RESUMEN
BACKGROUND: Mitochondria are essential organelles involved in cellular energy production. Changes in mitochondrial function can lead to dysfunction and cell death in aging and age-related disorders. Recent research suggests that mitochondrial dysfunction is closely linked to neurodegenerative diseases. Glucagon-like peptide-1 receptor (GLP-1R) agonist has gained interest as a potential treatment for Parkinson's disease (PD). However, the exact mechanisms responsible for the therapeutic effects of GLP-1R-related agonists are not yet fully understood. METHODS: In this study, we explores the effects of early treatment with PT320, a sustained release formulation of the GLP-1R agonist Exenatide, on mitochondrial functions and morphology in a progressive PD mouse model, the MitoPark (MP) mouse. RESULTS: Our findings demonstrate that administration of a clinically translatable dose of PT320 ameliorates the reduction in tyrosine hydroxylase expression, lowers reactive oxygen species (ROS) levels, and inhibits mitochondrial cytochrome c release during nigrostriatal dopaminergic denervation in MP mice. PT320 treatment significantly preserved mitochondrial function and morphology but did not influence the reduction in mitochondria numbers during PD progression in MP mice. Genetic analysis indicated that the cytoprotective effect of PT320 is attributed to a reduction in the expression of mitochondrial fission protein 1 (Fis1) and an increase in the expression of optic atrophy type 1 (Opa1), which is known to play a role in maintaining mitochondrial homeostasis and decreasing cytochrome c release through remodeling of the cristae. CONCLUSION: Our findings suggest that the early administration of PT320 shows potential as a neuroprotective treatment for PD, as it can preserve mitochondrial function. Through enhancing mitochondrial health by regulating Opa1 and Fis1, PT320 presents a new neuroprotective therapy in PD.
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Citocromos c , Exenatida , Agonistas Receptor de Péptidos Similares al Glucagón , Enfermedades Mitocondriales , Citocromos c/uso terapéutico , Enfermedades Mitocondriales/tratamiento farmacológico , Enfermedades Mitocondriales/metabolismo , Exenatida/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Modelos Animales de EnfermedadRESUMEN
INTRODUCTION: Tobacco products are addictive, with nicotine serving as the major addictive ingredient. Chronic tobacco use or chronic administration of nicotine alone results in both physiological and psychological dependence. Our previous studies indicated that dextromethorphan (DM) could effectively attenuate the dependence of morphine and methamphetamine. Thus, we further investigated the possible effects of DM on nicotine dependence. AIMS AND METHODS: Conditioned place preference (CPP) test was used to examine nicotine-induced rewarding effects as well as the drug-seeking-related behavior in rats. Nicotine dependence was induced by continuous subcutaneous infusion of nicotine via an osmotic minipump for 7 days and abstinence was initiated by removal of the pump. Withdrawal signs were observed and quantified. Locomotor activity was measured to determine the behavioral sensitization induced by nicotine. To investigate the activity of mesolimbic dopaminergic neuronal activity in correlation with the effects of nicotine, the animals were sacrificed and the nucleus accumbens (NAc), dorsal striatum (DS), and medial prefrontal cortex (mPFC) were dissected and used to determine the contents of dopamine (DA) and its metabolites using high-performance liquid chromatography (HPLC). RESULTS: Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. CONCLUSIONS: The results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence. IMPLICATIONS: Our results showed that DM could suppress nicotine-induced rewarding effect and drug-seeking-related behavior. In addition, co-administration and post-treatment of DM could both attenuate nicotine withdrawal signs. Moreover, DM could suppress nicotine-induced behavioral sensitization. Neurochemical experiments show that co-administration and post-treatment of DM abolished nicotine-induced increase of the DA turnover rate in the mPFC, but not in the NAc and DS. These results suggest that DM has a great therapeutic potential in the treatment of nicotine dependence.
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Síndrome de Abstinencia a Sustancias , Tabaquismo , Ratas , Animales , Nicotina/efectos adversos , Nicotina/metabolismo , Dextrometorfano/farmacología , Dextrometorfano/metabolismo , Ratas Sprague-Dawley , Tabaquismo/tratamiento farmacológico , Tabaquismo/metabolismo , Recompensa , Núcleo Accumbens/metabolismo , Dopamina/metabolismo , Síndrome de Abstinencia a Sustancias/tratamiento farmacológico , Síndrome de Abstinencia a Sustancias/metabolismoRESUMEN
To determine the efficacy of PT320 on L-DOPA-induced dyskinetic behaviors, and neurochemistry in a progressive Parkinson's disease (PD) MitoPark mouse model. To investigate the effects of PT320 on the manifestation of dyskinesia in L-DOPA-primed mice, a clinically translatable biweekly PT320 dose was administered starting at either 5 or 17-weeks-old mice. The early treatment group was given L-DOPA starting at 20 weeks of age and longitudinally evaluated up to 22 weeks. The late treatment group was given L-DOPA starting at 28 weeks of age and longitudinally observed up to 29 weeks. To explore dopaminergic transmission, fast scan cyclic voltammetry (FSCV) was utilized to measure presynaptic dopamine (DA) dynamics in striatal slices following drug treatments. Early administration of PT320 significantly mitigated the severity L-DOPA-induced abnormal involuntary movements; PT320 particularly improved excessive numbers of standing as well as abnormal paw movements, while it did not affect L-DOPA-induced locomotor hyperactivity. In contrast, late administration of PT320 did not attenuate any L-DOPA-induced dyskinesia measurements. Moreover, early treatment with PT320 was shown to not only increase tonic and phasic release of DA in striatal slices in L-DOPA-naïve MitoPark mice, but also in L-DOPA-primed animals. Early treatment with PT320 ameliorated L-DOPA-induced dyskinesia in MitoPark mice, which may be related to the progressive level of DA denervation in PD.
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Antiparkinsonianos , Discinesia Inducida por Medicamentos , Receptor del Péptido 1 Similar al Glucagón , Levodopa , Enfermedad de Parkinson , Animales , Ratones , Antiparkinsonianos/efectos adversos , Antiparkinsonianos/uso terapéutico , Preparaciones de Acción Retardada/uso terapéutico , Modelos Animales de Enfermedad , Dopamina/efectos adversos , Dopamina/uso terapéutico , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Receptor del Péptido 1 Similar al Glucagón/agonistas , Levodopa/efectos adversos , Levodopa/uso terapéutico , Oxidopamina , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
BACKGROUND: Peripartum cardiomyopathy (PPCM) is defined as an idiopathic cardiomyopathy occurring in the last month of pregnancy or the first 6 months postpartum without an identifiable cause. PPCM is suspected to be triggered by the generation of a cardiotoxic fragment of prolactin and the secretion of a potent antiangiogenic protein from the placental, but no single factor has been identified or defined as the underlying cause of the disease. Influenza virus can cause PPCM through immune-mediated response induced by proinflammatory cytokines from host immunity and endothelial cell dysfunction. We report a case in a parturient woman undergoing a cesarean delivery, who had influenza A pneumonia and PPCM. CASE PRESENTATION: A parturient woman at 40 weeks and 1 day of gestation who had experienced gestational hypertension accompanied by pulmonary edema developed hypotension after undergoing an emergency cesarean delivery. An elevation of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) was noted, and echocardiography revealed a left ventricular ejection fraction of 20%. She underwent a nasopharyngeal swab test, in which influenza A antigen was positive. She was diagnosed as having PPCM and received anti-viral treatment. After antiviral treatment, hemodynamic dysfunction stabilized. We present and discuss the details of this event. CONCLUSION: PPCM is a heart disease that is often overlooked by medical personnel. Rapid swab tests, serum creatine kinase measurement, and echocardiography are imperative diagnostic approaches for the timely recognition of virus-associated cardiomyopathy in peripartum women with influenza-like disease and worsening dyspnea, especially during the epidemic season. Prompt antiviral treatment should be considered, particularly after PPCM is diagnosed.
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Cardiomiopatías , Insuficiencia Cardíaca , Virus de la Influenza A , Gripe Humana , Neumonía , Complicaciones Cardiovasculares del Embarazo , Trastornos Puerperales , Antivirales/uso terapéutico , Cardiomiopatías/diagnóstico , Cardiomiopatías/etiología , Femenino , Humanos , Gripe Humana/complicaciones , Gripe Humana/diagnóstico , Gripe Humana/tratamiento farmacológico , Periodo Periparto , Placenta , Embarazo , Complicaciones Cardiovasculares del Embarazo/diagnóstico , Trastornos Puerperales/diagnóstico , Trastornos Puerperales/tratamiento farmacológico , Trastornos Puerperales/etiología , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
During the last three decades, a variety of different studies on bioactive peptides that are opioid receptor ligands, have been carried out, with regard to their isolation and identification, as well as their molecular functions in living organisms. Thus, in this review, we would like to summarize the present state-of-the art concerning hemorphins, methodological aspects of their identification, and their potential role as therapeutic agents. We have collected and discussed articles describing hemorphins, from their discovery up until now, thus presenting a very wide spectrum of their characteristic and applications. One of the major assets of the present paper is a combination of analytical and pharmacological aspects of peptides described by a team who participated in the initial research on hemorphins. This review is, in part, focused on the analysis of endogenous opioid peptides in biological samples using advanced techniques, description of the identification of synthetic/endogenous hemorphins, their involvement in pharmacology, learning, pain and other function. Finally, the part regarding hemorphin analogues and their synthesis, has been added.
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Péptidos Opioides/metabolismo , Dolor/metabolismo , Fragmentos de Péptidos/metabolismo , Receptores Opioides/metabolismo , Animales , HumanosRESUMEN
To determine the role of reduced dopaminergic transmission for declines of forced versus spontaneous behavior, we used a model of Parkinson's disease with progressive degeneration of dopamine (DA) neurons, the MitoPark mouse. Mice were subjected to rotarod tests of motor coordination, and open field and cylinder tests for spontaneous locomotor activity and postural axial support. To measure DA release in dorsal striatum and the shell of Nucleus Accumbens (NAc), we used ex vivo fast-scan cyclic voltammetry in 6- to 24-week-old mice. To determine decline of DA transporter function, we used 18FE-PE2I positron emission tomography. We show here that fast-scan cyclic voltammetry is a sensitive tool to detect evoked DA release dysfunction in MitoPark mice and that electrically evoked DA release is affected earlier in nigrostriatal than mesolimbic DA systems. DA reuptake was also affected more slowly in NAc shell. Positron emission tomography data showed DA uptake to be barely above detection levels in 16- and 20-week-old MitoPark mice. Rotarod performance was not impaired until mice were 16 weeks old, when evoked DA release in striatum had decreased to ≈ 40% of wild-type levels. In contrast, impairment of open field locomotion and rearing began at 10 weeks, in parallel with the initial modest decline of evoked DA release. We conclude that forced behaviors, such as motivation not to fall, can be partially maintained even when DA release is severely compromised, whereas spontaneous behaviors are much more sensitive to impaired DA release, and that presumed secondary non-dopaminergic system alterations do not markedly counteract or aggravate effects of severe impairment of DA release. OPEN SCIENCE BADGES: This article has received a badge for *Open Materials* because it provided all relevant information to reproduce the study in the manuscript. The complete Open Science Disclosure form for this article can be found at the end of the article. More information about the Open Practices badges can be found at https://cos.io/our-services/open-science-badges/.
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Conducta Animal/fisiología , Dopamina/metabolismo , Neuronas Dopaminérgicas/metabolismo , Degeneración Nerviosa/metabolismo , Trastornos Parkinsonianos/metabolismo , Animales , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Locomoción/fisiología , Ratones , Trastornos Parkinsonianos/complicacionesRESUMEN
This study analyzed gender differences in the progressive dopamine (DA) deficiency phenotype in the MitoPark (MP) mouse model of Parkinson's disease (PD) with progressive loss of DA release and reuptake in midbrain DA pathways. We found that the progressive loss of these DA presynaptic parameters begins significantly earlier in male than female MP mice. This was correlated with behavioral gender differences of both forced and spontaneous motor behavior. The degeneration of the nigrostriatal DA system in MP mice is earlier and more marked than that of the mesolimbic DA system, with male MP mice again being more strongly affected than female MP mice. After ovariectomy, DA presynaptic and behavioral changes in female mice become very similar to those of male animals. Our results suggest that estrogen, either directly or indirectly, is neuroprotective in the midbrain DA system. Our results are compatible with epidemiological data on incidence and symptom progression in PD, showing that men are more strongly affected than women at early ages.
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Dopamina/metabolismo , Actividad Motora , Enfermedad de Parkinson/fisiopatología , Animales , Conducta Animal , Modelos Animales de Enfermedad , Estimulación Eléctrica , Femenino , Masculino , Ratones Endogámicos C57BL , Ovariectomía , Probabilidad , Tirosina 3-Monooxigenasa/metabolismoRESUMEN
Background: Traumatic brain injury is known to impact dopamine-mediated reward pathways, but the underlying mechanisms have not been fully established. Methods: Nicotine-induced conditional place preference was used to study rats exposed to a 6-psi fluid percussion injury with and without prior exposure to nicotine. Preference was quantified as a score defined as (C1 - C2) / (C1 + C2), where C1 is time in the nicotine-paired compartment and C2 is time in the saline-paired compartment. Subsequent fast-scan cyclic voltammetry was used to analyze the impact of nicotine infusion on dopamine release in the shell portion of the nucleus accumbens. To further determine the influence of brain injury on nicotine withdrawal, nicotine infusion was administered to the rats after fluid percussion injury. The effects of fluid percussion injury on conditional place preference after prior exposure to nicotine and abstinence or withdrawal from nicotine were also assessed. Results: After traumatic brain injury, dopamine release was reduced in the nucleus accumbens shell, and nicotine-induced conditional place preference preference was significantly impaired. Preference scores of control, sham-injured, and fluid percussion injury groups were 0.1627±0.04204, 0.1515±0.03806, and -0.001300±0.04286, respectively. Nicotine-induced conditional place preference was also seen in animals after nicotine pretreatment, with a conditional place preference score of 0.07805±0.02838. Nicotine preexposure substantially increased tonic dopamine release in sham-injured animals, but it did not change phasic release; nicotine exposure after fluid percussion injury enhanced phasic release, though not to the same levels seen in sham-injured rats. Conditioned preference was related not only to phasic dopamine release (r=0.8110) but also to the difference between tonic and phasic dopamine levels (r=0.9521). Conclusions: Traumatic brain injury suppresses dopamine release from the shell portion of the nucleus accumbens, which in turn significantly alters reward-seeking behavior. These results have important implications for tobacco and drug use after traumatic brain injury.
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Condicionamiento Psicológico/efectos de los fármacos , Traumatismos Craneocerebrales/metabolismo , Traumatismos Craneocerebrales/psicología , Dopamina/metabolismo , Nicotina/farmacología , Núcleo Accumbens/metabolismo , Animales , Masculino , Microinyecciones , Ratas , Síndrome de Abstinencia a Sustancias/psicologíaRESUMEN
BACKGROUND: We demonstrated previously that angiotensin IV (Ang IV) and LVV-hemorphin 7 (LVV-H7) act through the blockade of insulin-regulated aminopeptidase to decrease oxytocin degradation, thereby causing antihyperalgesia at the spinal level in rats. We determined that intrathecal oxytocin can induce significant antihyperalgesia in male rats with inflammation but not in female rats. Thus, we speculate that Ang IV, LVV-H7, and oxytocin can induce antiallodynia, which could be of great therapeutic potential. Because the antihyperalgesia by using these peptides was with sex difference, their possible antiallodynia was examined in male and female mice for comparison. We investigated whether Ang IV, LVV-H7, and oxytocin produce antiallodynia at the spinal level in mice and whether this antiallodynia differs between the sexes. METHODS: Partial sciatic nerve ligation surgery was performed on adult male and female C57BL/6 mice from the same litter (25-30 g). The effects of intrathecal injections of Ang IV (25.8 nmol), LVV-H7 (27.2 nmol), and oxytocin (0.125 or 1.25 nmol) were assessed through the von Frey test 3 days after partial sciatic nerve ligation. RESULTS: Intrathecal injection of Ang IV, LVV-H7, and oxytocin all produced a potent antiallodynia in male mice. However, these antiallodynia effects were either extremely weak or absent in female mice at the same dose. CONCLUSIONS: Intrathecal Ang IV, LVV-H7, and oxytocin can all cause significant antiallodynia in male mice. The Ang IV-, LVV-H7-, and oxytocin-induced antiallodynia effects differed between the sexes at the spinal level in mice.
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Angiotensina II/análogos & derivados , Hemoglobinas/administración & dosificación , Hiperalgesia/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Oxitocina/administración & dosificación , Fragmentos de Péptidos/administración & dosificación , Caracteres Sexuales , Angiotensina II/administración & dosificación , Animales , Femenino , Hiperalgesia/patología , Inyecciones Espinales/métodos , Masculino , Ratones , Ratones Endogámicos C57BL , Neuralgia/patología , Manejo del Dolor/métodosRESUMEN
BACKGROUND: Neuropathic pain is a very troublesome and difficult pain to treat. Although opioids are the best analgesics for cancer and surgical pain in clinic, only oxycodone among opioids shows better efficacy to alleviate neuropathic pain. However, many side effects associated with the use of oxycodone render the continued use of it in neuropathic pain treatment undesirable. Hence, we explored whether dextromethorphan (DM, a known N-methyl-D-aspartate receptor antagonist with neuroprotective properties) could potentiate the anti-allodynic effect of oxycodone and underlying mechanisms regarding to glial cells (astrocytes and microglia) activation and proinflammatory cytokines release in a spinal nerve injury (SNL) mice model. RESULTS: Oxycodone produced a dose-dependent anti-allodynic effect. Co-administration of DM at a dose of 10 mg/kg (i.p.) (DM10) which had no anti-allodynic effect by itself enhanced the acute oxycodone (1 mg/kg, s.c.) effect. When the chronic anti-allodynic effects were examined, co-administration of DM10 also significantly enhanced the oxycodone effect at 3 mg/kg. Furthermore, oxycodone decreased SNL-induced activation of glial cells (astrocytes and microglia) and plasma levels of proinflammatory cytokines (IL-6, IL-1ß and TNF-α). Co-administration of DM10 potentiated these effects of oxycodone. CONCLUSION: The combined use of DM with oxycodone may have therapeutic potential for decreasing the effective dose of oxycodone on the treatment of neuropathic pain. Attenuation of the glial activation and proinflammatory cytokines in the spinal cord may be important mechanisms for these effects of DM.
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Dextrometorfano/farmacología , Neuralgia/tratamiento farmacológico , Oxicodona/farmacología , Animales , Astrocitos/metabolismo , Astrocitos/patología , Citocinas/metabolismo , Dextrometorfano/agonistas , Modelos Animales de Enfermedad , Sinergismo Farmacológico , Masculino , Ratones , Microglía/metabolismo , Microglía/patología , Neuralgia/metabolismo , Neuralgia/patología , Oxicodona/agonistasRESUMEN
Although nalbuphine, a semi-synthetic analgesic compound, is less potent than morphine in terms of alleviating severe pain, our recent findings have revealed that nalbuphine-6-glucuronide (N6G), one of the glucuronide metabolites of nalbuphine, promotes a significantly more robust analgesic effect than its parent drug. Nevertheless, despite these promising observations, the precise mechanisms underlying the analgesic effects of nalbuphine glucuronides have yet to be determined. In this study, we aim to elucidate the mechanisms associated with the analgesic effects of nalbuphine glucuronides. Pharmacokinetic and pharmacodynamic studies were conducted to investigate the relationship between the central and peripheral compartments of nalbuphine and its derivatives. The analgesic responses of these compounds were evaluated based on multiple behavioral tests involving thermal and mechanical stimuli. Radioligand binding assays were also performed to determine the binding affinity and selectivity of these compounds for different opioid receptors. The results of these tests consistently confirmed that the heightened analgesic effects of N6G are mediated through its enhanced binding affinity for both mu- and kappa-opioid receptors, even comparable to those of morphine. Notably, N6G exhibited fewer side effects and did not induce sudden death, thereby highlighting its superior safety profile. Additionally, pharmacokinetic studies indicated that N6G could cross the blood-brain barrier when administered peripherally, offering pain relief. Overall, N6G provides great analgesic efficacy and enhanced safety. These findings highlight the potential value of nalbuphine glucuronides, particularly N6G, as promising candidates for the development of novel analgesic drugs.
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Nalbufina , Receptores Opioides kappa , Humanos , Nalbufina/efectos adversos , Receptores Opioides mu , Glucurónidos/uso terapéutico , Analgésicos/farmacología , Analgésicos/uso terapéutico , Receptores Opioides/metabolismo , Morfina/efectos adversos , Dolor/tratamiento farmacológico , Dolor/inducido químicamente , Analgésicos Opioides/uso terapéuticoRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Piper methysticum G. Forst (Piperaceae) is traditionally consumed in Polynesian culture. The roots are used to produce an entheogenic drink and traditional medicine with sedative and anxiolytic properties. There is also evidence that it functions as a pain reliever. Kavalactones, its main active ingredients, exhibit psychoactive effects on the central nervous system. However, the active ingredients and pharmacological mechanisms underlying the analgesic effect of kavalactones are unclear. AIM OF THE STUDY: This study investigated the effects of kavain and yangonin on nociception, inflammatory hyperalgesia, and neuropathic mechanical allodynia at the spinal level. MATERIALS AND METHODS: Male Sprague-Dawley rats were administered kavain and yangonin (27.14 and 19.36 nmol/rat) via intrathecal injection. Tail-flick tests were performed to evaluate the anti-nociceptive properties. The efficacy of kavain and yangonin on inflammatory hyperalgesia was examined using a plantar test in rats with carrageenan-induced paw inflammation. The von Frey test was used to assess mechanical allodynia induced by partial sciatic nerve ligation. RESULTS: Intrathecal injection of yangonin demonstrated a relatively potent anti-nociceptive effect and attenuated carrageenan-induced hyperalgesia. These effects were completely reversed by the co-administration of PF 514273, a cannabinoid 1 (CB1) receptor antagonist. However, yangonin did not affect mechanical allodynia at the spinal level. Kavain, another abundant kavalactone, did not affect nociception, hyperalgesia, or mechanical allodynia at the spinal level. CONCLUSIONS: Overall, our study demonstrated that yangonin exerts anti-nociception and anti-inflammatory hyperalgesia effects via CB1 receptors at the spinal level. We identified a single kavalactone, yangonin, extracted from kava as a promising treatment for pain.
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Analgésicos , Hiperalgesia , Inyecciones Espinales , Receptor Cannabinoide CB1 , Animales , Masculino , Ratas , Analgésicos/farmacología , Analgésicos/aislamiento & purificación , Analgésicos/uso terapéutico , Carragenina , Hiperalgesia/tratamiento farmacológico , Lactonas/farmacología , Lactonas/aislamiento & purificación , Ratas Sprague-DawleyRESUMEN
Our previous studies have established that intrathecal oxytocin (OT) and angiotensin IV (Ang IV) injections induce antihyperalgesia and antiallodynia in rodents. Ang IV, a renin-angiotensin system hexapeptide, acts as an endogenous inhibitor that inhibits the oxytocin-degrading enzyme insulin-regulated aminopeptidase (IRAP). The pain inhibitory effects by Ang IV were found to be through its inhibition on IRAP to potentiate the effect of OT. However, these effects were found to be with a significant sex difference, which could be partially due to the higher expression of IRAP at the spinal cords of female. Therefore, we synthesized Ang IV and OT conjugates connected with a peptide bond and tested for their effects on hyperalgesia and allodynia. Carrageenan-induced hyperalgesia and partial sciatic nerve ligation (PSNL) were performed using rat models. Conjugates Ang IV-OT (Ang IV at the N-terminal) and OT-Ang IV (OT at the N-terminal) were synthesized and intrathecally injected into male and female rats. Our results showed that Ang IV-OT exhibited prominent antihyperalgesia in male rats, particularly during hyperalgesia recovery, whereas OT-Ang IV was more effective during development stage. Ang IV-OT showed clear antihyperalgesia in female rats, but OT-Ang IV had no significant effect. Notably, both conjugates alleviated neuropathic allodynia in male rats; however, OT-Ang IV had no effect in female rats, whereas Ang IV-OT induced significant antiallodynia. In conclusion, Ang IV-OT has greater therapeutic potential for treating hyperalgesia and allodynia than OT-Ang IV. Its effects were not affected by sex, unlike those of OT and OT-Ang IV, extending its possible clinical applications.
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Angiotensina II/análogos & derivados , Hiperalgesia , Oxitocina , Ratas , Femenino , Masculino , Animales , Oxitocina/farmacología , Oxitocina/uso terapéutico , Oxitocina/fisiología , Hiperalgesia/tratamiento farmacológico , Cistinil Aminopeptidasa/metabolismo , Angiotensina II/farmacología , Aminopeptidasas , Inyecciones EspinalesRESUMEN
BACKGROUND: The neurotoxicity of 3,4-methylenedioxy-methamphetamine (MDMA) to the serotonergic system is well-documented. Dextromethorphan (DM), an antitussive drug, decreased morphine- or methamphetamine (MA)-induced reward in rats and may prevent MDMA-induced serotonergic deficiency in primates, as indicated by increased serotonin transporter (SERT) availability. We aimed to investigate the effects of DM on reward, behavioral sensitization, and neurotoxicity associated with loss of SERT induced by chronic MDMA administration in rats. METHODS: Conditioned place preference (CPP) and locomotor activity tests were used to evaluate drug-induced reward and behavioral sensitization; 4-[ 18 F]-ADAM/animal-PET and immunohistochemistry were used to explore the effects of DM on MDMA-induced loss of SERT. RESULTS: MDMA significantly reduced SERT binding in the rat brain; however, co-administration of DM significantly restored SERT, enhancing the recovery rate at day 14 by an average of ~23% compared to the MDMA group. In confirmation of the PET findings, immunochemistry revealed MDMA reduced SERT immunoactivity in all brain regions, whereas DM markedly increased the serotonergic fiber density after MDMA induction. CONCLUSION: Behavioral tests and in vivo longitudinal PET imaging demonstrated the CPP indexes and locomotor activities of the reward system correlate negatively with PET 4-[ 18 F]ADAM SERT activity in the reward system. Our findings suggest MDMA induces functional abnormalities in a network of brain regions important to decision-making processes and the motivation circuit. DM may exert neuroprotective effects to reverse MDMA-induced neurotoxicity.
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Dextrometorfano , N-Metil-3,4-metilenodioxianfetamina , Recompensa , Proteínas de Transporte de Serotonina en la Membrana Plasmática , Animales , Masculino , Ratas , Dextrometorfano/farmacología , N-Metil-3,4-metilenodioxianfetamina/farmacología , Tomografía de Emisión de Positrones , Ratas Sprague-Dawley , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismoRESUMEN
Background: The serotonin (5-HT) system can manipulate the processing of exogenous L-DOPA in the DA-denervated striatum, resulting in the modulation of L-DOPA-induced dyskinesia (LID). Objective: To characterize the effects of the serotonin precursor 5-hydroxy-tryptophan (5-HTP) or the serotonin transporter (SERT) inhibitor, Citalopram on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. Methods: MitoPark (MP) mice at 20 weeks of age, subjected to a 14-day administration of L-DOPA/Carbidopa, displayed dyskinesia, referred to as LID. Subsequent investigations explored the effects of 5-HT-modifying agents, such as 5-HTP and Citalopram, on abnormal involuntary movements (AIMs), locomotor activity, neurochemical signals, serotonin transporter activity, and protein expression in the DA-denervated striatum of LID MP mice. Results: 5-HTP exhibited duration-dependent suppressive effects on developing and established LID, especially related to abnormal limb movements observed in L-DOPA-primed MP mice. However, Citalopram, predominantly suppressed abnormal axial movement induced by L-DOPA in LID MP mice. We demonstrated that 5-HTP could decrease L-DOPA-upregulation of DA turnover rates while concurrently upregulating 5-HT metabolism. Additionally, 5-HTP was shown to reduce the expressions of p-ERK and p-DARPP-32 in the striatum of LID MP mice. The effect of Citalopram in alleviating LID development may be attributed to downregulation of SERT activity in the dorsal striatum of LID MP mice. Conclusions: While both single injection of 5-HTP and Citalopram effectively mitigated the development of LID, the difference in mitigation of AIM subtypes may be linked to the unique effects of these two serotonergic agents on L-DOPA-derived DA and 5-HT metabolism.
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Citalopram , Modelos Animales de Enfermedad , Dopamina , Discinesia Inducida por Medicamentos , Levodopa , Serotonina , Animales , Levodopa/farmacología , Levodopa/efectos adversos , Discinesia Inducida por Medicamentos/metabolismo , Discinesia Inducida por Medicamentos/etiología , Discinesia Inducida por Medicamentos/tratamiento farmacológico , Ratones , Dopamina/metabolismo , Citalopram/farmacología , Serotonina/metabolismo , Proteínas de Transporte de Serotonina en la Membrana Plasmática/metabolismo , 5-Hidroxitriptófano/farmacología , Cuerpo Estriado/metabolismo , Cuerpo Estriado/efectos de los fármacos , Masculino , Inhibidores Selectivos de la Recaptación de Serotonina/farmacología , Carbidopa/farmacología , Antiparkinsonianos/farmacología , Antiparkinsonianos/efectos adversos , Enfermedad de Parkinson/metabolismo , Enfermedad de Parkinson/tratamiento farmacológicoRESUMEN
OBJECTIVE: To investigate the effects of systemic inflammation in the critical postnatal stages on neurophysiological actions of immune processes and neural plasticity in adult rats after kainic acid (KA)-induced seizures. METHODS: To determine changes in hippocampal synaptic plasticity after postnatal central nervous system inflammatory responses and seizure attacks, we performed intraperitoneal injections of lipopolysaccharide (LPS) in postnatal Sprague Dawley rats on day 14 (P14) to induce central nervous system inflammation. We then used a KA tail vein injection on P35 to induce seizure attacks. We compared the variability in synaptic plasticity in the hippocampal Schaffer collateral-CA1 region of seizure animals with or without LPS-induced inflammation preconditioning. RESULTS: P14 injection of LPS increased susceptibility to seizures, while treatment with KA on P35 induced seizures. Long-term potentiation (LTP) of the Schaffer collateral-CA1 region was impaired in seizure animals, and this effect was more pronounced in the P14 LPS injection group. Fluoro-Jade staining revealed an increase in degenerated hippocampal CA1 pyramidal cells in the P14 LPS injection group. Cytokine expression in the hippocampus in the pre-, peri- and postictus periods was greater in P14 LPS rats than in saline-treated rats. CONCLUSIONS: Intraperitoneal LPS injection on P14 induces higher cytokine secretion after KA-induced seizures, enhancing neuronal excitability, shortening seizure onset time and exacerbating neuronal degeneration and impairment of LTP formation in the hippocampal Schaffer collateral-CA1 region. Central nervous system inflammation during critical stages of childhood development could disrupt the balance needed for neurophysiological actions of immune processes, producing direct, pernicious effects on memory, neural plasticity and neurogenesis into adulthood.
Asunto(s)
Modelos Animales de Enfermedad , Hipocampo/patología , Plasticidad Neuronal/fisiología , Convulsiones/patología , Sinapsis/patología , Síndrome de Respuesta Inflamatoria Sistémica/patología , Animales , Animales Recién Nacidos , Femenino , Hipocampo/metabolismo , Ácido Kaínico/toxicidad , Lipopolisacáridos/toxicidad , Masculino , Técnicas de Cultivo de Órganos , Embarazo , Ratas , Ratas Sprague-Dawley , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Sinapsis/metabolismo , Síndrome de Respuesta Inflamatoria Sistémica/inducido químicamente , Síndrome de Respuesta Inflamatoria Sistémica/metabolismoRESUMEN
Cigarette smoking is the greatest risk factor for lung cancer, accounting for approximately 90% of all lung cancer-related deaths. Moreover, nicotine is associated with lung cancer onset and progression. Hypoxia-inducible factor 1α (HIF-1α) is involved in the metabolic reprogramming of cancer cells and accelerates cancer progression via regulation of pH and acid-base homeostasis. Previous studies have reported that nicotine upregulates HIF-1α expression. Therefore, we hypothesized that nicotine-mediated activation of HIF-1α regulates metabolic reprogramming and pH homeostasis in non-small cell lung cancer A549 cells and could potentially play a role in the progression of lung cancer. We examined the effects of nicotine on metabolic reprogramming and intracellular pH (pHi) homeostasis, which are critical for cancer progression. A549 cells were exposed to nicotine in the absence and presence of the nicotinic acetylcholine receptor antagonist, mecamylamine (MEC). We then analyzed glycolytic stress and the activity and expression of acid-extruder proteins, including the Na+-H+ exchanger 1 (NHE1) and monocarboxylate cotransporters 1 & 4 (MCT1 and MCT4, respectively). Nicotine promoted the Warburg effect, which is associated with accelerated migration of A549 cells through the activation of nicotinic acetylcholine receptors. Furthermore, nicotine upregulated the activities and expression of acid-extruder proteins, namely NHE1 and MCT4, and facilitated glycolysis. To the best of our knowledge, this is the first study to demonstrate that nicotine plays a pivotal regulatory role in metabolic reprogramming as well as regulation of pHi homeostasis in A549 cells via activation of nicotinic acetylcholine receptors and can therefore aggravate lung cancer progression.
Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Receptores Nicotínicos , Humanos , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Nicotina/farmacología , Receptores Nicotínicos/metabolismo , Neoplasias Pulmonares/metabolismo , Línea Celular Tumoral , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismoRESUMEN
In our previous study, we first demonstrated a significant effect of dextromethorphan (DM) on morphine-seeking behavior in morphine-dependent rats, when DM was given during morphine withdrawal. Using the same conditioned place preference (CPP) paradigm modified for measuring drug-seeking-related behavior, we further investigated the possible effect of DM on methamphetamine (MA)-seeking in MA-dependent rats. Our data showed that DM could also effectively suppress the drug-seeking behavior for MA, when administered during MA withdrawal. This suggests that DM may possess a pharmacological property to prevent drug-seeking behavior for addictive drugs in general. To examine the action sites of DM in the brain, DM was microinjected into the VTA or the NAc, and tested for its effect on MA-seeking during withdrawal. Both intra-VTA and intra-NAc injections of DM were able to block the MA-seeking, suggesting that DM has a dual action sites. In our neurochemical results, intra-NAc injection of DM showed a clear reduction of DA turnover rate at the NAc and the mPFC in response to MA challenge during withdrawal, which matched with the behavioral results. However, intra-VTA injection of DM reduced the DA turnover rate at the mPFC but did not have effect on the DA turnover rate at the NAc. Although further investigations may be needed to verify the connection between our neurochemical and behavioral results, the present study highlights the therapeutic potential of DM in antidrug-seeking behavior of MA and that the mechanism could be related to its effect on the mesolimbic and mesocortical dopaminergic pathways.
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Estimulantes del Sistema Nervioso Central/farmacología , Dextrometorfano/farmacología , Comportamiento de Búsqueda de Drogas/efectos de los fármacos , Antagonistas de Aminoácidos Excitadores/farmacología , Metanfetamina/farmacología , Animales , Dextrometorfano/administración & dosificación , Dopamina/análisis , Antagonistas de Aminoácidos Excitadores/uso terapéutico , Masculino , Núcleo Accumbens/química , Núcleo Accumbens/efectos de los fármacos , Especificidad de Órganos , Corteza Prefrontal/química , Corteza Prefrontal/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Recompensa , Área Tegmental Ventral/química , Área Tegmental Ventral/efectos de los fármacosRESUMEN
Our previous study verified a sex difference of anti-hyperalgesia in rats and anti-allodynia in mice induced by intrathecal oxytocin (OT). In the model of intraplantar carrageenan-induced inflammatory hyperalgesia, intrathecal OT injection induced a substantial anti-hyperalgesia in male rats even at a low dose (0.125 nmol). In contrast, female rats only responded to an extremely high dose (1.25 nmol). This sex difference concurs with a lower expression of OT receptors and higher expression of insulin-regulated aminopeptidase (IRAP; OT degrading enzyme) in the spinal cords of female rats. In this study, we further determined the role of female hormones in this sex difference by using ovariectomized rats. Our results show that a low dose of intrathecal OT caused a significant anti-hyperalgesia effect in ovariectomized female rats, similar to that seen in male rats. Ovariectomy did not cause any change of paw edema except at the late stage of convalescence when compared with the sham-operated group. Ovariectomy-induced faster recovery from edema but did not affect the severity of hyperalgesia. Moreover, there was a similar amount of IRAP expression in ovariectomized and sham rats. When estradiol (E2) was given together with OT, OT-induced anti-hyperalgesia was abolished at the developmental stage of hyperalgesia in ovariectomized rats. These results show an inhibitory role of female hormones generated from ovaries (mainly estrogen) in the sex difference of anti-hyperalgesia induced by OT. This study suggests the feasibility of a novel OT-based remedy to treat hyperalgesia in men and in menopausal women no receiving hormonal supplements.
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Hiperalgesia , Oxitocina , Animales , Edema/metabolismo , Estrógenos/metabolismo , Estrógenos/farmacología , Femenino , Humanos , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/metabolismo , Masculino , Ratones , Ovariectomía , Oxitocina/metabolismo , Ratas , Ratas Sprague-Dawley , Médula Espinal/metabolismoRESUMEN
BACKGROUND: L-DOPA-induced dyskinesia (LID), occurring with aberrant processing of exogenous L-DOPA in the dopamine-denervated striatum, is a main complication of levodopa treatment in Parkinson's disease. OBJECTIVE: To characterize the effects of the vesicular antagonist tetrabenazine (TBZ) on L-DOPA-induced behavior, neurochemical signals, and underlying protein expressions in an animal model of Parkinson's disease. METHODS: 20-week-old MitoPark mice were co-treated or separately administered TBZ and L-DOPA for 14 days. Abnormal involuntary movements (AIMs) and locomotor activity were analyzed. To explore dopamine (DA) transmission, fast scan cyclic voltammetry was used to assess presynaptic DA dynamics in striatal slices following treatments. PET imaging with 4-[18F]-PE2I, ADAM and immunoblotting assays were used to detect receptor protein changes in the DA-denervated striatum. Finally, nigrostriatal tissues were collected for HPLC measures of DA, serotonin and their metabolites. RESULTS: A single injection of TBZ given in the interval between the two L-DOPA/Carbidopa treatments significantly attenuated L-DOPA-induced AIMs expression and locomotor hyperactivity. TBZ was shown to reduce tonic and phasic release of DA following L-DOPA treatment in DA-denervated striatal tissue. In the DA-depleted striatum, TBZ decreased the expression of L-DOPA-enhanced D1 receptors and the serotonin reuptake transporter. Neurochemical analysis indicated that TBZ attenuated L-DOPA-induced surges of DA levels by promoting DA turnover in the nigrostriatal system. CONCLUSIONS: Our findings demonstrate that TBZ diminishes abnormal striatal DA transmission, which involves the ability of TBZ to modulate the presymptomatic dynamics of DA, and then mitigate aberrant release of exogenous L-DOPA from nerve terminals. The results support the potential of repositioning TBZ to counteract LID development.