while ETH injection caused eye twitching in a relatively fast and synchronous way. A single injection of ETH to crayfish resulted in a remarkable prolong molt period, at twice the normal molting cycle, suggesting that ETH plays a key role in controlling the molt cycle in decapod crustaceans. Given the key significance of ETH in molt regulation and its plausible application in pest control, we characterized ETH across the pancrustacean orders. Bioinformatic analysis shows the mature ETH sequence is identical in all studied decapod species. ETH can be classified into specific groups based on the associated motif in each insect order and shows an insect motif -KxxPRx to be conserved in crustaceans.
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Astacoidea/fisiología , Ecdisteroides/farmacología , Muda/fisiología , Secuencia de Aminoácidos , Animales , Conducta Animal/efectos de los fármacos , Ojo/efectos de los fármacos , Neuropéptidos/administración & dosificación , Neuropéptidos/químicaRESUMEN
BACKGROUND: Control of intracranial pressure (ICP) is a key element in neurointensive care for directing treatment decisions in patients with severe traumatic brain injury (TBI). The anti-inflammatory protein antisecretory factor (AF) has been demonstrated to reduce experimentally induced high ICP in animal models. This report describes the first steps to investigate the uptake, safety, and influence of AF for reduction of elevated ICP in patients with TBI in a clinical setting. METHOD: Four patients with severe TBI (Glasgow Coma Scale < 9) that required neurointensive care with ICP monitoring due to signs of refractory intracranial hypertension were investigated. One hundred milliliters of Salovum®, a commercially available egg yolk powder with high contents of AF peptides, was administrated either via nasogastric (patients 1 and 2) or rectal tube (patients 2, 3, and 4) every 8 h for 2 to 3 days as a supplement to the conventional neurointensive care. ICP was registered continuously. Plasma levels of AF were measured by enzyme-linked immunosorbent assay (ELISA) to confirm that Salovum® was absorbed appropriately into the bloodstream. RESULTS: In the first two patients, we observed that when delivered by the nasogastric route, there was an accumulation of the Salovum® solution in the stomach with difficulties to control ICP due to impaired gastric emptying. Therefore, we tested to administer Salovum® rectally. In the third and fourth patients, who both showed radiological signs of extensive brain edema, ICP could be controlled during the course of rectal administration of Salovum®. The ICP reduction was statistically significant and was accompanied by an increase in blood levels of AF. No adverse events that could be attributed to AF treatment or the rectal approach for Salovum® administration were observed. CONCLUSIONS: The outcomes suggest that AF can act as a suppressor of high ICP induced by traumatic brain edema. Use of AF may offer a new therapeutic option for targeting cerebral edema in clinical practice.
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Lesiones Traumáticas del Encéfalo/tratamiento farmacológico , Hipertensión Intracraneal/tratamiento farmacológico , Neuropéptidos/uso terapéutico , Adulto , Lesiones Traumáticas del Encéfalo/complicaciones , Femenino , Escala de Coma de Glasgow , Humanos , Hipertensión Intracraneal/etiología , Presión Intracraneal , Masculino , Neuropéptidos/administración & dosificación , Proyectos PilotoRESUMEN
AIMS: Immunization with neural-derived peptides (INDP) has demonstrated to be a promising therapy to achieve a regenerative effect in the chronic phase of the spinal cord injury (SCI). Nevertheless, INDP-induced neurogenic effects in the chronic stage of SCI have not been explored. METHODS AND RESULTS: In this study, we analyzed the effect of INDP on both motor and sensitive function recovery; afterward, we assessed neurogenesis and determined the production of cytokines (IL-4, IL-10, and TNF alpha) and neurotrophic factors (BDNF and GAP-43). During the chronic stage of SCI, rats subjected to INDP showed a significant increase in both motor and sensitive recovery when compared to the control group. Moreover, we found a significant increase in neurogenesis, mainly at the central canal and at both the dorsal and ventral horns of INDP-treated animals. Finally, INDP induced significant production of antiinflammatory and regeneration-associated proteins in the chronic stages of SCI. CONCLUSIONS: These findings suggest that INDP has a neurogenic effect that could improve motor and sensitive recovery in the chronic stage of SCI. Moreover, our results also envision the use of INDP as a possible therapeutic strategy for other trauma-related disorders like traumatic brain injury.
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Inmunización/métodos , Neurogénesis/efectos de los fármacos , Neuropéptidos/administración & dosificación , Traumatismos de la Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/terapia , Animales , Femenino , Mediadores de Inflamación/antagonistas & inhibidores , Mediadores de Inflamación/metabolismo , Neurogénesis/fisiología , Dimensión del Dolor/efectos de los fármacos , Dimensión del Dolor/métodos , Ratas , Ratas Sprague-Dawley , Traumatismos de la Médula Espinal/inmunologíaRESUMEN
Epidemiologic studies have shown that sleep disorders are associated with the development of hypertension. The present study investigated dynamic changes in sleep patterns during the development of hypertension across the lifespan in spontaneously hypertensive rats (SHRs) and the neural mechanism that underlies these comorbidities, with a focus on the orexinergic system. Blood pressure in rats was measured using a noninvasive blood pressure tail cuff. Sleep was monitored by electroencephalographic and electromyographic recordings. Immunohistochemistry was used to detect the density and activity of orexinergic neurons in the perifornical nucleus. Hcrt2-SAP (400 or 800 ng) was microinjected in the lateral hypothalamus to lesion orexinergic neurons. Compared with Wistar-Kyoto rats, SHRs exhibited various patterns of sleep disturbances. In SHRs, dynamic changes in hypersomnia in the rats' active phase was not synchronized with the development of hypertension, but hyperarousal in the inactive phase and difficulties in falling asleep were observed concurrently with the development of hypertension. Furthermore, the density and activity of orexinergic neurons in the perifornical nucleus were significantly higher in SHRs than in age-matched Wistar-Kyoto rats. The reduction of orexinergic neurons in the lateral hypothalamus partially ameliorated the development of hypertension and prevented difficulties in falling asleep in SHRs. These results indicate that although the correlation between sleep disturbances and hypertension is very complex, common mechanisms may underlie these comorbidities in SHRs. Overactivity of the orexin system may be one such common mechanism.
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Hipertensión/metabolismo , Neuronas/metabolismo , Orexinas/metabolismo , Trastornos del Sueño-Vigilia/metabolismo , Animales , Hipertensión/fisiopatología , Masculino , Microinyecciones , Neuronas/efectos de los fármacos , Neuropéptidos/administración & dosificación , Neuropéptidos/toxicidad , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKY , Saporinas/administración & dosificación , Saporinas/toxicidad , Trastornos del Sueño-Vigilia/fisiopatología , Toxinas Biológicas/administración & dosificación , Toxinas Biológicas/toxicidadRESUMEN
In recent years, neuropeptides which display potent regulatory control of stress-related behaviors have been extensively demonstrated to play a critical role in regulating behaviors associated with substance abuse and affective disorders. Somatostatin (SST) is one neuropeptide known to significantly contribute to emotionality and stress behaviors. However, the role of SST in regulating behavior has received relatively little attention relative to other stress-involved peptides, such as neuropeptide Y or corticotrophin releasing factor. This review characterizes our current understanding of the role of SST and SST-expressing cells in general in modulating several behaviors intrinsically linked to substance abuse and affective disorders, specifically: anxiety and fear; stress and depression; feeding and drinking; and circadian rhythms. We further summarize evidence of a direct role for the SST system, and specifically somatostatin receptors 2 and 4, in substance abuse disorders. This article is part of the special issue on 'Neuropeptides'.
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Trastornos del Humor/metabolismo , Neuropéptidos/metabolismo , Somatostatina/metabolismo , Trastornos Relacionados con Sustancias/metabolismo , Animales , Ansiedad/tratamiento farmacológico , Ansiedad/metabolismo , Ritmo Circadiano/efectos de los fármacos , Ritmo Circadiano/fisiología , Miedo/efectos de los fármacos , Miedo/fisiología , Humanos , Trastornos del Humor/tratamiento farmacológico , Neuropéptidos/administración & dosificación , Receptores de Somatostatina/agonistas , Receptores de Somatostatina/metabolismo , Somatostatina/administración & dosificación , Trastornos Relacionados con Sustancias/tratamiento farmacológicoRESUMEN
Neuropeptide S (NPS) is an endogenous peptide recently recognized to be presented in the brainstem and believed to play an important role in maintaining memory. The deletion of NPS or NPS receptor (NPSR) in mice shows a deficit in memory formation. Our recent studies have demonstrated that central administration of NPS facilitates olfactory function and ameliorates olfactory spatial memory impairment induced by muscarinic cholinergic receptor antagonist and N-methyl-D-aspartate receptor antagonist. However, it remains to be determined if endogenous NPS is an indispensable neuromodulator in the control of the olfactory spatial memory. In this study, we examined the effects of NPSR peptidergic antagonist [D-Val5]NPS (10 and 20 nmol, intracerebroventricular) and nonpeptidergic antagonist SHA 68 (10 and 50 mg/kg, intraperitoneal) on the olfactory spatial memory using computer-assisted 4-hole-board olfactory spatial memory test in mice. Furthermore, immunofluorescence was employed to identify the distributions of c-Fos and NPSR immunoreactive (-ir) neurons in olfactory system and hippocampal formation known to closely relate to the olfactory spatial memory. [D-Val5]NPS dosing at 20 nmol and SHA 68 dosing at 50 mg/kg significantly decreased the number of visits to the 2 odorants interchanged spatially, switched odorants, in recall trial, and simultaneously reduced the percentage of Fos-ir in NPSR-ir neurons, which were densely distributed in the anterior olfactory nucleus, piriform cortex, subiculum, presubiculum, and parasubiculum. These findings suggest that endogenous NPS is a key neuromodulator in olfactory spatial memory.
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Neuropéptidos/farmacología , Neurotransmisores/farmacología , Percepción Olfatoria/efectos de los fármacos , Memoria Espacial/efectos de los fármacos , Animales , Infusiones Intraventriculares , Masculino , Ratones , Ratones Endogámicos C57BL , Neuropéptidos/administración & dosificación , Neurotransmisores/administración & dosificación , Oxazolidinonas/administración & dosificación , Oxazolidinonas/farmacología , Pirazinas/administración & dosificación , Pirazinas/farmacología , Receptores de Neuropéptido/antagonistas & inhibidores , Receptores de Neuropéptido/metabolismoRESUMEN
Actions of kisspeptins (KISSs) and RFamide-related peptide-3 (RFRP-3) at the hypothalamus modulate female reproduction. The action of KISS and RFRP-3 in the pituitary gland of pigs during the estrous cycle has not yet been delineated. The present study was conducted to assess the effect of KISS and RFRP-3 on relative abundance of αGSU and ßLH mRNA transcript and LH secretion in vitro by pituitary cells of gilts during the estrous cycle. The cells were isolated from gilts on Days 2-3, 10-12, 15-16 and 19-20 of the estrous cycle and cultured in vitro without inclusion of GnRH (control) or with GnRH (100 ng/ml), KISS (10-6 M, 10-7 M) and RFRP-3 (10-6 M, 10-7 M) alone or in combination. The relative abundance of α-GSU and ß-LH mRNAs was examined. Treatment with KISS increased the synthesis and/or secretion of LH by pituitary cells and RFRP-3 inhibited the synthesis and secretion of LH in the presence of GnRH on Days 10-12 and 15-16 of the estrous cycle. The synthesis and secretion of LH was greater when there was treatment with KISS and GnRH during the late follicular phase. Treatments with KISS and RFRP-3 affected the synthesis and/or secretion of LH during the luteal phase and luteolysis. In conclusion, KISS and RFRP-3 apparently affects the synthesis and secretion of LH by pituitary cells of estrous cyclic pigs. There appears to be a greater effect of KISS in modulation of LH secretion than RFRP-3 in pigs.
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Kisspeptinas/farmacología , Hormona Luteinizante/metabolismo , Neuropéptidos/farmacología , Hipófisis/citología , Porcinos/fisiología , Animales , Células Cultivadas , Relación Dosis-Respuesta a Droga , Quimioterapia Combinada , Ciclo Estral/fisiología , Femenino , Regulación de la Expresión Génica/efectos de los fármacos , Kisspeptinas/administración & dosificación , Hormona Luteinizante/genética , Neuropéptidos/administración & dosificación , Hipófisis/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Reproduction and growth are under multifactorial control of neurohormones and peripheral hormones. This study investigated seasonally related effects of GnIH, GnRH, and T3 on the reproductive and growth axis in male goldfish at three stages of gonadal recrudescence. The effects of injection treatments with GnRH, GnIH and/or T3 were examined by measuring serum LH and GH levels, as well as peripheral transcript levels, using a factorial design. As expected, GnRH elevated serum LH and GH levels in a seasonally dependant manner, with maximal elevations of LH in late stages of gonadal recrudescence (Spring) and maximal increases in GH in the regressed gonadal stage (Summer). GnIH injection increased serum LH and GH levels only in fish at the regressed stage but exerted both stimulatory and inhibitory effects on GnRH-induced LH responses depending on season. T3 treatment mainly had stimulatory effects on circulating LH levels and inhibitory effects on serum GH concentrations. In the liver and testes, we observed seasonal differences in thyroid receptors, estrogen receptors, vitellogenin, follicle-stimulating hormone receptor, aromatase and IGF-I transcript levels that were tissue- and sex-specific. Generally, there were no clear correlation between circulating LH and GH levels and peripheral transcript levels, presumably due to time-related response and possible direct interaction of GnRH and GnIH at the level of liver and testis. The results support the hypothesis that GnRH and GnIH are important components of multifactorial mechanisms that work in concert with T3 to regulate reciprocal control of reproduction and growth in goldfish.