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Biogenic amines dopamine (DA) and serotonin (5-HT) are among the most significant monoaminergic neurotransmitters in the central nervous system (CNS). Separately, the physiological roles of DA and 5-HT have been studied in detail, and progress has been made in understanding their roles in normal and various pathological conditions (Parkinson's disease, schizophrenia, addiction, depression, etc.). In this article we showed that knockout of the gene encoding DAT leads not only to a profound dysregulation of dopamine neurotransmission in the striatum but also in the midbrain, prefrontal cortex, hippocampus, medulla oblongata and spinal cord. Furthermore, significant changes were observed in the production of mRNA of enzymes of monoamine metabolism, as well as to a notable alteration in the tissue level of serotonin, most clearly manifested in the cerebellum and the spinal cord. The observed region-specific changes in the tissue levels of serotonin and in the expression of dopamine and serotonergic metabolism enzymes in rats with an excess of dopamine can indicate important consequences for the pharmacotherapy of drugs that modulate the dopaminergic system. The drugs that affect the dopaminergic system could potently affect the serotonergic system, and this fact is important to consider when predicting their possible therapeutic or side effects.
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A commercial strain of Hafnia alvei (H. alvei) 4597 bacteria was shown to reduce food intake and promote weight loss, effects possibly induced by the bacterial protein ClpB, an antigen-mimetic of the anorexigenic α-melanocyte-stimulating hormone. A decrease in the basal plasma glucose levels was also observed in overweight fasted humans and mice receiving H. alvei. However, it is not known whether H. alvei influences sweet taste preference and whether its protein extract or ClpB are sufficient to increase glucose tolerance; these are the objectives tested in the present study. C57BL/6J male mice were kept under standard diet and were gavaged daily for 17 days with a suspension of H. alvei (4.5 × 107 CFU/animal) or with H. alvei total protein extract (5 µg/animal) or saline as a control. Sweet taste preference was analyzed via a brief-access licking test with sucrose solution. Glucose tolerance tests (GTT) were performed after the intraperitoneal (IP) or intragastric (IG) glucose administration at the 9th and 15th days of gavage, respectively. The expression of regulatory peptides' mRNA levels was assayed in the hypothalamus. In another experiment performed in non-treated C57BL/6J male mice, effects of acute IP administration of recombinant ClpB protein on glucose tolerance were studied by both IP- and IG-GTT. Mice treated with the H. alvei protein extract showed an improved glucose tolerance in IP-GTT but not in IG-GTT. Both groups treated with H. alvei bacteria or protein extract showed a reduction of pancreatic tissue weight but without significant changes to basal plasma insulin. No significant effects of H. alvei bacteria or its total protein extract administration were observed on the sweet taste preference, insulin tolerance and expression of regulatory peptides' mRNA in the hypothalamus. Acute administration of ClpB in non-treated mice increased glucose tolerance during the IP-GTT but not the IG-GTT, and reduced basal plasma glucose levels. We conclude that both the H. alvei protein extract introduced orally and the ClpB protein administered via IP improve glucose tolerance probably by acting at the glucose postabsorptive level. Moreover, H. alvei probiotic does not seem to influence the sweet taste preference. These results justify future testing of both the H. alvei protein extract and ClpB protein in animal models of diabetes.
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Hafnia alvei , Insulinas , Humanos , Ratones , Masculino , Animales , Hafnia alvei/metabolismo , Glucemia/metabolismo , Proteínas Bacterianas/metabolismo , Ratones Endogámicos C57BL , Glucosa/metabolismo , Insulinas/metabolismoRESUMEN
Calpain and calpastatin are the key components of the calcium-dependent proteolytic system. Calpains are regulatory, calcium-dependent, cytoplasmic proteinases, and calpastatin is the endogenous inhibitor of calpains. Due to the correlation between changes in the activity of the calpain-calpastatin system in the brain and central nervous system (CNS) pathology states, this proteolytic system is a prime focus of research on CNS pathological processes, generally characterized by calpain activity upregulation. The present review aims to generalize existing data on cerebral calpain distribution and function through mammalian ontogenesis. Special attention is given to the most recent studies on the topic as more information on calpain-calpastatin system involvement in normal CNS development and functioning has become available. We also discuss data on calpain and calpastatin activity and production in different brain regions during ontogenesis as comparative analysis of these results in association with ontogeny processes can reveal brain regions and developmental stages with pronounced function of the calpain system.
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Calcio , Calpaína , Animales , Calpaína/metabolismo , Calcio/metabolismo , Proteínas de Unión al Calcio/metabolismo , Encéfalo/metabolismo , Péptido Hidrolasas , Mamíferos/metabolismoRESUMEN
RATIONALE: Glibenclamide (GD) is a widely used medical drug; therefore, identifying the mechanisms underlying its pleiotropic effects in the central nervous system is urgent. OBJECTIVES: The aim of this work was to determine the ability of GD to modulate serotonin (5-hydroxytryptamine, 5-HT) and dopamine (DA) transmission and to assess the dose-dependent effect of GD on cognitive function in rats during natural ageing. METHODS: In Experiment 1, rats received 10, 25, or 50 µg/kg GD intraperitoneally for 10 days. In Experiment 2, rats received 50 µg/kg GD intraperitoneally for 30 days. Spatial and working memory was assessed in the MWM and Y-maze tests, respectively. In both experiments, the levels of DA and 5-HT, their metabolites, and turnover rate were analysed by HPLC-ED in the rat hippocampus and striatum. RESULTS: Changes in DA and 5-HT levels occurred only with a dose of 50 µg/kg GD. Therefore, in the second experiment, we administered a dose of 50 µg/kg GD. At this dose, GD prevented the development of impairments in spatial and working memory. The hippocampal concentrations of DA and DOPAC decreased, and the striatal concentrations of DA, DOPAC, 5-HT, and 5-HIAA increased. CONCLUSION: One of the possible mechanisms of the precognitive effect of GD is its ability to modulate monoamine transmission. Thus, in translating our results to humans, GD can be recommended as a prophylactic agent for natural ageing to reduce the risk of developing cognitive impairments.
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Disfunción Cognitiva , Serotonina , Ácido 3,4-Dihidroxifenilacético/metabolismo , Animales , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/metabolismo , Disfunción Cognitiva/prevención & control , Cuerpo Estriado , Dopamina/metabolismo , Gliburida/metabolismo , Gliburida/farmacología , Hipocampo , Humanos , Ácido Hidroxiindolacético/metabolismo , Ratas , Serotonina/metabolismoRESUMEN
Background: Essential tremor (ET) and Parkinson's disease (PD) are the two most common movement disorders in adults with similar clinical symptoms, which is hinting towards existence of coincident pathogenesis steps.Objectives: The objective of this report is to characterize the relationship between ET and PD severity and the activity of calcium-dependent proteases calpain in plasma.Methods: The study enrolled 12 volunteers for each condition: ET, PD, healthy. We evaluated the stage of PD on the H&Y scale in patients with PD, and the severity of tremor in patients with ET on the FTMS scale. IL-1ß, TNFα, IL6, IL10 were determined in plasma using ELISA. Calpain activity was measured using fluorescent substrate and zymography methods.Results: We demonstrated that the activity of calpains in plasma of patients with PD and ET increased 5.1 and 4.3 times, respectively. The increase of calpain activity in plasma of PD patients correlated with the content of IL-1ß, for ET such a connection was not found. At the advanced stages of PD calpain activity in plasma was significantly higher than that of the PD group at the early stage, and this increase was mediated by the increase in m-calpain activity. The increase in the tremor severity in ET did not lead to an increase in the activity of calpains in plasma.Conclusions: We observed general increase in the activity of calpains in plasma of both PD and ET patients that hints towards presence of the common steps in the pathogenesis of these diseases.
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Calpaína/sangre , Temblor Esencial/sangre , Temblor Esencial/diagnóstico , Enfermedad de Parkinson/sangre , Enfermedad de Parkinson/diagnóstico , Anciano , Biomarcadores/sangre , Activación Enzimática/fisiología , Temblor Esencial/enzimología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Parkinson/enzimología , Proyectos PilotoRESUMEN
Posttraumatic stress disorder (PTSD) causes mental and somatic diseases. Intermittent hypoxic conditioning (IHC) has cardio-, vaso-, and neuroprotective effects and alleviates experimental PTSD. IHC's ability to alleviate harmful PTSD effects on rat heart, liver, and brain was examined. PTSD was induced by 10-day exposure to cat urine scent (PTSD rats). Some rats were then adapted to 14-day IHC (PTSD+IHC rats), while PTSD and untreated control rats were cage rested. PTSD rats had a higher anxiety index (AI, X-maze test), than control or PTSD+IHC rats. This higher AI was associated with reduced glycogen content and histological signs of metabolic and hypoxic damage and of impaired contractility. The livers of PTSD rats had reduced glycogen content. Liver and blood alanine and aspartate aminotransferase activities of PTSD rats were significantly increased. PTSD rats had increased norepinephrine concentration and decreased monoamine oxidase A activity in cerebral cortex. The PTSD-induced elevation of carbonylated proteins and lipid peroxidation products in these organs reflects oxidative stress, a known cause of organ pathology. IHC alleviated PTSD-induced metabolic and structural injury and reduced oxidative stress. Therefore, IHC is a promising preventive treatment for PTSD-related morphological and functional damage to organs, due, in part, to IHC's reduction of oxidative stress.