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1.
Gen Physiol Biophys ; 38(6): 545-556, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31588916

RESUMO

Vascular dysfunctions in chronic kidney disease (CKD) include endothelial dysfunctions and vascular calcification (VC). In the present study, we examined the possible protective effect of nicorandil (potassium channel opener) on renal and vascular dysfunctions in a rat model of adenine-induced nephropathy and its underlying mechanisms. Thirty-four male Sprague-Dawley rats were randomly allocated into 3 groups: Control group, Adenine group (animals received high-adenine diet for 4 weeks), and Nicorandil group (animals received adenine for 4 weeks and nicorandil 1 mg/kg per oral for 4 weeks). The results showed significant reduction in the body weight, heart rate (HR), hemoglobin contents, serum Ca2+ and reduction in the expression of mRNA of endothelial nitric oxide synthase (eNOS) and nuclear factor erythroid related factor 2 (nrf2) genes in aortic tissues with significant increase in arterial blood pressure (ABP), serum creatinine, blood urea nitrogen (BUN), plasma renin activity (PRA), K+ and phosphate (PO43-), urinary albumin excretion (UAE) and aortic VC in Adenine group compared to normal group (p < 0.05). On the other hand, coadminsitration of nicorandil caused significant improvement in the studied parameters compared to Adenine group (p < 0.05). We concluded that nicorandil has a potential protective effect against the vascular and renal impairment induced by adenine, which might be due to attenuation of vascular calcifications, activation of Nrf2 and eNOS genes in aortic tissues.


Assuntos
Insuficiência Renal Crônica , Adenina , Animais , Rim , Masculino , Nicorandil , Ratos , Ratos Sprague-Dawley
2.
Acta Sci Pol Technol Aliment ; 18(3): 317-332, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31569913

RESUMO

BACKGROUND: The present work was designed to study the effects of methanolic stevia extracts and aerobic exercise and combination of both on renal I/R injury in male rats. METHODS: 60 adult male Sprague-Dawley rats were subdivided into five equal groups as sham, control, exercise, stevia, and stevia plus exercise group. After 5 weeks of exercise and stevia, animals were exposed to 45 min of left renal ischemia and right nephrectomy followed by reperfusion. Serum creatinine, creatinine clearance, fractional Na excretion (FENa+), malondialdehyde (MDA), reduced glutathione (GSH) and catalase (CAT) levels in kidney tissues were measured. Also, renal histopathology and the expression of caspase-3 by immunohistochemical examination were done. RESULTS: The results showed that stevia, exercise or combination of stevia and exercise caused a significant decrease in serum level of creatinine (p < 0.001) and FENa+ (p < 0.001) and an increase in creatinine clearance (p < 0.001). Moreover, this caused a significant decrease in (MDA; p < 0.046) and an increase in GSH (p < 0.01) and CAT (p < 0.01), as well as causing a significant decrease in caspase 3 expression compared to the control group. CONCLUSIONS: Pretreatment with either stevia or exercise of combination of both seem to have protective effects on renal I/R injury. However, the protective effect of exercise against renal I/R injury seems to be less than stevia. These effects might be due to attenuation of oxidative stress and apoptosis in kidney tissues.

3.
Artigo em Inglês | MEDLINE | ID: mdl-31544705

RESUMO

OBJECTIVES: The present study was designed to investigate the effects of renin angiotensin system (RAS) blockade on cardiac arrhythmias and sympathetic nerve remodelling in heart tissues of type 2 diabetic rats. METHODS: Thirty-two male Sprague Dawley rats were randomly allocated into 4 equal groups; a) normal control group: normal rats, b) DM group; after type 2 diabetes induction, rats received 2ml oral saline daily for 4 weeks, c) DM+ ACEi: after type 2 diabetes induction, rats were treated with enalapril (10 mg/kg, orally for 4 weeks) and d) DM+ ARBs: after type 2 diabetes induction, rats were treated with losartan (30 mg/kg, orally for 4 weeks). RESULTS: In type 2 diabetic rats, the results demonstrated significant prolongation in Q-T interval and elevation of blood sugar, HOMA-IR index, TC, TGs, LDL, serum CK-MB, myocardial damage, myocardial MDA, myocardial norepinephrine and tyrosine hydroxylase (TH) density with significant reduction in serum HDL, serum insulin and myocardial GSH and CAT. On the other hand, blockade of RAS at the level of either ACE by enalapril or angiotensin (Ag) receptors by losartan resulted in significant improvement in ECG parameters (Q-T), cardiac enzymes (CK-MB), cardiac morphology, myocardial oxidative stress (low MDA, high CAT and GSH) and myocardial TH density. CONCLUSIONS: RAS have a role in the cardiac sympathetic nerve sprouting and cardiac arrhythmias induced by type 2 DM and its blockade might have a cardioprotective effect via attenuation of sympathetic nerve fibres remodelling, myocardial norepinephrine contents and oxidative stress.

4.
Arab J Urol ; 17(2): 150-159, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31285928

RESUMO

Objectives: To design a new canine model to assess the renoprotective effect of local sildenafil administration, as the renoprotective effect of systemic sildenafil administration in renal ischaemia-reperfusion (IR) injury in animal models has been shown but its local effects have not been established to date. Materials and methods: In all, 120 dogs were assigned to five groups: sham, oral control (OC) group (right nephrectomy + left renal ischaemia for 60 min), oral sildenafil (OS) group (oral sildenafil 1 mg/kg, 60 min before ischaemia), local control (LC) group (local renal perfusion with saline and heparin for 5 min) and local sildenafil (LS) group (perfusion with sildenafil 0.5 mg/kg). Renal functions, histopathological changes, expression of caspase-3, nuclear factor erythroid 2-related factor 2 (Nrf2), inflammatory cytokines (intracellular adhesion molecule 1, tumour necrosis factor α and interleukin 1ß) and endothelial nitric oxide synthase (eNOS) in renal tissues were assessed in all groups at 1, 3, 7 and 14 days. Results: There were significant improvements in renal functions and cortical and medullary damage scores in the sildenafil-treated groups compared to their control groups (P < 0.05). Also, the LS group showed significantly better improvement of renal functions and cortical and medullary damage scores than the OS group (P < 0.05). Moreover, sildenafil significantly decreased the expression of caspase-3 and inflammatory cytokines and increased the expression of Nrf2 and eNOS in renal tissue, which were statistically significant in the LS group. Conclusion: LS has a greater renoprotective effect against renal IR injury than systemic administration via anti-inflammatory, antioxidant and anti-apoptotic pathways. Abbreviations: BUN: blood urea nitrogen; Ct: cycle threshold; eNOS: endothelial nitric oxide synthase; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; H&E: haematoxylin and eosin; IL-1ß: interleukin 1ß; NO: nitric oxide; Nrf2: nuclear factor erythroid 2-related factor 2; OC: oral control; OS: oral sildenafil; LC: local control; LS: local sildenafil.

5.
Neurochem Res ; 44(8): 1851-1868, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31187398

RESUMO

This study investigated the expression pattern, regulation of expression, and the role of hippocampal small-conductance Ca2+-activated K+ (SK) channels in memory deficits after cerebral hypoperfusion (CHP) with or without melatonin treatment, in rats. Adults male Wistar rats (n = 20/group) were divided into (1) a sham (2) a sham + melatonin (3) a two-vessel occlusion (2-VO) model, and (4) a 2-VO + melatonin. Melatonin was administered (i.p.) to all rats at a daily dose of 10 mg kg-1 for 7 days starting at the time of 2-VO-induction. In contrast to 2-VO rats, melatonin increased the latency of the passive avoidance learning test and decreased time to find the hidden platform in Water Morris Test in all tested rats. In addition, it concomitantly downregulated SK1, SK2, and SK3 channels, downregulated mRNA levels of TNFα and IL-1ß, enhanced BDNF levels and activity of PKA levels, and restored the levels of cholinergic markers in the hippocampi of the treated-rats. Mechanistically, melatonin significantly prevented CHP-induced activation of ERK1/2, JNK, and P38 MAPK at least by inhibiting ROS generation and enhancing the total antioxidant potential. In cultured hypoxic hippocampal neurons, individual blockage of MAPK signaling by the MEK1/2 inhibitor (U0126), but not by the P38 inhibitor (SB203580) or JNK inhibitor (SP600125), completely prevented the upregulation of all three kinds of SK channels. These data clearly confirm that upregulation of SK channels plays a role in CHP-induced memory loss and indicate that melatonin reverses memory deficits after CHP in rats, at least by, downregulation of SK1, SK2, and SK3 channels in their hippocampi.


Assuntos
Melatonina/uso terapêutico , Transtornos da Memória/tratamento farmacológico , Canais de Potássio Ativados por Cálcio de Condutância Baixa/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/genética , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Regulação para Baixo/efeitos dos fármacos , Hipocampo/efeitos dos fármacos , Interleucina-1beta/genética , Interleucina-1beta/metabolismo , Masculino , Transtornos da Memória/metabolismo , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Estresse Oxidativo/efeitos dos fármacos , RNA Mensageiro/metabolismo , Ratos Wistar , Canais de Potássio Ativados por Cálcio de Condutância Baixa/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/metabolismo , Regulação para Cima/efeitos dos fármacos
6.
Korean J Physiol Pharmacol ; 23(3): 203-217, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31080351

RESUMO

The present study was designed to examine the effect of heme oxygenase-1 (HO-1) induction by cobalt protoporphyrin (CoPP) on the cardiac functions and morphology, electrocardiogram (ECG) changes, myocardial antioxidants (superoxide dismutase [SOD] and glutathione [GSH]), and expression of heat shock protein (Hsp) 70 and connexin 43 (Cx-43) in myocardial muscles in isoproterenol (ISO) induced myocardial infarction (MI). Thirty two adult male Sprague Dawely rats were divided into 4 groups (each 8 rats): normal control (NC) group, ISO group: received ISO at dose of 150 mg/kg body weight intraperitoneally (i.p.) for 2 successive days; ISO + Trizma group: received (ISO) and Trizma (solvent of CoPP) at dose of 5 mg/kg i.p. injection 2 days before injection of ISO, with ISO at day 0 and at day 2 after ISO injections; and ISO + CoPP group: received ISO and CoPP at a dose of 5 mg/kg dissolved in Trizma i.p. injection as Trizma. We found that, administration of ISO caused significant increase in heart rate, corrected QT interval, ST segment, cardiac enzymes (lactate dehydrogenase, creatine kinase-muscle/brain), cardiac HO-1, Hsp70 with significant attenuation in myocardial GSH, SOD, and Cx-43. On the other hand, administration of CoPP caused significant improvement in ECG parameters, cardiac enzymes, cardiac morphology; antioxidants induced by ISO with significant increase in HO-1, Cx-43, and Hsp70 expression in myocardium. In conclusions, we concluded that induction of HO-1 by CoPP ameliorates ISO-induced myocardial injury, which might be due to up-regulation of Hsp70 and gap junction protein (Cx-43).

7.
Brain Sci ; 9(5)2019 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-31091715

RESUMO

Objectives: To study the possible anti-seizure and neuroprotective effect of glucagon like peptide 1 (GLP1) analogue (liraglutide) in a pentylenetetrazole (PTZ) induced kindled rat model and its underlying mechanisms. Methods: Thirty Sprague Dawley rats were allocated into 3 equal groups; i) Normal group: normal rats received normal saline, ii) PTZ (kindling) group: received PTZ (50 mg/Kg intraperitoneally (i.p.)) every other day for 2 weeks and iii) PTZ + GLP1 group: same as the PTZ group but rats received liraglutide (75 µg/kg i.p. daily) for 2 weeks before PTZ injection. Seizure severity score, seizure latency and duration were assessed. Also, the expression of caspase-3 (apoptotic marker) and ß-catenin (Wnt pathway) by western blotting, markers of oxidative stress (GSH, CAT and MDA) by biochemical assay and the expression of LC3 (marker of autophagy) and heat shock protein 70 (Hsp70) by immunostaining were assessed in hippocampal regions of brain tissues. Results: PTZ caused a significant increase in Racine score and seizure duration with a significant decrease in seizure latency. These effects were associated with a significant increase in MDA, ß-catenin, caspase-3, Hsp70 and LC3 in brain tissues (p < 0.05). Meanwhile, liraglutide treatment caused significant attenuation in PTZ-induced seizures, which were associated with significant improvement in markers of oxidative stress, reduction in LC3, caspase-3 and ß-catenin and marked increase in Hsp70 in hippocampal regions (p < 0.05). Conclusion: Activation of GLP1R might have anticonvulsant and neuroprotective effects against PTZ-induced epilepsy. These effects could be due to suppression of oxidative stress, apoptosis and autophagy and upregulation of Hsp70.

8.
Can J Physiol Pharmacol ; 97(1): 37-46, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30308130

RESUMO

The present study was designed to examine the possible neuroprotective and antiepileptic effects of metformin (Metf) in a rat model of pentylenetetrazole (PTZ)-induced epilepsy and its possible underlying mechanisms. Forty male albino rats were assigned to 4 groups of equal size: (1) normal control (NC) group, (2) Metf group: daily treatment with Metf (200 mg/kg, i.p.) for 2 weeks, (3) PTZ group: treatment with PTZ (50 mg/kg, i.p.) every other day for 2 weeks, and (4) Metf + PTZ group: daily treatment with PTZ and metformin (200 mg/kg, i.p.) for 2 weeks. Administration of PTZ caused a significant increase in seizure score and duration, induced a state of oxidative stress (high malondialdehyde, low reduced glutathione and catalase activity), and led to the upregulation of ß-catenin, caspase-3, and its cleavage products, Hsp70 and α-synuclein, in hippocampal regions as well as a significant reduction in seizure latency. While Metf treatment significantly ameliorated PTZ-induced seizures, attenuated oxidative stress, and upregulated α-synuclein and ß-catenin expression, it also inhibited caspase-3 activation and the release of the cleavage product and caused more upregulation in Hsp70 expression in hippocampal regions (p < 0.05). In conclusion, the antiepileptic and neuroprotective effects of Metf in PTZ-induced epilepsy might be due to the inhibition of apoptosis, attenuation of oxidative stress and α-synuclein expression, and upregulation of Hsp70.


Assuntos
Apoptose/efeitos dos fármacos , Epilepsia/induzido quimicamente , Epilepsia/metabolismo , Metformina/uso terapêutico , Pentilenotetrazol/toxicidade , alfa-Sinucleína/biossíntese , Animais , Apoptose/fisiologia , Convulsivantes/toxicidade , Epilepsia/prevenção & controle , Masculino , Metformina/farmacologia , Ratos , Ratos Sprague-Dawley
9.
CNS Neurol Disord Drug Targets ; 18(2): 156-169, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30113007

RESUMO

BACKGROUND & OBJECTIVE: This study investigated the effects of ferulic acid (FR), muscle exercise (Ex) and combination of them on rotenone (Rot)-induced Parkinson disease (PD) in mice as well as their underlying mechanisms. METHOD: 56 male C57BL/6 mice were allocated into 8 equal groups, 1) Normal control (CTL), 2) FR (mice received FR at 20 mg/kg/day), 3) Ex (mice received swimming Ex) and 4) Ex + FR (mice received FR and Ex), 5) Rot (mice received Rot 3 mg/Kg i.p. for 70 days), 6) ROT+ FR (mice received Rot + FR at 20 mg/kg/day), 7) ROT+ Ex (mice received Rot + swimming Ex) and 8) ROT+ Ex + FR (mice received Rot + FR and Ex). ROT group showed significant impairment in motor performance and significant reduction in tyrosine hydroxylase (TH) density and Hsp70 expression (p< 0.05) with Lewy bodies (alpha synuclein) aggregates in corpus striatum. Also, ROT+FR, ROT+EX and ROT + Ex+ FR groups showed significant improvement in behavioral and biochemical changes, however the effect of FR alone was more potent than Ex alone (p< 0.05) and addition of Ex to FR caused no more significant improvement than FR alone. CONCLUSION: We concluded that, FR and Ex improved the motor performance in rotenone-induced PD rodent model which might be due to increased Hsp70 expression and TH density in corpus striatum and combination of both did not offer more protection than FR alone.

10.
Acta Sci Pol Technol Aliment ; 17(3): 289-297, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30269468

RESUMO

BACKGROUND: Stevia rebaudiana Bertoni leaves are well-known for their sweetness and have been used        as a non-caloric sweetener in several countries. It has numerous therapeutic properties which have been proven safe and effective over hundreds of years. In the present study, we aimed to evaluate the possible antioxidant effects of stevia extracts and their role in regulating AMPK in type-1 diabetic rats. METHODS: Fifty male Sprague Dawely rats were divided into: (1) normal control (NC) group; normal rats receiving 0.5 ml normal saline, (2) DM group; diabetic rats receiving 0.5 ml normal saline, (3) DM + MSE group; DM rats receiving 200 mg/kg of methanolic extract of stevia, (4) DM + S group; DM rats receiving 2 mg/kg of pure stevioside, and (5) DM + CGA group; DM rats receiving 10 mg/kg of pure chlorogenic acid. Four weeks after treatment, AMPK activity, GLUT4 mRNA and oxidative stress markers were measured  in frozen muscles. Also, fasting blood glucose in serum, insulin and HbA1c were measured at the end of experiment. RESULTS: DM caused a significant increase in serum fasting glucose, HbA1c and muscle MDA with significant reduction in serum insulin, muscle SOD, catalase, GPx, AMPK activity and GLUT4 expression (p < 0.05). Treatment with stevia extract, pure stevioside and chlorogenic acid caused significant improvements in the studied parameters (p < 0.05). CONCLUSIONS: We concluded that stevia extracts and derivatives may improve metabolic dysfunction in skel- etal muscles via upregulation of AMPK and GLUT4 and suppression of oxidative stress.


Assuntos
Proteínas Quinases Ativadas por AMP/metabolismo , Antioxidantes/farmacologia , Diabetes Mellitus Tipo 1/metabolismo , Músculo Esquelético/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Extratos Vegetais/farmacologia , Stevia , Animais , Antioxidantes/metabolismo , Diabetes Mellitus Tipo 1/tratamento farmacológico , Transportador de Glucose Tipo 4/metabolismo , Masculino , Músculo Esquelético/metabolismo , Fitoterapia , Extratos Vegetais/uso terapêutico , Folhas de Planta , Ratos Sprague-Dawley , Regulação para Cima
11.
Steroids ; 135: 21-30, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29674209

RESUMO

AIMS: To investigate the effects of testosterone (Test) deficiency and testosterone replacement therapy (TRT) on the development of non-alcoholic fatty liver disease (NAFLD) and associated peripheral insulin resistance (IR) in male rats and to illustrate the underlying mechanisms of action. MATERIALS AND METHODS: male Sprague Dawley rats were divided into 3 groups as follows: 1) sham-operated group (n = 11), 2) ORCD-induced group (n = 9) exposed to orchidectomy (ORCD), achieved by complete surgical removal of testicles, and 3) ORCD + Test treated group (n = 10) (11 ng/mL Test propionate, 3x/week, S.C.). RESULTS: Data revealed significant increases in final body, liver, visceral and subcutaneous fats weights with significant increases in fasting plasma glucose and insulin levels and HOMA-IR. Additionally, ORCD rats had higher UAC for measured glucose levels and insulin levels during OGTT and higher AUC for measured glucose levels during ITT. Interesting, higher serum and hepatic levels of TGs and CHOL and higher serum levels of LDL were seen in ORCD-induced rats. Mechanistically, significant increases in mRNA levels of SREBP-1, SREBP-2, ACC-1, FAS, HMGCOAR and HMGCOAS with significant increases in protein levels of both precursor and mature SREBP-1 and SREBP-2, PPAR-α, p-PPAR-α, CPT-1 and UCP-2 and significant lower protein levels p-AMPK and p-ACC-1 were detected in livers of ORCD rats. Test administration to ORCD-induced rats significantly ameliorated all of the above mentioned biochemical endpoints and reversed the effect of ORCD on mRNA and protein levels of these targets. In conclusion, Test deficiency could be an independent risk factor for the development of NAFLD by upregulation of lipid synthesis and disturb fatty acids oxidation whereas Test therapy is a protective strategy.


Assuntos
Hipogonadismo/complicações , Hepatopatia Gordurosa não Alcoólica/complicações , Hepatopatia Gordurosa não Alcoólica/prevenção & controle , Testosterona/farmacologia , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Jejum/sangue , Regulação da Expressão Gênica/efeitos dos fármacos , Insulina/sangue , Resistência à Insulina , Gordura Intra-Abdominal/efeitos dos fármacos , Lipídeos/sangue , Fígado/efeitos dos fármacos , Fígado/metabolismo , Fígado/patologia , Masculino , Hepatopatia Gordurosa não Alcoólica/metabolismo , Hepatopatia Gordurosa não Alcoólica/patologia , Tamanho do Órgão/efeitos dos fármacos , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Proteína de Ligação a Elemento Regulador de Esterol 1/metabolismo , Proteína de Ligação a Elemento Regulador de Esterol 2/metabolismo , Gordura Subcutânea/efeitos dos fármacos
12.
Gen Physiol Biophys ; 37(2): 193-204, 2018 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-29593125

RESUMO

The current study investigated the effect of upregulation of heme oxygenase 1 (HO-1) by cobalt protoporphyrin (CoPP) on renal dysfunctions in renal ischemia/reperfusion (I/R) injury and its underlying mechanisms. 72 male Sprague Dawley rats were divided into 4 groups: sham group, ischemic group (left 45-min renal ischemia), CoPP-before group (as ischemic group with CoPP 20 mg/kg 30 min before ischemia) and CoPP-after group (as ischemic group with CoPP 20 mg/kg 20 min after ischemia). Serum creatinine, urea and TGF-ß1 and markers of redox state (MDA, SOD, GSH and CAT), nitric oxide (NO), TGF-ß1 and HO-1 in kidney tissues were measured. Serum creatinine and urea levels were significantly increased in ischemic group and attenuated in CoPP-treated groups (p < 0.05). Also, markers of redox state showed significant deteriorations in ischemic group which were improved significantly in CoPP-treated groups (p < 0.05). HO-1 expression in kidney tissues showed significant increase in ischemic group and showed more significant increase in CoPP-treated groups (p < 0.05). Moreover, serum and renal TGF-ß1 levels were significantly increased in ischemic group and attenuated in CoPP-treated groups (p ≶ 0.05). We concluded that up-regulation of HO-1 by CoPP treatment before and after renal I/R injury improved the kidney function and morphology and this might be due to impairment of oxidative stress and inflammatory cytokines in kidney tissues.


Assuntos
Heme Oxigenase-1/biossíntese , Inflamação/metabolismo , Nefropatias/metabolismo , Estresse Oxidativo/fisiologia , Traumatismo por Reperfusão/metabolismo , Animais , Masculino , Estresse Oxidativo/efeitos dos fármacos , Protoporfirinas/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Regulação para Cima
13.
Brain Sci ; 8(3)2018 Mar 14.
Artigo em Inglês | MEDLINE | ID: mdl-29538301

RESUMO

l-Carnitine is a unique nutritional supplement for athletes that has been recently studied as a potential treatment for certain neuropsychiatric disorders. However, its efficacy in seizure control has not been investigated. Sprague Dawley rats were randomly assigned to receive either saline (Sal) (negative control) or pentylenetetrazole (PTZ) 40 mg/kg i.p. × 3 times/week × 3 weeks. The PTZ group was further subdivided into two groups, the first received oral l-carnitine (l-Car) (100 mg/kg/day × 4 weeks) (PTZ + l-Car), while the second group received saline (PTZ + Sal). Daily identification and quantification of seizure scores, time to the first seizure and the duration of seizures were performed in each animal. Molecular oxidative markers were examined in the animal brains. l-Car treatment was associated with marked reduction in seizure score (p = 0.0002) that was indicated as early as Day 2 of treatment and continued throughout treatment duration. Furthermore, l-Car significantly prolonged the time to the first seizure (p < 0.0001) and shortened seizure duration (p = 0.028). In addition, l-Car administration for four weeks attenuated PTZ-induced increase in the level of oxidative stress marker malondialdehyde (MDA) (p < 0.0001) and reduced the activity of catalase enzyme (p = 0.0006) and increased antioxidant GSH activity (p < 0.0001). Moreover, l-Car significantly reduced PTZ-induced elevation in protein expression of caspase-3 (p < 0.0001) and ß-catenin (p < 0.0001). Overall, our results suggest a potential therapeutic role of l-Car in seizure control and call for testing these preclinical results in a proof of concept pilot clinical study.

14.
Can J Physiol Pharmacol ; 95(6): 732-742, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28177659

RESUMO

The present study investigated the effects of ferulic acid (FA) on pentylenetetrazole (PTZ)-induced seizures, oxidative stress markers (malondialdehyde (MDA), catalase, and reduced glutathione (GSH)), connexin (Cx) 43, heat shock protein 70 (Hsp 70), and monoamines (serotonin (5-HT) and norepinephrine (NE)) levels in a rat model of PTZ-induced kindling. Sixty Sprague Dawley rats were divided into 5 equal groups: (a) normal group; (b) FA group: normal rats received FA at a dose of 40 mg/kg daily; (c) PTZ group: normal rats received PTZ at a dose of 50 mg/kg i.p. on alternate days for 15 days; (d) FA-before group: treatment was the same as for the PTZ group, except rats received FA; and (e) FA-after group: rats received FA from sixth dose of PTZ. PTZ caused a significant increase in MDA, Cx43, and Hsp70 along with a significant decrease in GSH, 5-HT, and NE levels and CAT activity in the hippocampus (p < 0.05). Pre- and post-treatment with FA caused significant improvement in behavioral parameters, MDA, CAT, GSH, 5-HT, NE, Cx43 expression, and Hsp70 expression in the hippocampal region (p < 0.05). We conclude that FA has neuroprotective effects in PTZ-induced epilepsy, which might be due to attenuation of oxidative stress and Cx43 expression and upregulation of neuroprotective Hsp70 and neurotransmitters (5-HT and NE).


Assuntos
Monoaminas Biogênicas/metabolismo , Conexina 43/metabolismo , Ácidos Cumáricos/farmacologia , Proteínas de Choque Térmico HSP70/metabolismo , Hipocampo/efeitos dos fármacos , Excitação Neurológica/efeitos dos fármacos , Pentilenotetrazol/farmacologia , Animais , Região CA3 Hipocampal/efeitos dos fármacos , Região CA3 Hipocampal/metabolismo , Região CA3 Hipocampal/patologia , Catalase/metabolismo , Regulação da Expressão Gênica/efeitos dos fármacos , Hipocampo/metabolismo , Hipocampo/patologia , Masculino , Malondialdeído/metabolismo , Norepinefrina/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Convulsões/induzido quimicamente , Convulsões/metabolismo , Convulsões/patologia , Serotonina/metabolismo
15.
Nephron ; 134(2): 117-129, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27486809

RESUMO

BACKGROUND: It has been documented that remote limb ischemic preconditioning (rIPC) protect kidneys against renal ischemia/reperfusion (I/R). We hypothesized that osteopontin (OPN), transforming growth factor beta (TGF-ß), apoptotic proteins (survivin and caspase-3) and oxidative stress play role in the renoprotective effects of rIPC. MATERIALS AND METHODS: Fifty-four male Sprague-Dawley rats were randomized into 3 equal groups: sham group, I/R group (left renal 45 min ischemia) and rIPC group (as I/R group with 3 cycles of left hind limb ischemia just before renal ischemia). Each group was subdivided into 24, 48 and 72 h groups according to the time of sacrifice. We measured serum creatinine and blood urea nitrogen (BUN) at the baseline and end points. Also, left kidney was harvested at study end points for assessment of the expression of OPN, TGF-ß, apoptotic proteins (survivin and caspase-3) and oxidative stress markers (malondialdehyde (MDA), glutathione (GSH) and superoxide dismutase (SOD)) in kidney tissues and histopathological examination. RESULTS: Serum creatinine and BUN levels and histopathological damage score were significantly lower in rIPC group than I/R group (p < 0.005). Also, compared to I/R group, the levels of MDA and the expression of OPN, TGF-ß and caspase-3 in kidney tissues were significantly lower in rIPC group, while the levels of SOD and GSH and the expression of survivin in kidney tissues were significantly higher in rIPC group at all time points (p ≤ 0.05). CONCLUSIONS: rIPC exhibited protective effects against renal I/R injury which might be due to inhibition of OPN expression, inflammatory cytokine TGF-ß and caspase-3 and activation of anti-apoptotic protein survivin as well as improvement of oxidative stress in kidney tissues.


Assuntos
Membro Posterior/irrigação sanguínea , Proteínas Inibidoras de Apoptose/fisiologia , Precondicionamento Isquêmico , Rim/fisiopatologia , Osteopontina/fisiologia , Fator de Crescimento Transformador beta/fisiologia , Animais , Biomarcadores/sangue , Biomarcadores/metabolismo , Rim/patologia , Masculino , Ratos , Ratos Sprague-Dawley , Survivina
16.
J Epilepsy Res ; 6(1): 8-15, 2016 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-27390674

RESUMO

BACKGROUND AND PURPOSE: This study aimed to investigate the effect of ceftriaxone on oxidative stress and gap junction protein (connexin 43, Cx-43) expression in pentylenetetrazole (PTZ) induced kindling model. METHODS: Twenty four Sprague dawely rats were divided into 3 equal groups (a) normal group: normal rats. (b) PTZ kindled group: received PTZ at the dose of 50 mg/kg via intraperitoneal injection (i.p.) every other day for 2 weeks (c) ceftriaxone treated group: received ceftriaxone at the dose 200 mg\kg/12 hrs via i.p. injection daily from the 6th dose of PTZ for 3 days. Racine score, latency before beginning the first myoclonic jerk and duration of the jerks used as parameters of behavioral assessment. Immunohistopathological study for Cx-43 expression in hippocampus and measurement of markers of oxidative stress (malondialdehyde [MDA], low reduced glutathione [GSH] and catalase [CAT]) in hippocampal neurons were done. RESULTS: PTZ kindling was associated with behavioral changes (in the form high stage of Racine score, long seizure duration and short latency for the first jerk), enhanced oxidative stress state (as demonstrated by high MDA, low GSH and CAT) and up regulation of Cx43 in hippocampal regions. While, ceftriaxone treatment ameliorated, significantly, PTZ-induced convulsions and caused significant improvement in oxidative stress markers and Cx-43 expression in hippocamal regions (p < 0.05). CONCLUSIONS: These findings support the anticonvulsive effects of some beta-lactams antibiotics which could offer a possible contributor in the basic treatment of temporal lobe epilepsy. This effect might be due to reduction of oxidative stress and Cx43 expression.

17.
Can J Physiol Pharmacol ; 94(9): 936-46, 2016 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-27411029

RESUMO

The present study investigated the effects of combination of ischemic preconditioning (Ipre) and adipose-derived mesenchymal stem cells (ADMSCs) on renal ischemia-reperfusion (I-R) injury in rats. 90 male Sprague Dawley rats were divided into 5 equal groups; sham operated, control (45 min left renal ischemia), Ipre group as control group with 3 cycles of Ipre just before renal ischemia, ADMSCs-treated group (as control with ADMSCs 10(6) cells in 0.1 mL via penile vein 60 min before ischemia time), and Ipre + ADMSCs group as ADMCs group with 3 cycles of Ipre. Ipre and ADMSCs groups showed significant decrease in serum creatinine and blood urea nitrogen (BUN) and caspase-3 and CD45 expression in kidney and significant increase in HIF-1α, SDF-1α, CD31, and Ki67 expressions in kidney compared with the control group (p < 0.05). Moreover, the Ipre + ADMSCs group showed significant decrease in serum BUN and caspase-3 and CD45 expression in kidney with significant increase in HIF-1α, SDF-1α, CD31, and Ki67 expression in kidney compared with the Ipre and ADMCs groups (p < 0.05). We concluded that Ipre potentiates the renoprotective effect of ADMSCs against renal I/R injury probably by upregulation of HIF-1α, SDF-1α, CD31, and Ki67 and downregulation of caspase-3 and CD45.


Assuntos
Tecido Adiposo/citologia , Precondicionamento Isquêmico , Rim/metabolismo , Rim/patologia , Transplante de Células-Tronco Mesenquimais , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Animais , Nitrogênio da Ureia Sanguínea , Caspase 3/biossíntese , Quimiocina CXCL12/biossíntese , Creatinina/sangue , Subunidade alfa do Fator 1 Induzível por Hipóxia/biossíntese , Antígeno Ki-67/biossíntese , Antígenos Comuns de Leucócito/biossíntese , Masculino , Molécula-1 de Adesão Celular Endotelial a Plaquetas/biossíntese , Ratos , Traumatismo por Reperfusão/sangue
18.
Can J Physiol Pharmacol ; 94(8): 829-37, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27322834

RESUMO

The present study investigated the possible renoprotective effect of direct renin inhibitor (aliskiren) on renal dysfunctions, as well as its underlying mechanisms in rat model of adenine-induced tubulointerstitial nephropathy. Forty male Sprague-Dawley rats were randomized into 4 groups; normal group, aliskiren group (normal rats received 10 mg/kg aliskiren), adenine group (animals received high-adenine diet for 4 weeks and saline for 12 weeks), and adenine + aliskiren group (animals received adenine for 4 weeks and aliskiren 10 mg/kg for 12 weeks). It was found that adenine caused significant decrease in body mass, Hb, HR, serum Ca(2+), eNOS and nrf2 expression, GSH, and catalase in kidney tissues with significant increase in arterial blood pressure (ABP), serum creatinine, BUN, plasma renin activity (PRA), K(+) and P, urinary albumin excretion (UAE), caspase-3, and MDA (lipid peroxidation marker) in kidney tissues compared to normal group (p < 0.05). Administration of aliskiren caused significant improvement in all studied parameters compared to adenine group (p < 0.05). We concluded that aliskiren has renoprotective effect against adenine-induced nephropathy. This might be due to inhibition of PRA, attenuation of oxidative stress, activation of Nrf2 and eNOS genes, and suppression of caspase-3.


Assuntos
Adenina/toxicidade , Amidas/uso terapêutico , Fumaratos/uso terapêutico , Nefrite Intersticial/induzido quimicamente , Nefrite Intersticial/prevenção & controle , Renina/antagonistas & inibidores , Adenina/administração & dosagem , Amidas/farmacologia , Animais , Apoptose/efeitos dos fármacos , Apoptose/fisiologia , Fumaratos/farmacologia , Masculino , Nefrite Intersticial/metabolismo , Substâncias Protetoras , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Renina/metabolismo
19.
Can J Physiol Pharmacol ; 94(8): 868-78, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27191243

RESUMO

The objectives of present study were to examine the effects of aluminum oxide (Al2O3) nanoparticles on myocardial functions, electrical activities, morphology, inflammation, redox state, and myocardial expression of connexin 43 (Cx43) and the effect of gallic acid (GA) on these effects in a rat animal model. Forty male albino rats were divided into 4 equal groups: the control (normal) group; the Al2O3 group, rats received Al2O3 (30 mg·kg(-1), i.p.) daily for 14 days; the nano-alumina group, rats received nano-alumina (30 mg·kg(-1), i.p.) daily for 14 days; and the nano-alumina + GA group, rats received GA (100 mg·kg(-1) orally once daily) for 14 days before nano-alumina administration. The results showed disturbed ECG variables and significant increases in serum levels of LDH, creatine phosphokinase (CPK), CK-MB, triglycerides (TGs), cholesterol and LDL, nitric oxide (NO), and TNF-α and myocardial concentrations of NO, TNF-α, and malondialdehyde (MDA), with significant decreases in serum HDL and myocardial GSH, SOD, catalase (CAT), and Cx43 expression in the nano-alumina group. Pretreatment with GA improved significantly all parameters except serum and myocardial NO. We concluded that chronic administration of Al2O3 NPs caused myocardial dysfunctions, and pretreatment with GA ameliorates myocardial injury induced by nano-alumina, probably through its hypolipidaemic, anti-inflammatory, and antioxidant effects and upregulation of Cx43 in heart.


Assuntos
Óxido de Alumínio/toxicidade , Cardiotônicos/farmacologia , Conexina 43/biossíntese , Ácido Gálico/farmacologia , Mediadores da Inflamação/sangue , Lipídeos/sangue , Nanopartículas/toxicidade , Animais , Cardiomiopatias/sangue , Cardiomiopatias/induzido quimicamente , Cardiomiopatias/prevenção & controle , Cardiotônicos/uso terapêutico , Conexina 43/antagonistas & inibidores , Citocinas/sangue , Eletrocardiografia/efeitos dos fármacos , Ácido Gálico/uso terapêutico , Mediadores da Inflamação/antagonistas & inibidores , Masculino , Oxirredução/efeitos dos fármacos , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley
20.
Int Urol Nephrol ; 48(2): 287-97, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26660954

RESUMO

OBJECTIVES: To study the effects of darbepoetin-α (DPO-α) (erythropoietin analog) on adriamycin (ADR)-induced chronic nephropathy in rats. METHODS: Sixty-nine male Sprague-Dawley rats divided into 3 groups (23 rats each): negative control group: normal rats received saline as a vehicle; positive control (ADR) group: rats received 2 iv injection of ADR via penile vein at 14-day interval without treatment; and DPO-α group: as ADR group but rats received sc DPO-α (0.3 µg/kg bw) once weekly for 12 weeks. By the end of experiment hemoglobin (Hb) content, serum creatinine, BUN, albumin, triglycerides and cholesterol, urinary protein excretion and kidney injury molecule-1 (KIM-1). GSH, malondialdehyde, caspase-3 expression histopathological and electron microscopic examinations for kidney tissues were done. RESULTS: DPO-α significantly improved the animal survival rate and body weight, Hb, serum BUN, triglycerides, cholesterol, and albumin and urinary protein excretion and KIM-1 in urine. Also, administration of DPO-α improved the morphological damage in glomeruli and renal tubules as well as caspase-3 expression and markers of oxidative stress in kidney tissues. CONCLUSION: Administration of DPO-α alleviates ADR nephropathy and this might due to improvement of Hb content, hyperlipidemia, enhancement of endogenous antioxidants, reduction of apoptosis and tubulointerstitial injury and maintaining the integrity of glomerular membrane.


Assuntos
Darbepoetina alfa/administração & dosagem , Glomérulos Renais/ultraestrutura , Túbulos Renais/ultraestrutura , Insuficiência Renal Crônica/tratamento farmacológico , Animais , Apoptose/efeitos dos fármacos , Biomarcadores/metabolismo , Modelos Animais de Doenças , Doxorrubicina/toxicidade , Hematínicos/administração & dosagem , Glomérulos Renais/efeitos dos fármacos , Túbulos Renais/efeitos dos fármacos , Peroxidação de Lipídeos , Masculino , Microscopia Eletrônica , Ratos , Ratos Sprague-Dawley , Insuficiência Renal Crônica/metabolismo , Insuficiência Renal Crônica/patologia
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