RESUMEN
AIM: There is a need for effective treatments for non-alcoholic fatty liver disease (NAFLD) that are economically inexpensive, and have few side effects. The present study aimed to investigate exercise training and silymarin on hepatocyte death factors in rats with liver damage. METHODS: Forty-nine male Wistar rats were assigned to seven groups: sedentary control, fatty liver control (DEX), fatty liver + high-intensity interval training (HIIT), fatty liver + HIIT + silymarin (HIIT + SILY), fatty liver + continuous training (CT), fatty liver + CT + silymarin (CT + SILY), and fatty liver + silymarin (SILY). A subcutaneous injection of dexamethasone for 7 days was used to induce fatty liver in rats. Masson's trichrome and hematoxylin-eosin staining were done to evaluate hepatic injury. The hepatocyte apoptosis was determined by TUNEL assay. Real-Time PCR was conducted to evaluate the gene expressions of caspase-9, adenosine monophosphate-activated protein kinase (AMPKα1), mitofusin 2 (Mfn2), and damage-regulated autophagy modulator (DRAM). Liver tissue changes and serum levels of liver enzymes were also evaluated. RESULTS: Liver apoptosis was decreased in the CT, HIIT, HIIT + SILY and CT + SILY groups compared to the DEX group. Both continuous and high-intensity training models produced beneficial alterations in liver morphology and hepatic injuries that were significant in exercise training + silymarin group. This impact was accompanied by increased AMPKα1 and DRAM gene expression and decreased caspase-9 and Mfn2 gene expression. Liver enzyme levels were high in the DEX group and treatment with silymarin significantly reduced it. CONCLUSION: Silymarin supplementation combined with interval or continuous training substantially improves DEX-induced hepatic steatosis and hepatocyte injury mostly through suppressing liver apoptosis and upregulating autophagy, which may provide a novel perspective for NAFLD treatment.
Asunto(s)
Apoptosis , Autofagia , Dexametasona , Hígado , Enfermedad del Hígado Graso no Alcohólico , Condicionamiento Físico Animal , Ratas Wistar , Silimarina , Animales , Silimarina/farmacología , Autofagia/efectos de los fármacos , Dexametasona/farmacología , Apoptosis/efectos de los fármacos , Masculino , Ratas , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/terapia , Enfermedad del Hígado Graso no Alcohólico/tratamiento farmacológico , Enfermedad del Hígado Graso no Alcohólico/inducido químicamente , Enfermedad del Hígado Graso no Alcohólico/patología , Hígado/efectos de los fármacos , Hígado/metabolismo , Hígado/patología , Hepatocitos/metabolismo , Hepatocitos/efectos de los fármacos , Proteínas Quinasas Activadas por AMP/metabolismo , Modelos Animales de Enfermedad , Caspasa 9/metabolismo , Caspasa 9/genética , GTP Fosfohidrolasas/metabolismo , GTP Fosfohidrolasas/genética , Proteínas MitocondrialesRESUMEN
AIM: Molecular alterations of diabetic gastroenteropathy are poorly identified. This study investigates the effects of prolonged GABA supplementation on key protein expression levels of trypsin-1, PAR-1, PAR-2, PAR-3, PI3K, Akt, COX-2, GABAA, and GABAB receptors in the gastric tissue of type 2 diabetic rats (T2DM). METHOD: -To induce T2DM, a 3-month high-fat diet and 35 mg/kg of streptozotocin was used. Twenty-four male Wistar rats were divided into 4 groups: (1) control, (2) T2DM, (3) insulin-treated (2.5 U/kg), and (4) GABA-treated (1.5 g/kg GABA). Blood glucose was measured weekly. The protein expressions were assessed using western blotting. Histopathological changes were examined by H&E and Masson's staining. RESULTS: -Diabetic rats show reduced NOS1 and elevated COX-2 and trypsin-1 protein expression levels in gastric tissue. Insulin and GABA therapy restored the NOS1 and COX-2 levels to control values. Insulin treatment increased PI3K, Akt, and p-Akt and, decreased trypsin-1, PAR-1, PAR-2, and PAR-3 levels in the diabetic rats. Levels of GABAA and GABAB receptors normalized following insulin and GABA therapy. H&E staining indicated an increase in mucin secretion following GABA treatment. CONCLUSION: -These results suggest that GABA by acting on GABA receptors may regulate the trypsin-1/PARs/Akt/COX-2 pathway and thereby improve complications of diabetic gastroenteropathy.
RESUMEN
Precise control of norepinephrine (NE) levels and NE-receptor interaction is crucial for proper function of the brain. Much evidence for this view comes from experimental studies that indicate an important role for NE in the pathophysiology and treatment of various conditions, including cognitive dysfunction, Alzheimer's disease, Parkinson's disease, multiple sclerosis, and sleep disorders. NE provides neuroprotection against several types of insults in multiple ways. It abrogates oxidative stress, attenuates neuroinflammatory responses in neurons and glial cells, reduces neuronal and glial cell activity, promotes autophagy, and ameliorates apoptotic responses to a variety of insults. It is beneficial for the treatment of neurodegenerative diseases because it improves the generation of neurotrophic factors, promotes neuronal survival, and plays an important role in the regulation of adult neurogenesis. This review aims to present the evidence supporting a principal role for NE in neuroprotection, and molecular mechanisms of neuroprotection.
RESUMEN
In this study, we evaluated the hepatoprotective effects of astaxanthin, a natural carotenoid, against the cholestatic liver fibrosis induced by bile duct ligation (BDL). Toward this end, male rats were subjected to BDL and treated with astaxanthin for 35 days. Afterwards, their serum and liver biochemical factors were assessed. Also, histopathological and immunohistochemical analyses were performed to determine the fibrosis and the expression levels of alpha-smooth muscle actin (α-SMA) and transforming growth factor beta (TGF-ß1) in the liver tissue. Based on the results, BDL caused a significant increase in liver enzyme levels, blood lipids, and bilirubin, while decreasing the activity of superoxide dismutase(SOD), catalase (CAT), and glutathione (GSH) enzymes. Also, in the BDL rats, hepatocyte necrosis, infiltration of inflammatory lymphocytes, and hyperplasia of bile ducts were detected, along with a significant increase in α-SMA and TGF-ß1 expression. Astaxanthin, however, significantly prevented the BDL's detrimental effects. In all, 10 mg/kg of this drug maintained the bilirubin and cholesterol serum levels of BDL rats at normal levels. It also reduced the liver enzymes' activity and serum lipids, while increasing the SOD, CAT, and GSH activity in BDL rats. The expression of α-SMA and TGF-ß1 in the BDL rats treated with 10 mg/kg of astaxanthin was moderate (in 34%-66% of cells) and no considerable cholestatic fibrosis was observed in this group. However, administrating the 20 mg/kg of astaxanthin was not effective in this regard. These findings showed that astaxanthin could considerably protect the liver from cholestatic damage by improving the biochemical features and regulating the expression of related proteins.
Asunto(s)
Conductos Biliares , Colestasis , Cirrosis Hepática , Ratas Wistar , Xantófilas , Animales , Xantófilas/farmacología , Xantófilas/uso terapéutico , Masculino , Ratas , Colestasis/patología , Colestasis/metabolismo , Colestasis/tratamiento farmacológico , Cirrosis Hepática/metabolismo , Cirrosis Hepática/patología , Cirrosis Hepática/tratamiento farmacológico , Cirrosis Hepática/prevención & control , Ligadura , Conductos Biliares/cirugía , Hígado/efectos de los fármacos , Hígado/patología , Hígado/metabolismo , Factor de Crecimiento Transformador beta1/metabolismoRESUMEN
CRH neurons are found in the paraventricular nucleus(PVN) and central amygdala(CeA) nuclei. This study investigated the effects of sub-chronic CRH administration into the PVN and CeA nuclei on food intake biomarkers in rats divided into five groups: control, two shams, and two CRH-PVN and CRH-CeA groups(receiving CRH in nuclei for seven days). The CRH-PVN group had significantly higher cumulative food intake and food intake trends than the CRH-CeA group. The CRH-CeA and CRH-PVN groups exhibited significant increases in food intake during hours 1 and 2, respectively. Moreover, to be time-dependent, food intake is modulated by different brain nuclei. The CRH signaling pathway appeared to be activated later in the PVN than CeA. Both groups exhibited significantly higher leptin levels, the CRH-PVN group exhibited higher ghrelin levels and lower glucose levels. Repetitive administration of CRH into the PVN and CeA significantly reduced body weight differences. CRH administration into the PVN affected both leptin and ghrelin levels, but ghrelin had a greater impact on glucose variations and cumulative food intake than leptin. Finally, CRH administration into the PVN and CeA likely activated the HPA axis, and the CeA had a greater impact on the stress circuit than on food intake behavior.
Asunto(s)
Núcleo Amigdalino Central , Hormona Liberadora de Corticotropina , Ratas , Masculino , Animales , Hormona Liberadora de Corticotropina/metabolismo , Hormona Liberadora de Corticotropina/farmacología , Núcleo Amigdalino Central/metabolismo , Leptina/metabolismo , Ghrelina , Sistema Hipotálamo-Hipofisario/metabolismo , Sistema Hipófiso-Suprarrenal/metabolismo , Ingestión de Alimentos/fisiología , GlucosaRESUMEN
Increasing evidence suggests that elevated intracellular levels of reactive oxygen species (ROS) play a significant role in the pathogenesis of many diseases. Increased intracellular levels of ROS can lead to the oxidation of lipids, DNA, and proteins, contributing to cellular damage. Hence, the maintenance of redox hemostasis is essential. Naringenin (NAR) is a flavonoid included in the flavanones subcategory. Various pharmacological actions have been ascribable to this phytochemical composition, including antioxidant, anti-inflammatory, antibacterial, antiviral, antitumor, antiadipogenic, neuro-, and cardio-protective activities. This review focused on the underlying mechanism responsible for the antioxidative stress properties of NAR and its' nanoformulations. Several lines of in vitro and in vivo investigations suggest the effects of NAR and its nanoformulation on their target cells via modulating signaling pathways. These nanoformulations include nanoemulsion, nanocarriers, solid lipid nanoparticles (SLN), and nanomicelle. This review also highlights several beneficial health effects of NAR nanoformulations on human diseases including brain disorders, cancer, rheumatoid arthritis, and small intestine injuries. Employing nanoformulation can improve the pharmacokinetic properties of NAR and consequently efficiency by reducing its limitations, such as low bioavailability. The protective effects of NAR and its' nanoformulations against oxidative stress may be linked to the modulation of Nrf2-heme oxygenase-1, NO/cGMP/potassium channel, COX-2, NF-κB, AMPK/SIRT3, PI3K/Akt/mTOR, BDNF, NOX, and LOX-1 pathways. Understanding the mechanism behind the protective effects of NAR can facilitate drug development for the treatment of oxidative stress-related disorders.
RESUMEN
Background: The goal of the current research was to further elucidate the role of adenosine triphosphate (ATP)-sensitive potassium (KATP) channels in the motility and contractility force of gastric smooth muscle of diabetic rats. Materials and Methods: Male Wistar rats (190-230 g) were grouped into control and streptozotocin (STZ)-induced diabetes (55 mg/kg) rats. Thirty days later, gastric muscle contractility was measured using a myograph and a force transducer of antral segments immersed in a tissue bath. Gastric emptying response was measured through feeding of standard pellet. Furthermore, the expression of KATP channel subunits in antral smooth muscle was determined by western blot technique. Results: The amplitude of KCl-evoked twitch contractions of diabetic antral strips was about 25% more than control (P < 0.05). Application of minoxidil, a KATP channel opener, dose dependently decreased the force of twitch contractions in both normal and diabetic antral strips. Application of 10 µM glibenclamide, a KATP channel blocker, did not antagonize the minoxidil-induced relaxation of antral strips. Diabetic gastric emptying was faster than normal, although not significant. Despite the relaxant effect of minoxidil on gastric emptying rate in normal rats (P < 0.05), this effect was not observed in diabetic rats. Also, glibenclamide increased gastric emptying and antagonized minoxidil-induced relaxation in normal rats (P < 0.05). Furthermore, the expression of KATP Kir6.1 and SUR2B subunits was substantially reduced in antral smooth muscle in diabetic condition (P < 0.01). Conclusion: These results propose that KATP channels may contribute to the development of gastric motility disorders in diabetes.
RESUMEN
OBJECTIVES: Exercise is assumed to attenuate age-related neuronal apoptosis, but the detailed mechanism(s) is not fully understood. α1-Adrenergic receptors (ARs) can either trigger or suppress apoptosis, therefore, here we determined the impact of treadmill exercise on the expression of the apoptosis regulatory proteins as well as α1-AR subtypes α1A- and α1B-ARs, in order to elucidate a possible association between apoptosis and the hippocampal expression of α1-ARs in aged male rats. METHODS: Twenty-one male Wistar rats were divided into 3 groups (n=7): young control, aged sedentary, and aged + exercise. Western blot for α1A- and α1B-ARs as well as pro-(Bax and p53) and anti-apoptotic (Bcl2) proteins was conducted. An 8-week regular moderate-intensity treadmill exercise intervention was carried out in exercise group. RESULTS: In aged rats, α1A-AR expression in the hippocampus was significantly increased, and exercise markedly prevented this event. While α1B-AR expression was no altered with aging, a marked reduction in α1B-AR level was detected in exercise group when compared to aged group. Furthermore, pro-apoptotic protein levels of Bax and p53 were upregulated and anti-apoptotic protein Bcl2 was downregulated in the aging hippocampus, but could be reversed by treadmill exercise. In the present research, exercise-induced reduction in α1A- and α1B-ARs was associated with an obvious downregulation of Bax/Bcl2 ratio in aged rats, suggesting that exercise may inhibit apoptosis through regulating α1-ARs, particularly α1A-AR. CONCLUSIONS: Our study suggests that manipulations attenuating α1-AR activity, including nonselective α1-adrenergic antagonists, may protect against hippocampal neurodegeneration in aging brains.
Asunto(s)
Apoptosis , Proteína p53 Supresora de Tumor , Ratas , Masculino , Animales , Proteína p53 Supresora de Tumor/metabolismo , Proteína X Asociada a bcl-2/metabolismo , Ratas Wistar , Hipocampo/metabolismo , Receptores Adrenérgicos/metabolismo , Receptores Adrenérgicos alfa 1/metabolismoRESUMEN
Purpose: Gastric inflammation is common and usually severe in patients with type 2 diabetes mellitus (T2DM). Evidence suggests protease-activated receptors (PARs) are a link between inflammation and gastrointestinal dysfunction. Given that magnesium (Mg2+) deficiency is a highly prevalent condition in T2DM patients, we assessed the therapeutic role of Mg2+ on the factors involved in gastric inflammation in T2DM. Methods: A rat model of T2DM gastropathy was established using a long-term high-fat diet + a low dose of streptozocin. Twenty-four rats were divided into control, T2DM , T2DM + insulin (positive control), and T2DM + Mg2+ groups. At the end of 2-month therapies, changes in the expression of gastric trypsin-1, PAR1, PAR2, PAR3, PI3K/Akt, and COX-2 proteins were measured by western blot. Hematoxylin and eosin and Masson's trichrome staining were used to detect gastric mucosal injury and fibrosis. Results: The expression of trypsin-1, PAR1, PAR2, PAR3, and COX-2 increased in diabetes, and Mg2+/insulin treatment strongly decreased their expression. The PI3K/p-Akt significantly decreased in T2DM, and treatment with Mg2+/insulin improved PI3K in T2DM rats. Staining of the gastric antrum tissue of the insulin/Mg2+-treated T2DM rats showed a significantly minimal mucosal and fibrotic injury compared with those of rats from the T2DM group. Conclusion: Mg2+ supplement, comparable to insulin, via decreasing PARs expression, mitigating COX-2 activity, and decreasing collagen deposition could exert a potent gastroprotective effect against inflammation, ulcer, and fibrotic development in T2DM patients.
RESUMEN
Gut barrier disintegrity and endotoxin translocation to the liver and systemic circulation are serious clinical complications associated with the stoppage of intestinal bile flow. There is no precise pharmacological option to prevent increased intestinal permeability after bile duct ligation (BDL). Lubiprostone, a chloride channel-2 agonist, has been shown to accelerate restoration of epithelial barrier dysfunction caused by injury, but the exact mechanisms underlying the beneficial effects of lubiprostone on intestine barrier integrity remain unknown. Here, we assessed the beneficial effect of lubiprostone on cholestasis caused by BDL and relevant mechanisms. Male rats were subjected to BDL for 21 days. Seven days after BDL induction, lubiprostone was administered twice daily (10 µg/kg of body weight). Intestinal permeability was assessed through measurements of serum lipopolysaccharide (LPS) concentration. Real-time PCR was conducted to assess expression of intestinal claudin-1 occludin and FXR genes, which are important in preserving the intestinal epithelial barrier integrity, as well as claudin-2 being involved in a leaky gut barrier. Histopathological alterations were also monitored for liver injury. Lubiprostone significantly decreased BDL-induced systemic LPS elevation in rats. BDL induced a significant reduction in FXR, occludin, and claudin-1 genes expression, while increased claudin-2 expression in rat colon. Treatment with lubiprostone significantly restored expression of these genes to the control values. BDL also increased the level of hepatic enzymes ALT, ALP, AST, and total bilirubin, while lubiprostone could preserve the hepatic enzymes and total bilirubin in the treated BDL rats. Lubiprostone also caused a significant reduction in BDL-induced liver fibrosis and intestinal damage in rats. Our results suggest that lubiprostone favorably prevents BDL-induced alterations in intestinal epithelial barrier integrity possibly via modulating intestinal FXRs and tight junction gene expression.
Asunto(s)
Colestasis , Claudina-2 , Ratas , Masculino , Animales , Ocludina , Lubiprostona/farmacología , Claudina-1 , Claudinas , Lipopolisacáridos , Hígado/metabolismo , Colestasis/tratamiento farmacológico , Colestasis/metabolismo , Conductos Biliares/cirugía , Bilirrubina , PermeabilidadRESUMEN
Hippocampal-dependent memory abilities including spatial memory decline with age. Exercise improves memory decline in aging brain, but, the precise mechanisms are still unknown. Learning and memory are recently hypothesized to be mediated by a ß-arrestin (ßArr)-dependent ß-adrenergic pathway. Hence, we examined the effect of 8 weeks of treadmill exercise on hippocampal expression of ß-adrenergic receptors (ß-ARs; members of the G protein-coupled receptor family), and ßArrs as well as spatial learning and memory in aged male rats to determine whether ß-AR/ßArr pathway could be involved in age-related memory decline. A total of 24 young (3-month-old) and aged (18-month-old) male Wistar rats were divided into young control, aged sedentary, and aged + exercise (n = 8 for each). Western blot for ß1- and ß2-ARs as well as ßArr1 and ßArr2 was performed. Spatial learning and memory were evaluated with the Morris water maze. The results showed significant up-regulation of ß1-ARs as well as significant down-regulation of ß2-AR and ßArrs (ßArr1 and ßArr2) in the hippocampus of aged rats. Spatial memory, but not spatial learning, was impaired in aging, and treadmill exercise improved it. Notably, the improvement in spatial memory was accompanied by amelioration of ß-ARs dysregulation and increase in ßArr2 levels after exercise. There was a negative association between the expression of ßArr2 and ß1-AR, but not ß2-AR, such that an increase in ßArr2 by exercise was associated with reduced ß1-AR expression, suggesting ßArr2 may contribute to posttranslational down-regulation of ß1-ARs. These data suggest that both G protein-dependent and ß-arrestin-dependent ß-AR pathways may regulate spatial learning and memory in aging brain.
Asunto(s)
Receptores Adrenérgicos beta , Memoria Espacial , Ratas , Masculino , Animales , Receptores Adrenérgicos beta/metabolismo , beta-Arrestinas/metabolismo , Ratas Wistar , Hipocampo/metabolismo , Trastornos de la Memoria , Proteínas de Unión al GTP/metabolismoRESUMEN
Anesthesia and analgesia are major components of many interventional studies on laboratory animals. However, various studies have shown improper reporting or use of anesthetics/analgesics in research proposals and published articles. In many cases, it seems "anesthesia" and "analgesia" are used interchangeably, while they are referring to two different concepts. Not only this is an unethical practice, but also it may be one of the reasons for the proven suboptimal quality of many animal researches. This is a widespread problem among investigations on various species of animals. However, it could be imagined that it may be more prevalent for the most common species of laboratory animals, such as the laboratory mice. In this review, proper anesthetic/analgesic methods for routine procedures on laboratory mice are discussed. We considered the available literature and critically reviewed their anesthetic/analgesic methods. Detailed dosing and pharmacological information for the relevant drugs are provided and some of the drugs' side effects are discussed. This paper provides the necessary data for an informed choice of anesthetic/analgesic methods in some routine procedures on laboratory mice.
RESUMEN
In this study, we aimed to investigate whether the anti-diabetic effects of γ-aminobutyric acid (GABA) and insulin can be mediated through the regulation of gene expression related to irisin production and mitochondrial biogenesis in type 2 diabetic mellitus (T2DM) rats. Four groups (n = 6) were used in this study: control, T2DM, T2DM + insulin, and T2DM + GABA groups. After T2DM induction for 3 months (high-fat diet + 35 mg/kg streptozotocin) and treatment with GABA or insulin for 3 months, circulating levels of FBG, triglyceride, LDL, Ox-LDL, and insulin as well as hepatic and serum irisin levels were measured. The mRNA expressions of fibronectin type III domain-containing protein 5 (FNDC5), mitochondrial transcription factor A (TFAM), and mitochondrial uncoupling protein 3 (UCP3) were also evaluated in the skeletal muscle of all groups. GABA therapy improved the FBG and insulin levels in diabetic rats. Insulin treatment significantly reduced FBG and failed to maintain glucose close to the control level. Insulin or GABA therapy significantly decreased the levels of LDL, Ox-LDL, and HOMA-IR index. Circulating irisin levels were markedly decreased in insulin-treated group, while irisin levels did not show significant changes in GABA-treated group compared with control group. GABA or insulin therapy increased mRNA expressions of TFAM and UCP3 in diabetic rats. GABA therapy also led to a significant increase in FNDC5 mRNA. Our findings suggest that the anti-diabetic effect of GABA may be mediated, in part, by a decrease in Ox-LDL levels and an increase in the levels of irisin as well as FNDC5, TFAM, and UCP3 gene expression in T2DM rats.
Asunto(s)
Diabetes Mellitus Experimental , Fibronectinas , Factores de Transcripción , Proteína Desacopladora 3 , Ácido gamma-Aminobutírico , Animales , Diabetes Mellitus Experimental/tratamiento farmacológico , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2 , Fibronectinas/sangre , Músculo Esquelético/metabolismo , ARN Mensajero/metabolismo , Ratas , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Proteína Desacopladora 3/genética , Proteína Desacopladora 3/metabolismo , Ácido gamma-Aminobutírico/farmacologíaRESUMEN
BACKGROUND: Hypomagnesemia has been associated with development of type 2 diabetes mellitus (T2DM) and its complications. Irisin has beneficial effects on glucose uptake and improves hepatic glucose and lipid metabolism. In this study, we aimed to evaluate the effects of long-term treatment of MgSO4 and insulin on insulin resistance, dyslipidemia, serum and hepatic irisin levels, skeletal muscle gene expression of fibronectin type III domain-containing protein 5 (FNDC5), mitochondrial transcription factor A (TFAM) and mitochondrial uncoupling protein 3 (UCP3) in T2DM rats. METHODS AND RESULTS: Twenty-four rats were divided into four groups: Control group, diabetic control (DC) using a high-fat diet + streptozotocin, insulin-treated diabetic group (DC + Ins), MgSO4-treated diabetic group (DC + Mg). At the end of therapies, serum concentrations of FBG, TG, insulin, Ox-LDL, along with serum and hepatic irisin levels were measured. FNDC5, TFAM, and UCP3 mRNA expressions were measured in the skeletal muscle by Real-time PCR. In comparison with DC group, MgSO4 therapy resulted in decreased FBG, TG, Ox-LDL, improved serum insulin and irisin levels, and increased mRNA expressions of FNDC5, UCP3 and TFAM. Insulin therapy significantly decreased FBG, Ox-LDL, FNDC5 and serum irisin levels compared with the control group. While, insulin therapy markedly increased TFAM and UCP3 compared with the DC group. CONCLUSIONS: In conclusion, MgSO4 can improve insulin resistance and hyperlipidemia partly through decreasing Ox-LDL, increasing serum irisin levels as well as increasing FNDC5, TFAM, and UCP3 mRNA expressions in T2DM rats. These findings can be considered in the management of diabetes treatment.
Asunto(s)
Diabetes Mellitus Experimental , Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Animales , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/genética , Fibronectinas/genética , Fibronectinas/metabolismo , Músculo Esquelético/metabolismo , ARN Mensajero/genética , ARN Mensajero/metabolismo , Ratas , Factores de Transcripción/genética , Factores de Transcripción/metabolismoRESUMEN
OBJECTIVES: Dopamine neurotransmission is implicated in multiple neuropsychiatric disorders, most strikingly in Parkinson's disease, bipolar disorder, attention-deficit hyperactivity disorder and schizophrenia. In addition to canonical pathway, D2-receptor (D2R) exerts some of its biological actions through regulating the activity of Akt and GSK3, which in turn were found to be altered in several psychiatric illnesses. The present study examined the impacts of maternal separation, an early-life stress model which has been associated with disturbed neurodevelopment and appearance of many psychiatric disorders, on developmental changes in dopamine concentration and the expression of D2Rs, Akt and GSK-3ß in the medial prefrontal cortex (PFC; a key target of stress) in adolescent and young adult male rats. METHODS: Maternal separation was performed 3 h per day from postnatal days 2 to 11. The PFC protein and dopamine contents were determined using western blotting analysis and Eliza, respectively. RESULTS: Results indicated long-term increases in the prefrontal dopamine levels in stressed adolescent and young adult male rats, accompanied by significant downregulation of D2R as well as upregulation of p-Akt and GSK-3ß contents in stressed adolescence compared to controls, with all protein levels that returned to control values in stressed adult rats. CONCLUSIONS: Our findings suggest that early-life stress differentially modulates prefrontal D2R/Akt/GSK-3ß levels during development. Since adolescence period is susceptible to the onset of specific mental illnesses, disruption of noncanonical components of D2R signaling during this critical period may have an important role in programming neurobehavioral phenotypes in adulthood and manipulations influencing Akt/GSK-3ß pathway may improve the expression of specific dopamine-related behaviors and the effects of dopaminergic drugs.
Asunto(s)
Dopamina , Corteza Prefrontal , Receptores de Dopamina D2 , Estrés Psicológico , Animales , Masculino , Ratas , Dopamina/metabolismo , Glucógeno Sintasa Quinasa 3/metabolismo , Glucógeno Sintasa Quinasa 3/farmacología , Glucógeno Sintasa Quinasa 3 beta/metabolismo , Glucógeno Sintasa Quinasa 3 beta/farmacología , Privación Materna , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-akt/genética , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-akt/farmacología , Receptores de Dopamina D2/metabolismo , Transducción de Señal/fisiologíaRESUMEN
The hippocampus has been implicated in modulating anxiety. It interacts with a variety of brain regions, both cortical and subcortical areas regulating emotion and stress responses, including prefrontal cortex, amygdala, hypothalamus, and the nucleus accumbens, to adjust anxiety levels in response to a variety of stressful conditions. Growing evidence indicates that anxiety is associated with increased neuronal excitability in the hippocampus, and alterations in local regulation of hippocampal excitability have been suggested to underlie behavioral disruptions characteristic of certain anxiety disorders. Furthermore, studies have shown that some anxiolytics can treat anxiety by altering the excitability and plasticity of hippocampal neurons. Hence, identifying cellular and molecular mechanisms and neural circuits that regulate hippocampal excitability in anxiety may be beneficial for developing targeted interventions for treatment of anxiety disorders particularly for the treatment-resistant cases. We first briefly review a role of the hippocampus in fear. We then review the evidence indicating a relationship between the hippocampal activity and fear/anxiety and discuss some possible mechanisms underlying stress-induced hippocampal excitability and anxiety-related behavior.
Asunto(s)
Hipocampo , Neuronas , Ansiedad , Trastornos de Ansiedad , Miedo/fisiología , Hipocampo/fisiología , Humanos , Neuronas/fisiologíaRESUMEN
OBJECTIVES: We investigated effect of the ventromedial hypothalamus (VMH) dopamine D2 receptor inhibition on food intake and plasma ghrelin following chronic free or scheduled meal with different caloric intakes. METHODS: Male Wistar rats (220-250 g) were fed diets containing free (control) or three scheduled diets of standard, restricted and high-fat for 1 month. The animals stereotaxically received an intra VMH single dose of sulpiride (0.005 µg)/or saline (0.5 µL) before meal time. Thirty minutes later, food intake and circulating ghrelin were measured. RESULTS: Sulpiride significantly reduced food intake and ghrelin concentration in freely fed and scheduled-standard diet (p<0.05), while increased food intake, with ghrelin level on fasted level in scheduled-restricted group (p<0.01) compared to control. Food intake and ghrelin concentration between scheduled-high fat and freely fed or scheduled-standard diets did not show significant changes. CONCLUSIONS: The VMH D2 receptors are possibly involved in controlling scheduled eating behavior, depending on energy balance context.
Asunto(s)
Antagonistas de los Receptores de Dopamina D2/farmacología , Ingestión de Alimentos , Ghrelina , Hipotálamo/efectos de los fármacos , Sulpirida/farmacología , Animales , Ghrelina/sangre , Masculino , Ratas , Ratas Wistar , Receptores de Dopamina D2RESUMEN
INTRODUCTION: Corticotropin-Releasing Hormone (CRH) is involved in stress and energy homeostasis. On the other hand, CRH receptors also exist within the paraventricular nucleus (PVN) and Central Amygdala (CeA) nuclei. The present study compared the effect of CRH microinjections into PVN and CeA on three consecutive hours and cumulative food intake, internal regulatory factors of food intake, such as serum leptin and ghrelin, as well as blood glucose levels in rats under different acute psychological (Social Stress [SS] and Isolation Stress [IS] group) stresses. METHODS: Sixty-six male Wistar rats were randomly allocated to 11 groups: Control, Sham, CRH-PVN, CRH-CeA, SS, IS, SS-CRH-PVN, SS-CRH-CeA, IS-CRH-PVN, and IS-CRH-CeA groups. The CRH (2 µg/kg in 0.5 µL saline) was injected into PVN and CeA nuclei in rats under everyday, acute social stress and isolation stress conditions. RESULTS: Acute isolation and social stresses did not affect cumulative food intake. Whereas isolation stress led to changes in both leptin and glucose levels, social stress reduced only glucose levels. Cumulative food intake significantly decreased under acute CRH injection into the CeA and particularly into the PVN. Blood glucose significantly reduced in all the groups receiving CRH into their CeA. CONCLUSION: The PVN played a more important role compared to CeA on food intake. These nuclei probably employ different mechanisms for their effects on food intake. Besides, it seems that exogenously CRH injection into the PVN probably had a more anorectic effect than naturally activated CRH by stresses. Acute isolation stress had a greater impact than social stress on leptin level and cumulative food intake. Thus, elevated food intake related to leptin compared to ghrelin and glucose levels in the CRH-PVN group under acute social stress.
RESUMEN
OBJECTIVES: Resveratrol as a natural polyphenolic agent can alleviate neuropathic pain symptoms. The mechanism of analgesic activity of resveratrol is far from clear. The current study examine whether analgesic activity of resveratrol is mediated by its neuroprotective and anti-oxidant activity in the neuropathic pain. We further examine whether analgesic activity of resveratrol is mediated by ß-adrenoceptors in the brain. METHODS: Neuropathic pain induced by L5 spinal nerve ligation (SNL). Male Wistar rats assigned into sham, SNL, SNL + resveratrol (40 µg/5 µL), and SNL + resveratrol + propranolol (a non-selective ß-adrenoceptor antagonist, 30 µg/5 µL) groups. Drugs injected intracerebroventricular (ICV) at day SNL surgery and daily for 6 days following SNL. Thermal allodynia and anxiety examined on days of -1, 2, 4, and 6 following SNL. Electrophysiological study performed on day 6 following SNL for evaluation of resveratrol effects on sciatic nerve conduction velocity (NCV). The activity of catalase (Cat) and superoxide dismutase (SOD) enzymes in the brain assessed on days 6 following SNL. RESULTS: Resveratrol significantly decreased thermal allodynia (and not anxiety) in all experimental days. Additionally, resveratrol significantly increased NCV, and also normalized the disrupted Cat and SOD activities following neuropathic pain. Furthermore, propranolol significantly blocked the analgesic and neuroprotective effects of resveratrol. CONCLUSIONS: It is suggested that the analgesic effects of resveratrol is mediated by its neuroprotective and antioxidant activities in the neuropathic rats. Furthermore, propranolol blocked the analgesic and neuroprotective effects of resveratrol.