Sildenafil alters biogenic amines and increases oxidative damage in brain regions of insulin-hypoglycemic rats

The aim of the present study was to determine the effect of sildenafil on dopamine, 5-hydroxyindol acetic acid (5-HIAA) and selected biomarkers of oxidative stress in the brain of hypoglycemic rats. The animals were treated intraperitoneally as follows: group 1 (control), saline solution; group 2, insulin (10 U per rat or 50 U kg–1); group 3, insulin + single dose of sildenafil (50 U kg–1 + 50 mg kg–1); group 4, insulin + three doses of sildenafil every 24 hours (50 U kg–1 + 50 mg kg–1). In groups 2, 3 and 4, insulin was administered every 24 hours for 10 days. Blood glucose was measured after the last treatment. On the last day of the treatment, the animals´ brains were extracted to measure the levels of oxidative stress markers [H2O2, Ca2+,Mg2+-ATPase, glutathione and lipid peroxidation (TBARS)], dopamine and 5-HIAA in the cortex, striatum and cerebellum/medulla oblongata by validated methods. The results suggest that administration of insulin in combination with sildenafil induces hypoglycemia and hypotension, enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines. Administration of insulin and sildenafil promotes biometabolic responses in glucose control, namely, it induces hypoglycemia and hypotension. It also enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines

β-Cyclodextrin and oleic acid increase levels of dopamine and potentiates oxidative damage in young and adult rat brain

Abstract Background Cyclodextrins are active pharmaceutical ingredients to treat neurological diseases by reducing neurotoxicity. The aim of this study was to test if combined consumption of β-cyclodextrin (BCD) and Oleic acid (OA) potentiates brain antioxidant protection. Methods Four groups of young Wistar rats, grouped in 6 animals each, were treated as follows: Group (G) 1, saline solution 0.9% (control); G2, BCD (0.7 g/kg); G3, OA (15 ml/kg); G4, BCD + OA. The same design was assayed for groups of adult rats. Treatments were daily administered by oral means for five consecutive days. On the last day of administration, brains of the animals were extracted to measure dopamine, 5-HIAA, glutathione (GSH), ATPase, Lipoperoxidation and H2O2. Results Oleic acid and β-cyclodextrin upgraded the levels of dopamine, 5-HIAA and lipid peroxidation and downgraded the concentrations of GSH and H2O2 in cortex, hemispheres (striatum) and cerebellum/medulla oblongata regions. Conclusions The results of the present study suggest that combined use of oleic acid and β-cyclodextrin may increase oxidative damage in brain regions and promote alteration in dopamine and 5-HIAA amines and hence, constitutes health risks among age of subjects

Efecto de la desnutrición pre y posnatal y la exposición posnatal a vapores de tolueno sobre el desempeño en campo abierto en ratas

El objetivo, del presente estudio fue investigar los efectos de la desnutrición prenatal y posnatal, y la exposición posnatal a vapores de tolueno, sobre la actividad conductual en campo abierto en ratas wistar. Material y métodos: se desnutrieron ratas hembras vírgenes, con el 50% del alimento que consumían las ratas nutridas. Esta dieta se inició desde tres semanas antes de la cruza y se mantuvo durante la gestación, lactancia y hasta los 60 días de vida posnatal de los críos. La inhalación de tolueno en los críos se llevó a cabo de los 40 a los 60 días de edad. La dosis de tolueno fue de 0.4 ml y el cual se colocó en una cámara de cristal con capacidad de 3.7 l durante 15 minutos por día. Se formaron 6 grupos con 10-14 animales, tres grupos bien nutridos, el mantenido en condiciones de laboratorio (N), expuesto a vapores de tolueno (NT) y control de manejo (NM), y tres grupos desnutridos, el mantenidos en condiciones de laboratorio (D), expuesto a vapores de tolueno (DT) y control de manejo (DM). Los animales de cada uno de los grupos se sometieron a una prueba de desempeño en campo abierto en la que se filmó su desplazamiento en una caja de madera de 100 x 100 x 45 cm durante 5 minutos. Se calculó la distancia total recorrida por medio de un monitor. El peso y recorrido fueron analizados con Bonferroni, bolos fecales U de Mann-Witney y acicalamiento con ANOVA. Resultados: la desnutrición y la exposición mostraron acción aditiva reduciendo significativamente el peso corporal de las ratas. Las ratas de los grupos nutridos y desnutridos, que se introdujeron en la cámara de inhalación pero sin el solvente (NM y DM), desplegaron mayor actividad en el campo abierto en tanto que los grupos sometidos al solvente mostraron menor actividad. Discusión: la desnutrición y el manejo por separado indujeron mayor actividad motora comparada con el grupo control sano; la exposición al solvente redujo la actividad

Sildenafil alters biogenic amines and increases oxidative damage in brain regions of insulin-hypoglycemic rats

The aim of the present study was to determine the effect of sildenafil on dopamine, 5-hydroxyindol acetic acid (5-HIAA) and selected biomarkers of oxidative stress in the brain of hypoglycemic rats. The animals were treated intraperitoneally as follows: group 1 (control), saline solution; group 2, insulin (10 U per rat or 50 U kg−1); group 3, insulin + single dose of sildenafil (50 U kg−1 + 50 mg kg–1); group 4, insulin + three doses of sildenafil every 24 hours (50 U kg−1 + 50 mg kg−1). In groups 2, 3 and 4, insulin was administered every 24 hours for 10 days. Blood glucose was measured after the last treatment. On the last day of the treatment, the animals´ brains were extracted to measure the levels of oxidative stress markers [H2O2, Ca2+,Mg2+-ATPase, glutathione and lipid peroxidation (TBARS)], dopamine and 5-HIAA in the cortex, striatum and cerebellum/medulla oblongata by validated methods. The results suggest that administration of insulin in combination with sildenafil induces hypoglycemia and hypotension, enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines. Administration of insulin and sildenafil promotes biometabolic responses in glucose control, namely, it induces hypoglycemia and hypotension. It also enhances oxidative damage and provokes changes in the brain metabolism of biogenic amines

Riboflavin and pyridoxine restore dopamine levels and reduce oxidative stress in brain of rats

Abstract Background Neurological disorders suggest that the excitotoxicity involves a drastic increase in intracellular Ca2+ concentrations and the formation of reactive oxygen species. The presence of these free radicals may also affect the dopaminergic system. The aim of this work was to determine if riboflavin (B2) and pyridoxine (B6) provide protection to the brain against free radicals generated by 3-nitropropionic acid (3-NPA) by measuring the levels of dopamine (DA) and selected oxidative stress markers. Methods Male Fisher rats were grouped (n = 6) and treated as follows: group 1, control (NaCl 0.9%); group 2, 3-NPA (20 mg/kg); group 3, B2 (10 mg/kg); group 4, B2 (10 mg/kg) + 3-NPA (20 mg/kg); group 5, B6 (10 mg/kg) and group 6, B6 + 3-NPA. All treatments were administered every 24 h for 5 days by intraperitoneal route. After sacrifice, the brain was obtained to measure DA, GSH, and lipid peroxidation, Ca2+, Mg2+, ATPase and H2O2. Main findings Levels of dopamine increased in cortex, striatum and cerebellum/medulla oblongata of animals that received 3-NPA alone. The lipid peroxidation increased in cortex, striatum, and cerebellum/medulla oblongata, of animals treated with B2 vitamin alone. ATPase dependent on Ca+2, Mg+2 and H2O2 increased in all regions of animals that received 3-NPA alone. Conclusion The results confirm the capacity of 3-NPA to generate oxidative stress. Besides, the study suggests that B2 or B6 vitamins restored the levels of DA and reduced oxidative stress in brain of rats. We believe that these results would help in the study of neurodegenerative diseases

Effect of cerebrolysin on dopaminergic neurodegeneration of rat with oxidative stress induced by 3-nitropropionic acid

The study tested the hypothesis that cerebrolysin protects the brain from free radicals in rats treated with 3-nitropropionic acid (3-NPA). To address this hypothesis, the levels of dopamine (DA) and some oxidative stress biomarkers were measured after administration of 3-NPA. Young male Fischer rats were treated for three days with cerebrolysin, 3-NPA or both substances. Their brains were extracted, and DA, lipid peroxidation (LP), glutathione (GSH), calcium, and H2O2 were measured using validated methods. In the cortex, hemispheres and cerebellum/medulla oblongata of the group treated with cerebrolysin and 3-NPA, the levels of DA and LP decreased. In addition, calcium and H2O2 levels decreased in the hemispheres of the same group, while GSH increased in cortex. The increased dopamine metabolism due to the administration of cerebrolysin led to increased formation of radical species and oxidative stress, especially when free radicals were generated by 3-NPA

Effect of cerebrolysin on dopaminergic neurodegeneration of rat with oxidative stress induced by 3-nitropropionic acid

The study tested the hypothesis that cerebrolysin protects the brain from free radicals in rats treated with 3-nitropropionic acid (3-NPA). To address this hypothesis, the levels of dopamine (DA) and some oxidative stress biomarkers were measured after administration of 3-NPA. Young male Fischer rats were treated for three days with cerebrolysin, 3-NPA or both substances. Their brains were extracted, and DA, lipid peroxidation (LP), glutathione (GSH), calcium, and H2O2 were measured using validated methods. In the cortex, hemispheres and cerebellum/medulla oblongata of the group treated with cerebrolysin and 3-NPA, the levels of DA and LP decreased. In addition, calcium and H2O2 levels decreased in the hemispheres of the same group, while GSH increased in cortex. The increased dopamine metabolism due to the administration of cerebrolysin led to increased formation of radical species and oxidative stress, especially when free radicals were generated by 3-NPA

Neuropsychological Alterations in Patients with Congenital Hypothyroidism Treated with Levothyroxine: Linked Factors and Thyroid Hormone Hyposensitivity

Eighty-five percent of the studies of patients with congenital hypothyroidism (CH) treated with Levothyroxine (L-T4) report neuropsychological sequelae throughout life. In neonates and infants, there is a deficit in sensorimotor skills (impaired balance). In preschool and elementary school children and adolescents, there are alterations in intellectual quotient (low scores), language (delayed phonological acquisition), memory (visual, verbal, visuospatial, visuoconstructive, autobiographical, and semantic), sensorimotor skills (impaired fine and gross motor control), and visuoconstructive–visuospatial domain (low scores in spatial location, block design, and object assembly). These neuropsychological domains are also affected in young adults, except for language (adequate verbal fluency) and visuoconstructive–visuospatial domain (no data). The onset and severity of neuropsychological sequelae in patients with treated CH depend on several factors: extrinsic, related to L-T4 treatment and social aspects, and intrinsic, such as severity and etiology of CH, as well as structural and physiological changes in the brain. In this review, we hypothesized that thyroid hormone hyposensitivity (THH) could also contribute to neuropsychological alterations by reducing the effectiveness of L-T4 treatment in the brain. Thus, further research could approach the THH hypothesis at basic and clinical levels to implement new endocrinological and neuropsychological therapies for CH patients

Pharmacological Approaches for the Modulation of the Potassium Channel KV4.x and KChIPs

Ion channels are macromolecular complexes present in the plasma membrane and intracellular organelles of cells. Dysfunction of ion channels results in a group of disorders named channelopathies, which represent an extraordinary challenge for study and treatment. In this review, we will focus on voltage-gated potassium channels (KV), specifically on the KV4-family. The activation of these channels generates outward currents operating at subthreshold membrane potentials as recorded from myocardial cells (ITO, transient outward current) and from the somata of hippocampal neurons (ISA). In the heart, KV4 dysfunctions are related to Brugada syndrome, atrial fibrillation, hypertrophy, and heart failure. In hippocampus, KV4.x channelopathies are linked to schizophrenia, epilepsy, and Alzheimer’s disease. KV4.x channels need to assemble with other accessory subunits (β) to fully reproduce the ITO and ISA currents. β Subunits affect channel gating and/or the traffic to the plasma membrane, and their dysfunctions may influence channel pharmacology. Among KV4 regulatory subunits, this review aims to analyze the KV4/KChIPs interaction and the effect of small molecule KChIP ligands in the A-type currents generated by the modulation of the KV4/KChIP channel complex. Knowledge gained from structural and functional studies using activators or inhibitors of the potassium current mediated by KV4/KChIPs will better help understand the underlying mechanism involving KV4-mediated-channelopathies, establishing the foundations for drug discovery, and hence their treatments.Ministerio de Ciencia e Innovacion (MICIU) Spain SAF201675021-R PID2019-104366RB-C21 RTI2018-097189-B-C22 PID2019-104366RBC22Instituto de Salud Carlos III CIBERCV program CB/11/00222Consejo Superior de Investigaciones Cientificas (CSIC) PIE 201820E104 2019AEP148 201880E109European Fund for Economic and Regional Development (FEDER)Spanish Ministry of Economy, Industry, and Competitivity (MINECO)Consejo Superior de Investigaciones Cientificas (CSIC) BES-2017-080184 FPU2017/02731Department of Atomic Energy (DAE)CUNY Research Scholars ProgramCollegiate Science Technology Entry Program (CSTEP)Hostos Office of Academic AffairsCSIC Open Access Publication Support Initiative through its Unit of Information Resources for Research (URICI