RESUMEN
Despite the large arsenal of analgesic medications, neuropathic pain (NP) management is not solved yet. Angiotensin II receptor type 1 (AT1) has been identified as a potential target in NP therapy. Here, we investigate the antiallodynic effect of AT1 blockers telmisartan and losartan, and particularly their combination with morphine on rat mononeuropathic pain following acute or chronic oral administration. The impact of telmisartan on morphine analgesic tolerance was also assessed using the rat tail-flick assay. Morphine potency and efficacy in spinal cord samples of treated neuropathic animals were assessed by [35S]GTPγS-binding assay. Finally, the glutamate content of the cerebrospinal fluid (CSF) was measured by capillary electrophoresis. Oral telmisartan or losartan in higher doses showed an acute antiallodynic effect. In the chronic treatment study, the combination of subanalgesic doses of telmisartan and morphine ameliorated allodynia and resulted in a leftward shift in the dose-response curve of morphine in the [35S]GTPγS binding assay and increased CSF glutamate content. Telmisartan delayed morphine analgesic-tolerance development. Our study has identified a promising combination therapy composed of telmisartan and morphine for NP and opioid tolerance. Since telmisartan is an inhibitor of AT1 and activator of PPAR-γ, future studies are needed to analyze the effect of each component.
Asunto(s)
Analgésicos Opioides , Neuralgia , Ratas , Animales , Analgésicos Opioides/uso terapéutico , Telmisartán/farmacología , Telmisartán/uso terapéutico , Losartán/uso terapéutico , Guanosina 5'-O-(3-Tiotrifosfato) , Tolerancia a Medicamentos , Analgésicos/farmacología , Analgésicos/uso terapéutico , Morfina/farmacología , Morfina/uso terapéutico , Neuralgia/tratamiento farmacológico , Glutamatos/uso terapéuticoRESUMEN
Gangliosides are glycosphingolipids of the plasma membrane and are highly enriched in the nervous system where they play a vital role in normal cell functions. Furthermore, several studies suggest their potential involvement in the pathogenesis of neurological conditions. Since cyclodextrins (CDs) can form inclusion complexes with various lipids, methylated beta-CDs are widely used in biomedical research to extract cholesterol from the membrane and study its cellular role. Despite CDs being known to interact with other membrane lipid components, their effect on gangliosides is poorly characterized. The aim of this research was to investigate the effect of dimethyl-beta-cyclodextrin (DIMEB), hydroxypropyl-beta-cyclodextrin (HPBCD), randomly methylated-alpha-cyclodextrin (RAMEA), and hydroxypropyl-alpha-cyclodextrin (HPACD) on ganglioside and cholesterol levels in rat brain synaptosomes. Their effect on membrane integrity and viability was also assessed. We examined the role of lipid depletion by CDs on the release of the major excitatory neurotransmitter, glutamate. Selective concentration range for cholesterol depletion was only found with HPBCD, but not with DIMEB. Selective depletion of gangliosides was achieved by both RAMEA and HPACD. The inhibition of stimulated glutamate release upon ganglioside depletion was found, suggesting their potential role in neurotransmission. Our study highlights the importance of the characterization of the lipid depleting capability of different CDs.
Asunto(s)
Ciclodextrinas , Trastornos del Metabolismo de los Lípidos , 2-Hidroxipropil-beta-Ciclodextrina/farmacología , Animales , Colesterol/metabolismo , Ciclodextrinas/metabolismo , Ciclodextrinas/farmacología , Gangliósidos/metabolismo , Ácido Glutámico/metabolismo , Trastornos del Metabolismo de los Lípidos/metabolismo , Microdominios de Membrana/metabolismo , Ratas , Sinaptosomas/metabolismoRESUMEN
Current treatment approaches to manage neuropathic pain have a slow onset and their use is largely hampered by side-effects, thus there is a significant need for finding new medications. Tolperisone, a centrally acting muscle relaxant with a favorable side effect profile, has been reported to affect ion channels, which are targets for current first-line medications in neuropathic pain. Our aim was to explore its antinociceptive potency in rats developing neuropathic pain evoked by partial sciatic nerve ligation and the mechanisms involved. Acute oral tolperisone restores both the decreased paw pressure threshold and the elevated glutamate level in cerebrospinal fluid in neuropathic rats. These effects were comparable to those of pregabalin, a first-line medication in neuropathy. Tolperisone also inhibits release of glutamate from rat brain synaptosomes primarily by blockade of voltage-dependent sodium channels, although inhibition of calcium channels may also be involved at higher concentrations. However, pregabalin fails to affect glutamate release under our present conditions, indicating a different mechanism of action. These results lay the foundation of the avenue for repurposing tolperisone as an analgesic drug to relieve neuropathic pain.
Asunto(s)
Neuralgia , Tolperisona , Analgésicos/farmacología , Analgésicos/uso terapéutico , Animales , Modelos Animales de Enfermedad , Ácido Glutámico , Neuralgia/tratamiento farmacológico , Pregabalina/farmacología , Pregabalina/uso terapéutico , Ratas , Tolperisona/farmacología , Tolperisona/uso terapéuticoRESUMEN
Recently neuronal insulin resistance was suggested playing a role in Alzheimer's disease. Streptozotocin (STZ) is commonly used to induce impairment in insulin metabolism. In our previous work on undifferentiated SH-SY5Y cells the compound exerted cytotoxicity without altering insulin sensitivity. Nevertheless, differentiation of the cells to a more mature neuron-like phenotype may considerably affect the significance of insulin signaling and its sensitivity to STZ. We aimed at studying the influence of STZ treatment on insulin signaling in SH-SY5Y cells differentiated by retinoic acid (RA). Cytotoxicity of STZ or low serum (LS) condition and protective effect of insulin were compared in RA differentiated SH-SY5Y cells. The effect of insulin and an incretin analogue, exendin-4 on insulin signaling was also examined by assessing glycogen synthase kinase-3 (GSK-3) phosphorylation. STZ was found less cytotoxic in the differentiated cells compared to our previous results in undifferentiated SH-SY5Y cells. The cytoprotective concentration of insulin was similar in the STZ and LS groups. However, the right-shifted concentration-response curve of insulin induced GSK-3 phosphorylation in STZ-treated differentiated cells is suggestive of the development of insulin resistance that was further confirmed by the insulin potentiating effect of exendin-4. Differentiation reduced the sensitivity of SH-SY5Y cells for the non-specific cytotoxicity of STZ and enhanced the relative significance of development of insulin resistance. The differentiated cells thus serve as a better model for studying the role of insulin signaling in neuronal survival. However, direct cytotoxicity of STZ also contributes to the cell death.
Asunto(s)
Diferenciación Celular/fisiología , Resistencia a la Insulina/fisiología , Insulina/farmacología , Estreptozocina/toxicidad , Diferenciación Celular/efectos de los fármacos , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Exenatida/farmacología , Glucógeno Sintasa Quinasa 3/química , Glucógeno Sintasa Quinasa 3/metabolismo , Humanos , Fosforilación/efectos de los fármacos , Fosforilación/fisiología , Transducción de Señal/efectos de los fármacos , Tretinoina/farmacologíaRESUMEN
The limited effect of current medications on neuropathic pain (NP) has initiated large efforts to develop effective treatments. Animal studies showed that glycine transporter (GlyT) inhibitors are promising analgesics in NP, though concerns regarding adverse effects were raised. We aimed to study NFPS and Org-25543, GlyT-1 and GlyT-2 inhibitors, respectively and their combination in rat mononeuropathic pain evoked by partial sciatic nerve ligation. Cerebrospinal fluid (CSF) glycine content was also determined by capillary electrophoresis. Subcutaneous (s.c.) 4 mg/kg NFPS or Org-25543 showed analgesia following acute administration (30-60 min). Small doses of each compound failed to produce antiallodynia up to 180 min after the acute administration. However, NFPS (1 mg/kg) produced antiallodynia after four days of treatment. Co-treatment with subanalgesic doses of NFPS (1 mg/kg) and Org-25543 (2 mg/kg) produced analgesia at 60 min and thereafter meanwhile increased significantly the CSF glycine content. This combination alleviated NP without affecting motor function. Test compounds failed to activate G-proteins in spinal cord. To the best of our knowledge for the first time we demonstrated augmented analgesia by combining GlyT-1 and 2 inhibitors. Increased CSF glycine content supports involvement of glycinergic system. Combining selective GlyT inhibitors or developing non-selective GlyT inhibitors might have therapeutic value in NP.
Asunto(s)
Proteínas de Transporte de Glicina en la Membrana Plasmática/antagonistas & inhibidores , Glicina/líquido cefalorraquídeo , Hiperalgesia/prevención & control , Neuralgia/tratamiento farmacológico , Sarcosina/análogos & derivados , Animales , Hiperalgesia/metabolismo , Hiperalgesia/patología , Masculino , Actividad Motora , Neuralgia/metabolismo , Neuralgia/patología , Ratas , Ratas Wistar , Sarcosina/farmacología , Médula Espinal/efectos de los fármacos , Médula Espinal/metabolismo , Médula Espinal/patologíaRESUMEN
The current protocols for neuropathic pain management include µ-opioid receptor (MOR) analgesics alongside other drugs; however, there is debate on the effectiveness of opioids. Nevertheless, dose escalation is required to maintain their analgesia, which, in turn, contributes to a further increase in opioid side effects. Finding novel approaches to effectively control chronic pain, particularly neuropathic pain, is a great challenge clinically. Literature data related to pain transmission reveal that angiotensin and its receptors (the AT1R, AT2R, and MAS receptors) could affect the nociception both in the periphery and CNS. The MOR and angiotensin receptors or drugs interacting with these receptors have been independently investigated in relation to analgesia. However, the interaction between the MOR and angiotensin receptors has not been excessively studied in chronic pain, particularly neuropathy. This review aims to shed light on existing literature information in relation to the analgesic action of AT1R and AT2R or MASR ligands in neuropathic pain conditions. Finally, based on literature data, we can hypothesize that combining MOR agonists with AT1R or AT2R antagonists might improve analgesia.
Asunto(s)
Dolor Crónico/tratamiento farmacológico , Receptores de Angiotensina/efectos de los fármacos , Receptores Opioides mu/efectos de los fármacos , Analgésicos/farmacología , Analgésicos Opioides/farmacología , Animales , Humanos , Neuralgia/tratamiento farmacológico , Nocicepción/efectos de los fármacos , Manejo del Dolor/métodos , Proto-Oncogenes Mas , Receptores de Angiotensina/metabolismo , Receptores Opioides/agonistas , Receptores Opioides mu/agonistas , Receptores Opioides mu/metabolismoRESUMEN
Recently, it is suggested that brain insulin resistance may contribute to the development of Alzheimer's disease; therefore, there is a high interest in its investigation. Streptozotocin (STZ) is often used to induce dysregulation of glucose and insulin metabolism in animal and cell culture models. Alteration in insulin sensitivity however, has not yet been assessed in neuronal cells after STZ treatment. We aimed at studying the concentration dependence of the protective effect of insulin on STZ-induced damage using SH-SY5Y cell line. Cells were treated with STZ and cell viability was assessed by resazurin reduction and lactate dehydrogenase release assays. Low serum (LS) medium was used as control damage. The effect of various concentrations (30, 100, 300, 1000 nM) of insulin was studied on cell viability and glycogen synthase kinase-3 (GSK-3) phosphorylation, an indicator of insulin signaling. STZ induced dose- and time-dependent cytotoxicity, its 1 mM concentration exerted a low, gradually developing damage. The cytoprotective effect of insulin was demonstrated in both STZ and LS groups. Its maximal effect was lower in the STZ-treated cells; however, its effective concentration remained largely unaltered. Insulin-induced GSK-3 phosphorylation was similar in the STZ- and LS-treated cells suggesting unchanged insulin signaling. Our present results indicate that STZ does not induce significant impairment in insulin sensitivity in SH-SY5Y cells, thus in this cell line it is not a good tool for studying the role of insulin resistance in neurodegeneration and to examine protective agents acting by improving insulin signaling.
Asunto(s)
Antibióticos Antineoplásicos/farmacología , Resistencia a la Insulina , Insulina/farmacología , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Fármacos Neuroprotectores/farmacología , Estreptozocina/farmacología , Línea Celular Tumoral , HumanosRESUMEN
Monoamine oxidase B (MAO-B) inhibitors have an established role in the treatment of Parkinson's disease as monotherapy or adjuvant to levodopa. Two major recognitions were required for their introduction into this therapeutic field. The first was the elucidation of the novel pharmacological properties of selegiline as a selective MAO-B inhibitor by Knoll and Magyar and the original idea of Riederer and Youdim, supported by Birkmayer, to explore its effect in parkinsonian patients with on-off phases. In the 1960s, MAO inhibitors were mainly studied as potential antidepressants, but Birkmayer found that combined use of levodopa and various MAO inhibitors improved akinesia in Parkinson's disease. However, the serious side effects of the first non-selective MAO inhibitors prevented their further use. Later studies demonstrated that MAO-B, mainly located in glial cells, is important for dopamine metabolism in the brain. Recently, cell and molecular studies revealed interesting properties of selegiline opening new possibilities for neuroprotective mechanisms and a disease-modifying effect of MAO-B inhibitors.
Asunto(s)
Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Enfermedad de Parkinson/tratamiento farmacológico , Selegilina/farmacología , Animales , HumanosRESUMEN
Background and Objectives: The use of the dopamine-partial agonist subclass (also termed dopamine stabilizers) of atypical antipsychotics for the treatment of negative schizophrenia symptoms and some mood disorders has increased recently. Similar to other second-generation antipsychotics (SGAs), aripiprazole (ARI) and cariprazine (CAR) also influence food intake, but the peripheral effects of these drugs on adipose-tissue homeostasis, including adipokine secretion as well as lipo- and adipogenesis, are not fully elucidated. In this study, we explored the adipocyte-related mechanisms induced by second-generation antipsychotics (SGAs), leading to changes in peripheral signals involved in energy homeostasis. Materials and Methods: CAR, a new SGA, was compared with ARI and olanzapine (OLA), using cell cultures to study adipogenesis, and the expression levels of peroxisome proliferator-activated receptor-γ (PPAR-γ) was measured in adipocytes derived from mouse fibroblasts, by western blotting on days 7, 14, and 21 postinduction. The triglyceride (TG) content of the cells was also evaluated on day 15 using Oil Red O staining, and the adiponectin (AN) content in the cell culture supernatants was quantified on days 7 and 15 by enzyme-linked immunosorbent assay. Cells were treated with two concentrations of ARI (0.5 and 20 µg/mL), OLA (1 and 20 µg/mL), and CAR (0.1 and 2 µg/mL). Results: Both concentrations of ARI and OLA, as well as the lower concentration of CAR, significantly increased the TG contents. The AN levels in the supernatants were significantly increased by the higher concentration of ARI on days 7 and 15 (p < 0.05). Although PPAR-γ levels were not significantly affected by ARI and OLA, the lower concentration of CAR induced a significant time-dependent decrease in PPAR-γ expression (p < 0.05). Conclusions: The in vitro adipogenesis considered from TG accumulation, AN secretion, and PPAR-γ expression was differently influenced by ARI, CAR, and OLA. Understanding the adipocyte-related mechanisms of antipsychotics could contribute to understanding their weight-influencing effect.
Asunto(s)
Aripiprazol/uso terapéutico , Fibroblastos/efectos de los fármacos , Olanzapina/uso terapéutico , Piperazinas/uso terapéutico , Adiponectina/análisis , Adiponectina/sangre , Animales , Aripiprazol/administración & dosificación , Aripiprazol/farmacología , Diferenciación Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Fibroblastos/patología , Ratones , Trastornos del Humor/tratamiento farmacológico , Olanzapina/administración & dosificación , Olanzapina/farmacología , PPAR gamma/análisis , PPAR gamma/sangre , Piperazinas/administración & dosificación , Piperazinas/farmacología , Triglicéridos/análisis , Triglicéridos/sangreRESUMEN
The era of MAO-B inhibitors dates back more than 50 years. It began with Kálmán Magyar's outstanding discovery of the selective inhibitor, selegiline. This compound is still regarded as the gold standard of MAO-B inhibition, although newer drugs have also been introduced to the field. It was revealed early on that selective, even irreversible inhibition of MAO-B is free from the severe side effect of the non-selective MAO inhibitors, the potentiation of tyramine, resulting in the so-called 'cheese effect'. Since MAO-B is involved mainly in the degradation of dopamine, the inhibitors lack any antidepressant effect; however, they became first-line medications for the therapy of Parkinson's disease based on their dopamine-sparing activity. Extensive studies with selegiline indicated its complex pharmacological activity profile with MAO-B-independent mechanisms involved. Some of these beneficial effects, such as neuroprotective and antiapoptotic properties, were connected to its propargylamine structure. The second MAO-B inhibitor approved for the treatment of Parkinson's disease, rasagiline also possesses this structural element and shows similar pharmacological characteristics. The preclinical studies performed with selegiline and rasagiline are summarized in this review.
Asunto(s)
Indanos/uso terapéutico , Inhibidores de la Monoaminooxidasa/uso terapéutico , Neuroprotección/efectos de los fármacos , Fármacos Neuroprotectores/uso terapéutico , Enfermedad de Parkinson/tratamiento farmacológico , Selegilina/uso terapéutico , Humanos , Indanos/farmacología , Inhibidores de la Monoaminooxidasa/farmacología , Fármacos Neuroprotectores/farmacología , Selegilina/farmacologíaRESUMEN
d-Amino acid oxidase (DAAO) is a potential target in the treatment of schizophrenia as its inhibition increases brain d-serine level and thus contributes to NMDA receptor activation. Inhibitors of DAAO were sought testing [6+5] type heterocycles and identified isatin derivatives as micromolar DAAO inhibitors. A pharmacophore and structure-activity relationship analysis of isatins and reported DAAO inhibitors led us to investigate 1H-indazol-3-ol derivatives and nanomolar inhibitors were identified. The series was further characterized by pKa and isothermal titration calorimetry measurements. Representative compounds exhibited beneficial properties in in vitro metabolic stability and PAMPA assays. 6-fluoro-1H-indazol-3-ol (37) significantly increased plasma d-serine level in an in vivo study on mice. These results show that the 1H-indazol-3-ol series represents a novel class of DAAO inhibitors with the potential to develop drug candidates.
Asunto(s)
D-Aminoácido Oxidasa/antagonistas & inhibidores , Inhibidores Enzimáticos/farmacología , Indazoles/farmacología , Animales , D-Aminoácido Oxidasa/metabolismo , Relación Dosis-Respuesta a Droga , Descubrimiento de Drogas , Inhibidores Enzimáticos/síntesis química , Inhibidores Enzimáticos/química , Hepatocitos/efectos de los fármacos , Humanos , Indazoles/síntesis química , Indazoles/química , Masculino , Ratones , Microsomas Hepáticos/efectos de los fármacos , Modelos Moleculares , Estructura Molecular , Serina/sangre , Relación Estructura-ActividadRESUMEN
D-aspartate (D-Asp) modulates adult neural plasticity and embryonic brain development by promoting cell proliferation, survival and differentiation. Here, developmental changes of the excitatory amino acids (EAAs) L-Glu, L-Asp and D-Asp were determined during the first postembryonic days, a time window for early learning, in selected brain regions of domestic chickens after chiral separation and capillary electrophoresis. Extracellular concentration (ECC) of EAAs was measured in microdialysis samples from freely moving chicks. ECC of D-Asp (but not L-EAAs) decreased during the first week of age, with no considerable regional or learning-related variation. ECC of L-Asp and L-Glu (but not of D-Asp) were elevated in the mSt/Ac in response to a rewarding stimulus, suggesting importance of Asp-Glu co-release in synaptic plasticity of basal ganglia. Potassium-evoked release of D-Asp, with a protracted transient, was also demonstrated. D-Asp constitutes greater percentage of total aspartate in the extracellular space than in whole tissue extracts, thus the bulk of D-Asp detected in tissue appears in the extracellular space. Conversely, only a fraction of tissue L-EAAs can be detected in extracellular space. The lack of changes in tissue D-Asp following avoidance learning indicates a tonic, rather than phasic, mechanism in the neuromodulatory action of this amino acid.
Asunto(s)
Ácido Aspártico/metabolismo , Reacción de Prevención/fisiología , Encéfalo/metabolismo , Ácido D-Aspártico/metabolismo , Factores de Edad , Animales , Encéfalo/embriología , Encéfalo/crecimiento & desarrollo , Embrión de Pollo , Pollos , Espacio Extracelular/efectos de los fármacos , Espacio Extracelular/metabolismo , Glucosa/metabolismo , Memoria/fisiología , Microdiálisis , Potasio/farmacología , Factores de TiempoRESUMEN
AIM: To determine the levels of circulating soluble receptor for advanced glycation end products (sRAGE), as a biomarker of risk of metabolic syndrome and cardiovascular disease development in centrally obese (CO) women considered metabolically healthy (COH) in comparison with those metabolically unhealthy (COU). METHODS: 47 lean healthy, 17 COH (presenting waist-to-height ratio ≥0.5 but not elevated blood pressure, atherogenic lipid profile, and insulin resistance), and 50 COU (CO presenting ≥2 risk factors) women aged 40-45 years were included. Anthropometric characteristics, blood chemistry and hematology data, adipokines, markers of inflammation, sRAGE, soluble vascular adhesion protein-1 (sVAP-1), and the activity of semicarbazide sensitive amine oxidase (SSAO) were determined. RESULTS: Central obesity associated with low sRAGE levels (lean healthy: 1503±633 pg/mL; COH: 1103±339 pg/mL, P<0.05; COU: 1106±367 ng/mL, P<0.0.1), hyperleptinemia, and elevated markers of inflammation irrespective of the presence or absence of cardiometabolic risk factors. COU women presented high adiponectin levels. SVAP-1 concentrations and the activity of SSAO were similar in all 3 groups. CONCLUSION: COH women present abnormalities in non-standard markers of cardiometabolic risk (sRAGE, leptin, high sensitive C-reactive protein), supporting the view that there is no healthy pattern of obesity. The clinical impact of our findings for future prognosis of metabolically healthy obese subjects remains to be elucidated in longitudinal studies.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/metabolismo , Moléculas de Adhesión Celular/metabolismo , Obesidad Abdominal/fisiopatología , Complicaciones del Embarazo/fisiopatología , Receptor para Productos Finales de Glicación Avanzada/sangre , Adulto , Antropometría , Biomarcadores , Proteína C-Reactiva/metabolismo , Enfermedades Cardiovasculares/fisiopatología , Femenino , Humanos , Inflamación/sangre , Mediadores de Inflamación/metabolismo , Resistencia a la Insulina/fisiología , Lípidos/sangre , Síndrome Metabólico/fisiopatología , Persona de Mediana Edad , Embarazo , Factores de RiesgoRESUMEN
AIM: To study the effect of resveratrol on survival and caspase 3 activation in non-transformed cells after serum deprivation. METHODS: Apoptosis was induced by serum deprivation in primary mouse embryonic fibroblasts. Caspase 3 activation and lactate dehydrogenase release were assayed as cell viability measure by using their fluorogenic substrates. The involvement of PI3K, ERK, JNK, p38, and SIRT1 signaling pathways was also examined. RESULTS: Serum deprivation of primary fibroblasts induced significant activation of caspase 3 within 3 hours and reduced cell viability after 24 hours. Resveratrol dose-dependently prevented caspase activation and improved cell viability with 50% inhibitory concentration (IC50)=66.3±13.81 µM. It also reduced the already up-regulated caspase 3 activity when it was added to the cell culture medium after 3 hour serum deprivation, suggesting its rescue effect. Among the major signaling pathways, p38 kinase was critical for the protective effect of resveratrol which was abolished completely in the presence of p38 inhibitor. CONCLUSION: Resveratrol showed protective effect against cell death in a rather high dose. Involvement of p38 kinase in this effect suggests the role of mild stress in its cytoprotective action. Furthermore due to its rescue effect, resveratrol may be used not only for prevention, but also treatment of age-related degenerative diseases, but in the higher dose than consumed in conventional diet.
Asunto(s)
Antioxidantes/farmacología , Caspasa 3/metabolismo , Fibroblastos/efectos de los fármacos , Estilbenos/farmacología , Animales , Apoptosis/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Embrión de Mamíferos/citología , Fibroblastos/enzimología , L-Lactato Deshidrogenasa/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Ratones , Fosfatidilinositol 3-Quinasas/metabolismo , Resveratrol , Transducción de Señal , Sirtuina 1/metabolismo , Regulación hacia ArribaRESUMEN
AIM: To assess the impact of prenatal exposure to Maillard reaction products (MRPs) -rich diet and postnatal Coca-Cola consumption on metabolic status of female rats. Diet rich in MRPs and consumption of saccharose/fructose sweetened soft drinks is presumed to impose increased risk of development of cardiometabolic afflictions, such as obesity or insulin resistance. METHODS: At the first day of pregnancy, 9 female Wistar rats were randomized into two groups, pair-fed either with standard rat chow (MRP-) or MRPs-rich diet (MRP+). Offspring from each group of mothers was divided into two groups and given either water (Cola-) or Coca-Cola (Cola+) for drinking ad libitum for 18 days. Oral glucose tolerance test was performed, and circulating markers of inflammation, oxidative stress, glucose and lipid metabolism were assessed. RESULTS: MRP+ groups had higher weight gain, significantly so in the MRP+/Cola- vs MRP-/Cola-. Both prenatal and postnatal intervention increased carboxymethyllysine levels and semicarbazide-sensitive amine oxidase activity, both significantly higher in MRP+/Cola + than in MRP-/Cola-. Total antioxidant capacity was lower in MRP+ groups, with significant decrease in MRP+/Cola + vs MRP-/Cola+. Rats drinking Coca-Cola had higher insulin, homeostatic model assessment of insulin resistance, heart rate, advanced oxidation of protein products, triacylglycerols, and oxidative stress markers measured as thiobarbituric acid reactive substances compared to rats drinking water, with no visible effect of MRPs-rich diet. CONCLUSION: Metabolic status of rats was affected both by prenatal and postnatal dietary intervention. Our results suggest that combined effect of prenatal MRPs load and postnatal Coca-Cola drinking may play a role in development of metabolic disorders in later life.
Asunto(s)
Bebidas Gaseosas , Dieta , Reacción de Maillard , Enfermedades Metabólicas/etiología , Efectos Tardíos de la Exposición Prenatal/etiología , Animales , Glucemia/metabolismo , Peso Corporal/efectos de los fármacos , Femenino , Prueba de Tolerancia a la Glucosa , Metabolismo de los Lípidos , Enfermedades Metabólicas/sangre , Estrés Oxidativo , Embarazo , Fenómenos Fisiologicos de la Nutrición Prenatal , Ratas , Ratas Wistar , Sustancias Reactivas al Ácido Tiobarbitúrico/metabolismoRESUMEN
Chiral CE method has been developed for quantitative determination of d-amino acid modulators of NMDA glutamate receptor; d-serine and d-aspartate along with l-glutamate and l-aspartate in biological samples. These ligands are suggested to be involved in regulation of NMDA receptor related brain functions, such as neurogenesis, neuronal plasticity, and memory formation. For sensitive determination of the amino acids LIF detection was chosen, and a fluorogenic reagent, 7-fluoro-4-nitro-2,1,3-benzoxadiazole was used for derivatization. An amino-modified ß-CD, 6-monodeoxy-6-mono(3-hydroxy)propylamino-ß-CD (HPA-ß-CD) was applied as chiral selector. Determinations were accomplished in a polyacrylamide coated capillary and reverse polarity was used for the analysis of the negatively charged analytes. The method was optimized and validated; 6 mM HPA-ß-CD in 50 mM HEPES buffer, pH 7 was appropriate to achieve baseline separation of the analytes. The limit of quantification with acceptable accuracy is 0.05 µM for both d-amino acids. The method was used for the determination of d-aspartate and d-serine content in various brain regions of adult mice.
Asunto(s)
Química Encefálica , Electroforesis Capilar/métodos , Aminoácidos Excitadores/análisis , Aminoácidos Excitadores/química , Animales , Modelos Lineales , Masculino , Ratones , Ratones Endogámicos C57BL , Reproducibilidad de los Resultados , Sensibilidad y Especificidad , EstereoisomerismoRESUMEN
SSAO/VAP-1 participates in the accumulation of leukocytes at the site of inflammation. A new SSAO inhibitor, SzV-1287 was demonstrated to inhibit both acute and chronic inflammation in rats more effectively than the known enzyme inhibitor, LJP-1207. Surprisingly, the SSAO activity was not increased, but decreased both in acute and chronic inflammation. Though experiments are in progress to clarify these findings, the enzyme might play a role in the very early phase of inflammation and be inactivated during leukocyte extravasation.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/metabolismo , Artritis Experimental/tratamiento farmacológico , Inhibidores Enzimáticos/uso terapéutico , Inflamación/tratamiento farmacológico , Inflamación/etnología , Oxazoles/uso terapéutico , Oximas/uso terapéutico , Animales , Artritis Experimental/inducido químicamente , Carragenina/toxicidad , Modelos Animales de Enfermedad , Lateralidad Funcional , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hidrazinas/uso terapéutico , Inflamación/inducido químicamente , Masculino , Ratas , Ratas Wistar , Factores de TiempoRESUMEN
The aim of this study is to determine the efficacy of a potent and specific vascular adhesive protein-1/semicarbazide-sensitive amine oxidase (VAP-1/SSAO) inhibitor, LJP 1207, as a potential antiangiogenic and anti-inflammatory agent in the therapy of corneal neovascularization. Corneal neovascularization was induced with intrastromal suturing in rabbits (n = 20). Topical treatment with VAP-1/SSAO inhibitor LJP 1207 (n = 5, 4 times a day), bevacizumab (n = 5, daily), their combination (n = 5) and vehicle only (n = 5, 4 times a day) were applied postoperatively for 2 weeks. The development and extent of corneal neovascularization were evaluated by digital image analysis. At the end of the observation period, the level of corneal and serum VAP-1/SSAO activity was measured fluorometrically and radiochemically. The corneal VAP-1/SSAO activity was significantly elevated in the suture-challenged vehicle-treated group (3,075 ± 1,009 pmol/mg/h) as compared to unoperated controls (464.2 ± 135 pmol/mg/h, p < 0.001). Treatment with LJP 1207 resulted in slower early phase neovascularization compared to vehicle-treated animals (not significant). At days 7-14, there was no significant difference in the extent of corneal neovascularization between inhibitor- and vehicle-treated corneas, even though inhibitor treatment caused a normalization of corneal VAP-1/SSAO activity (885 ± 452 pmol/mg/h). Our results demonstrate that the significant elevation of VAP-1/SSAO activity due to corneal injury can be prevented with VAP-1/SSAO inhibitor LJP 1207 treatment. However, normalization of VAP-1/SSAO activity in this model does not prevent the development of corneal neovascularization.
Asunto(s)
Amina Oxidasa (conteniendo Cobre)/metabolismo , Córnea/enzimología , Neovascularización de la Córnea/metabolismo , Inhibidores de la Angiogénesis/uso terapéutico , Animales , Antiinflamatorios/uso terapéutico , Anticuerpos Monoclonales Humanizados/uso terapéutico , Bevacizumab , Neovascularización de la Córnea/sangre , Neovascularización de la Córnea/tratamiento farmacológico , Neovascularización de la Córnea/etiología , Modelos Animales de Enfermedad , Interacciones Farmacológicas , Hidrazinas/sangre , Hidrazinas/uso terapéutico , Masculino , Conejos , Técnicas de Sutura/efectos adversos , Factores de TiempoRESUMEN
Deprescribing is a planned, systematic process supervised by a healthcare professional. It is considered to be a fundamental part of good prescribing. Deprescribing can be defined as the complete withdrawal of medications as well as dose reduction. The patient's health status, life expectancy, values, preferences and the therapeutic goals should be given serious consideration while planning the deprescribing process. The main objective of deprescribing may vary but reaching the patients' goals and improving their quality of life remain constant priorities. In our article, based on the international literature, we review potential deprescribing targets such as the characteristics of high-risk patients, medications that should prompt a therapy review and the ideal settings for deprescribing. We also cover the steps, risks and benefits of the process, and discuss the existing specific guidelines and algorithms. We provide information on the enablers and barriers of deprescribing among both patients and healthcare professionals, and discuss international initiatives as well as the future of deprescribing. Orv Hetil. 2023; 164(24): 931-941.
Asunto(s)
Deprescripciones , Humanos , Calidad de Vida , Polifarmacia , Personal de SaludRESUMEN
Oxidative stress and sterile inflammation play roles in the induction and maintenance of metabolic syndrome (MetS). This study cohort included 170 females aged 40 to 45 years who were categorized according to the presentation of MetS components (e.g., central obesity, insulin resistance, atherogenic dyslipidemia, and elevated systolic blood pressure) as controls not presenting a single component (n = 43), those with pre-MetS displaying one to two components (n = 70), and females manifesting MetS, e.g., ≥3 components (n = 53). We analyzed the trends of seventeen oxidative and nine inflammatory status markers across three clinical categories. A multivariate regression of selected oxidative status and inflammatory markers on the components of MetS was performed. Markers of oxidative damage (malondialdehyde and advanced-glycation-end-products-associated fluorescence of plasma) were similar across the groups. Healthy controls displayed lower uricemia and higher bilirubinemia than females with MetS; and lower leukocyte counts, concentrations of C-reactive protein, interleukine-6, and higher levels of carotenoids/lipids and soluble receptors for advanced glycation end-products than those with pre-MetS and MetS. In multivariate regression models, levels of C-reactive protein, uric acid, and interleukine-6 were consistently associated with MetS components, although the impacts of single markers differed. Our data suggest that a proinflammatory imbalance precedes the manifestation of MetS, while an imbalance of oxidative status accompanies overt MetS. Further studies are needed to elucidate whether determining markers beyond traditional ones could help improve the prognosis of subjects at an early stage of MetS.