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1.
J Int Soc Sports Nutr ; 18(1): 60, 2021 Sep 09.
Artigo em Inglês | MEDLINE | ID: mdl-34503541

RESUMO

BACKGROUND: Numerous studies have demonstrated the efficacy of creatine supplementation for improvements in exercise performance. Few studies, however, have examined the effects of phosphocreatine supplementation on exercise performance. Furthermore, while polyphenols have antioxidant and anti-inflammatory properties, little is known regarding the influence of polyphenol supplementation on muscular strength, power, and endurance. Thus, the purpose of the present study was to compare the effects of 28 days of supplementation with phosphocreatine disodium salts plus blueberry extract (PCDSB), creatine monohydrate (CM), and placebo on measures of muscular strength, power, and endurance. METHODS: Thirty-three men were randomly assigned to consume either PCDSB, CM, or placebo for 28 days. Peak torque (PT), average power (AP), and percent decline for peak torque (PT%) and average power (AP%) were assessed from a fatigue test consisting of 50 maximal, unilateral, isokinetic leg extensions at 180°·s- 1 before and after the 28 days of supplementation. Individual responses were assessed to examine the proportion of subjects that exceeded a minimal important difference (MID). RESULTS: The results demonstrated significant (p < 0.05) improvements in PT for the PCDSB and CM groups from pre- (99.90 ± 22.47 N·m and 99.95 ± 22.50 N·m, respectively) to post-supplementation (119.22 ± 29.87 N·m and 111.97 ± 24.50 N·m, respectively), but no significant (p = 0.112) change for the placebo group. The PCDSB and CM groups also exhibited significant improvements in AP from pre- (140.18 ± 32.08 W and 143.42 ± 33.84 W, respectively) to post-supplementation (170.12 ± 42.68 W and 159.78 ± 31.20 W, respectively), but no significant (p = 0.279) change for the placebo group. A significantly (p < 0.05) greater proportion of subjects in the PCDSB group exceeded the MID for PT compared to the placebo group, but there were no significant (p > 0.05) differences in the proportion of subjects exceeding the MID between the CM and placebo groups or between the CM and PCDSB groups. CONCLUSIONS: These findings indicated that for the group mean responses, 28 days of supplementation with both PCDSB and CM resulted in increases in PT and AP. The PCDSB, however, may have an advantage over CM when compared to the placebo group for the proportion of individuals that respond favorably to supplementation with meaningful increases in muscular strength.


Assuntos
Força Muscular/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Fosfocreatina/farmacologia , Resistência Física/efeitos dos fármacos , Extratos Vegetais/farmacologia , Mirtilos Azuis (Planta)/química , Creatina , Suplementos Nutricionais , Método Duplo-Cego , Humanos , Masculino , Torque , Adulto Jovem
2.
Toxicology ; 460: 152881, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34358621

RESUMO

Myocardial apoptosis and necroptosis are the major etiological factor during doxorubicin (DOX) induced cardiotoxicity, and one of the important reasons that limit the drug's clinical application. Up to date, its mechanism has not been fully elucidated. The protective role of phosphocreatine (PCr) in heart surgery and medical cardiology has been observed in numerous clinical trials. This study aimed to evaluate cardioprotective actions of PCr against DOX-induced cardiotoxicity and investigate the underlying mechanism involving in transforming growth factor ß-activated kinase 1 (TAK1) mediated myocardial survive signaling pathway. Male Sprague-Dawleyrats were intraperitoneally (ip) injected with normal saline (NS) or DOX (2 mg/kg) alone or DOX with PCr (200 mg/kg) used as animal model. The data showed that DOX significantly impaired cardiac function and structure, induced oxidative stress, myocardial apoptosis and necroptosis, and dramatically down-regulated the expression level of TAK1, while the intervention of PCr obviously attenuated cardiac dysfunction, oxidative stress, myocardial apoptosis and necroptosis, especially alleviated the decrease of TAK1 expression. In vitro analysis, after H9c2 cells were pretreated with or without PCr (0.5 mM) or N-Acetyl-L-cysteine (NAC, 0.5 mM) or 5Z-7-oxozeaenol (5z-7-Ox, 1 µM) for 1 h, subsequently treated with DOX (1 µM) for 24 h. The results revealed that inhibition of TAK1 further deteriorated apoptotic and necroptotic cell death induced by DOX in H9c2 cells, but didn't affect oxidative stress. While the pretreatment of PCr or NAC enhanced antioxidant activity to reduce oxidative stress, significantly alleviated apoptotic and necroptotic cell death induced by DOX in H9c2 cells. Consistent with the results in vivo, PCr or NAC significantly inhibited the decrease of TAK1 expression induced by DOX. In conclusion, oxidative stress induced by DOX inhibits the expression of TAK1, and leads to myocardial apoptotic and necroptotic death, while the intervention of PCr increases antioxidant activity to alleviate oxidative stress, which in turn activates TAK1 signaling pathway to promote myocardial survival, and finally attenuate DOX-induced cardiotoxicity.


Assuntos
Cardiotoxinas/toxicidade , Doxorrubicina/toxicidade , MAP Quinase Quinase Quinases/metabolismo , Miocárdio/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfocreatina/farmacologia , Animais , Antibióticos Antineoplásicos/toxicidade , Antioxidantes/farmacologia , Masculino , Miocárdio/patologia , Estresse Oxidativo/fisiologia , Ratos , Ratos Sprague-Dawley
3.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808213

RESUMO

BACKGROUND: Cyclocreatine phosphate (CCrP) is a potent bioenergetic cardioprotective compound known to preserve high levels of cellular adenosine triphosphate during ischemia. Using the standard Isoproterenol (ISO) rat model of heart failure (HF), we recently demonstrated that the administration of CCrP prevented the development of HF by markedly reducing cardiac remodeling (fibrosis and collagen deposition) and maintaining normal ejection fraction and heart weight, as well as physical activity. The novel inflammatory mediator, Nourin is a 3-KDa formyl peptide rapidly released by ischemic myocardium and is associated with post-ischemic cardiac inflammation. We reported that the Nourin-associated miR-137 (marker of cell damage) and miR-106b-5p (marker of inflammation) are significantly upregulated in unstable angina patients and patients with acute myocardial infarction, but not in healthy subjects. OBJECTIVES: To test the hypothesis that Nourin-associated miR-137 and miR-106b-5p are upregulated in ISO-induced "HF rats" and that the administration of CCrP prevents myocardial injury (MI) and reduces Nourin gene expression in "non-HF rats". METHODS: 25 male Wistar rats (180-220 g) were used: ISO/saline (n = 6), ISO/CCrP (0.8 g/kg/day) (n = 5), control/saline (n = 5), and control/CCrP (0.8 g/kg/day) (n = 4). In a limited study, CCrP at a lower dose of 0.4 g/kg/day (n = 3) and a higher dose of 1.2 g/kg/day (n = 2) were also tested. The Rats were injected SC with ISO for two consecutive days at doses of 85 and 170 mg/kg/day, respectively, then allowed to survive for an additional two weeks. CCrP and saline were injected IP (1 mL) 24 h and 1 h before first ISO administration, then daily for two weeks. Serum CK-MB (U/L) was measured 24 h after the second ISO injection to confirm myocardial injury. After 14 days, gene expression levels of miR-137 and miR-106b-5p were measured in serum samples using quantitative real-time PCR (qPCR). RESULTS: While high levels of CK-MB were detected after 24 h in the ISO/saline rats indicative of MI, the ISO/CCrP rats showed normal CK-MB levels, supporting prevention of MI by CCrP. After 14 days, gene expression profiles showed significant upregulation of miR-137 and miR-106b-5p by 8.6-fold and 8.7-fold increase, respectively, in the ISO/saline rats, "HF rats," compared to the control/saline group. On the contrary, CCrP treatment at 0.8 g/kg/day markedly reduced gene expression of miR-137 by 75% and of miR-106b-5p by 44% in the ISO/CCrP rats, "non-HF rats," compared to the ISO/Saline rats, "HF rats." Additionally, healthy rats treated with CCrP for 14 days showed no toxicity in heart, liver, and renal function. CONCLUSIONS: Results suggest a role of Nourin-associated miR-137 and miR-106b-5p in the pathogenesis of HF and that CCrP treatment prevented ischemic injury in "non-HF rats" and significantly reduced Nourin gene expression levels in a dose-response manner. The Nourin gene-based mRNAs may, therefore, potentially be used as monitoring markers of drug therapy response in HF, and CCrP-as a novel preventive therapy of HF due to ischemia.


Assuntos
Imidazolidinas/farmacologia , MicroRNAs/genética , Fosfocreatina/análogos & derivados , Angina Instável/genética , Animais , Biomarcadores Farmacológicos , Insuficiência Cardíaca/tratamento farmacológico , Insuficiência Cardíaca/genética , Humanos , Imidazolidinas/metabolismo , Isoproterenol/uso terapêutico , Masculino , MicroRNAs/metabolismo , Infarto do Miocárdio/genética , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Fosfocreatina/genética , Fosfocreatina/metabolismo , Fosfocreatina/farmacologia , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar
4.
Free Radic Biol Med ; 162: 181-190, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33131696

RESUMO

Alzheimer (AD) is a degenerative disease that can lead memory loss and behavioral dysfunction. Aß protein and phosphorylation of Tau protein are related to the onset of AD. However, at present, its treatment and drugs are limited. The purpose of our study is to evaluate whether phosphocreatine (PCr) could protect neuronal injury induced by Aß protein in vivo and in vitro through AKT/GSK-3ß/Tau/APP/CDK5 pathways. Differentiated PC-12 cells were cultured with Aß25-35 for 24 h, while the mice were injected with D-Galactose for eight weeks, both of them were pretreated with PCr for 2 h. The results showed PCr could obviously induce cells and hippocampus apoptosis using DAPI and TUNEL. PCr decreased the levels of intercellular reactive oxygen species (ROS) and malondialdehyde (MDA), and increased the activities of superoxide dismutase (SOD). Besides, the apoptosis pathway was detected using Western blot, showing that PCr could significantly reduce caspase-3, caspase-9, Bcl-2/Bax expression in vivo and in vitro. At the same time, PCr could decreased Ca2+ and apoptosis by Flow Cytometry in PC-12 cells. We observed that the morphological alteration of hippocampus injury was mitigated with the pretreatment of PCr. Furthermore, PCr pretreatment could decrease Aß25-35-induced PC-12 cells apoptosis with APP cDNA transfection, which up-regulated AKT/GSK-3ß/CDK5 pathways and induced Tau phosphorylation. In summary, PCr could reduce Aß25-35 toxicity to protect neuronal cells via AKT/GSK-3ß/CDK5 pathways.


Assuntos
Peptídeos beta-Amiloides , Fármacos Neuroprotetores , Peptídeos beta-Amiloides/toxicidade , Animais , Apoptose , Morte Celular , Glicogênio Sintase Quinase 3 beta/genética , Camundongos , Fármacos Neuroprotetores/farmacologia , Fosfocreatina/farmacologia , Fosforilação , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-akt/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismo
5.
Curr Pharm Biotechnol ; 22(5): 609-621, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33198615

RESUMO

BACKGROUND: Osteoporosis, characterized by bone loss, usually occurs with the increased bone resorption and decreased bone formation. H2O2-induced MC3T3-E1 cells are commonly used for the study of osteoblastic activities, which play a crucial role in bone formation. OBJECTIVE: This study aimed to investigate the effects of Phosphocreatine (PCr) on the osteoblastic activities in H2O2-induced MC3T3-E1 cells and elaborate on the possible molecular mechanism. METHODS: The Osteoprotegerin (OPG)/Receptor Activator of NF-κB Ligand (RANKL) ratio and osteogenic markers were detected to investigate the effects of PCr on osteoblastic activities, and the osteoblastic apoptosis was detected using Hochest staining. Moreover, oxidative stress, Adenosine Triphosphate (ATP) generation and the expression of Sirtuin 1 (SIRT1), Forkhead Box O 1 (FOXO1) and Peroxisome Proliferator-Activated Receptor Γ Coactivator-1α (PGC-1α) were also examined to uncover the possible molecular mechanism in H2O2-induced MC3T3-E1 cells. RESULT: The results showed that PCr promoted the osteoblastic differentiation by increasing the expression levels of osteogenic markers of Alkaline Phosphatase (ALP) and Runt-related transcription factor 2 (Runx2), as well as increased the OPG/RANKL ratio and suppressed the osteoblastic apoptosis in H2O2-induced MC3T3-E1 cells. Moreover, treatment with PCr suppressed reactive oxygen species (ROS) over-generation and promoted the ATP production as well as increased the PGC-1α, FOXO1 and SIRT1 protein expression levels in H2O2-induced MC3T3-E1 cells. CONCLUSION: PCr treatment could promote osteoblastic activities via suppressing oxidative stress and increasing the ATP generation in H2O2-induced MC3T3-E1 cells. In addition, the positive effects of PCr on osteoblasts might be regulated by SIRT1/FOXO1/ PGC-1α signaling pathway.


Assuntos
Proteína Forkhead Box O1/efeitos dos fármacos , Peróxido de Hidrogênio/farmacologia , Osteoblastos/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo/efeitos dos fármacos , Fosfocreatina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Sirtuína 1/efeitos dos fármacos , Células 3T3 , Fosfatase Alcalina/biossíntese , Fosfatase Alcalina/efeitos dos fármacos , Animais , Apoptose/efeitos dos fármacos , Subunidade alfa 1 de Fator de Ligação ao Core/biossíntese , Subunidade alfa 1 de Fator de Ligação ao Core/efeitos dos fármacos , Camundongos , Osteoprotegerina/efeitos dos fármacos , Osteoprotegerina/metabolismo , Estresse Oxidativo , Ligante RANK/efeitos dos fármacos , Ligante RANK/metabolismo , Espécies Reativas de Oxigênio
6.
Medicine (Baltimore) ; 99(28): e20934, 2020 Jul 10.
Artigo em Inglês | MEDLINE | ID: mdl-32664090

RESUMO

This study aimed to investigate the myocardial protective effect of liquid sodium phosphocreatine cardiac arrest in extracorporeal circulation surgery treating infants with atrial septal defects.Eighty-four infants with atrial septal defects who required extracorporeal circulation surgery treatment at our hospital from January 2016 to June 2018 were divided into an observation group and a control group through a digitally randomized method, with 42 cases in each group. The control group adopted the conventional modified St Thomas II high potassium cold liquid crystal cardiac arrest, while the observation group adopted the liquid sodium phosphocreatine cardiac arrest.The myocardial enzyme indexes of the 2 groups 3, 6, 12, and 24 hours postoperatively were higher than before establishing the cardiopulmonary bypass and the enzyme indexes of the control group at the same time were higher than that of the observation group; adenosine triphosphate, adenosine diphosphate, and other energy levels and the postoperative recovery rate energy levels of the observation group were higher than those in the control group, the difference was statistically significant (P < .05).Liquid sodium phosphocreatine cardiac arrest used in extracorporeal circulation surgery treating infants with atrial septal defects can reduce myocardial ischemia-reperfusion injury, maintain energy supply during ischemia, strengthen the St Thomas II effect, and aid postoperative cardiac function recovery of high potassium cold liquid crystal cardiac arrest used in infants with atrial septal defects and treated with extracorporeal circulation surgery.


Assuntos
Ponte Cardiopulmonar/métodos , Cardiotônicos/farmacologia , Parada Cardíaca Induzida/métodos , Comunicação Interatrial/cirurgia , Fosfocreatina/farmacologia , Difosfato de Adenosina/metabolismo , Trifosfato de Adenosina/metabolismo , Cardiotônicos/administração & dosagem , Estudos de Casos e Controles , Pré-Escolar , Circulação Extracorpórea/métodos , Feminino , Parada Cardíaca/induzido quimicamente , Comunicação Interatrial/diagnóstico , Comunicação Interatrial/tratamento farmacológico , Humanos , Lactente , Masculino , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/química , Miocárdio/enzimologia , Preservação de Órgãos/métodos , Fosfocreatina/administração & dosagem , Período Pós-Operatório , Cloreto de Potássio/administração & dosagem , Cloreto de Potássio/farmacologia , Substâncias Protetoras/administração & dosagem , Recuperação de Função Fisiológica/efeitos dos fármacos
7.
Drug Des Devel Ther ; 13: 2081-2096, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31417240

RESUMO

Purpose: To investigate the mitochondria-related mechanism of Gynura segetum (GS)-induced apoptosis and the protective effect of phosphocreatine (PCr), a mitochondrial respiration regulator. Methods: First, the mechanism was explored in human hepatocyte cell line. The mitochondrial oxidative stress was determined by fluorescence assay. The level of sirtuin 3 (SIRT3), acetylated superoxide dismutase 2 (Ac-SOD2), SOD2, and apoptosis were detected by Western blotting. Mito-TEMPO and cell lines of viral vector-mediated overexpression of SIRT3 and SIRT3H248Y were used to further verify the mechanism of GS-induced apoptosis. GS-induced liver injury mice models were built by GS through intragastric administration and interfered by PCr through intraperitoneal injection. A total of 30 C57BL/6J mice were assigned to 5 groups and treated with either saline, PCr (100 mg/kg), GS (30 g/kg), or PCr (50 or 100 mg/kg)+GS (30 g/kg). Liver hematoxylin and eosin (HE) staining, immunohistochemical analysis, and blood biochemical evaluation were performed. Results: GS induced hepatocyte apoptosis and elevated levels of mitochondrial ROS in L-02 cells. The expression of SIRT3 was decreased. Downregulation of SIRT3 was associated with increased levels of Ac-SOD2, which is the inactivated enzymatic form of SOD2. Conversely, when overexpressing SIRT3 in GS-treated cells, SOD2 activity was restored, and mitochondrial ROS levels and hepatocyte apoptosis declined. Upon administration of PCr to GS-treated cells, they exhibited a significant upregulation of SIRT3 and were protected against apoptosis. In animal experiments, serum ALT level and mitochondrial ROS of the mice treated with GS and 50 mg/kg PCr were significantly attenuated compared with only GS treated. The changes in SIRT3 expression were also consistent with the in vitro results. In addition, immunohistochemical analysis of the mouse liver showed that Ac-SOD2 was decreased in the PCr and GS co-treated group compared with GS treated group. Conclusion: GS caused liver injury by dysregulating mitochondrial ROS generation via a SIRT3-SOD2 pathway. PCr is a potential agent to treat GS-induced liver injury by mitochondrial protection.


Assuntos
Apoptose/efeitos dos fármacos , Medicamentos de Ervas Chinesas/farmacologia , Hepatócitos/efeitos dos fármacos , Fosfocreatina/farmacologia , Substâncias Protetoras/farmacologia , Espécies Reativas de Oxigênio/metabolismo , Animais , Sobrevivência Celular/efeitos dos fármacos , Células Cultivadas , Relação Dose-Resposta a Droga , Células HEK293 , Hepatócitos/metabolismo , Humanos , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/análise , Sirtuína 3/antagonistas & inibidores , Sirtuína 3/metabolismo , Relação Estrutura-Atividade , Superóxido Dismutase/antagonistas & inibidores , Superóxido Dismutase/metabolismo
8.
Biochem Biophys Res Commun ; 506(3): 611-618, 2018 11 30.
Artigo em Inglês | MEDLINE | ID: mdl-30366667

RESUMO

Diabetes mellitus (DM) associated liver damage is a major health burden. Hepatocellular-damage in DM characterized with elevated endoplasmic reticulum stress (ER) and may enhanced insulin-resistance. Phosphocreatine (PCr) a rapidly high-energy-reserve molecule of phosphates naturally occurs in liver, brain and skeletal muscle. This study aimed to investigate the protective effect of PCr on the liver-injury-associated with DM and to report the mechanism involved. Wistar rat's diabetes model was induced using streptozotocin (STZ), and the animals were treated with 20 mg/kg, or 50 mg/kg PCr injection. Blood glucose level, and body wt were recorded. Liver tissues homogenate were analyzed for liver damage markers alanine transaminase (ALT), aspartate transaminase (AST). Liver tissues proteins further evaluated for apoptosis, endoplasmic reticulum stress (ER), and insulin resistance biomarkers using western blotting. Our results revealed that PCr reduced blood glucose level, improved body wt, ameliorates liver function enzymes. Furthermore, PCr upregulates anti-apoptotic Bcl2 proteins expression, and down-regulates significantly pro-apoptotic casp3 and Bax proteins expression in vivo and invitro. Moreover, ER stress CHOP, GRP78 and ATF4 biomarkers level were significantly attenuated in PCr treated animals comparing to STZ diabetes associated liver-damage model with significant improving in insulin-resistance Akt and IRS-1. Our results revealed that treating with PCr in diabetes-associated liver injury models decreased blood glucose level and possess protective effect in-vitro and in-vivo, which could be suggested as potential therapeutic strategy for diabetes associated liver injury patients.


Assuntos
Apoptose/efeitos dos fármacos , Carcinoma Hepatocelular/patologia , Diabetes Mellitus Experimental/patologia , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Resistência à Insulina , Neoplasias Hepáticas/patologia , Fosfocreatina/farmacologia , Animais , Biomarcadores Tumorais/metabolismo , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Forma Celular/efeitos dos fármacos , Sobrevivência Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/sangue , Modelos Animais de Doenças , Células Hep G2 , Humanos , Fígado/efeitos dos fármacos , Fígado/metabolismo , Metaboloma , Estresse Oxidativo/efeitos dos fármacos , Substâncias Protetoras/farmacologia , Substâncias Protetoras/uso terapêutico , Ratos Wistar , Transdução de Sinais/efeitos dos fármacos , Estreptozocina
9.
Acta Cir Bras ; 33(2): 117-124, 2018 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-29513810

RESUMO

PURPOSE: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). METHODS: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B <intraperitoneally injected with 20 mg/kg (10 mg/ml) of saline before preparing the ischemia-reperfusion (IR) model>, and group C <intraperitoneally injected with 20 mg/kg (10 mg/ml) of PCr immediately before preparing the IR model>. After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. RESULTS: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. CONCLUSIONS: Phosphocreatine pre-administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra.


Assuntos
Isquemia Encefálica/metabolismo , Cardiotônicos/farmacologia , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Mitocondriais/metabolismo , Fosfocreatina/farmacologia , Traumatismo por Reperfusão/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Animais , Apoptose/efeitos dos fármacos , Proteínas Reguladoras de Apoptose , Isquemia Encefálica/prevenção & controle , Caspase 3/metabolismo , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Masculino , Fármacos Neuroprotetores/farmacologia , Distribuição Aleatória , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/prevenção & controle
10.
Free Radic Biol Med ; 120: 228-238, 2018 05 20.
Artigo em Inglês | MEDLINE | ID: mdl-29559323

RESUMO

Methylglyoxal (MGO), an active metabolite of glucose, is observed in high levels in the tissues and blood of diabetic patients. Phosphocreatine (PCr), a high-energy phosphate compound, exhibits a range of pharmacological actions but little is well known of its neuroprotective action. The aim of the present study was to investigate the neuroprotective effects and the possible mechanisms of PCr. Diabetes is closely associated with neurodegenerative diseases, leading not only to the peripheral nervous system (PNS) and but also to central nervous system (CNS) damage. Therefore, we established two rat models of diabetes in vivo induced by MGO and streptozocin (STZ) respectively, while utilized differentiated PC-12 cells in vitro. Treatment of PC-12 cells with PCr markedly attenuated MGO-induced change of viability, apoptosis, accompanied by decreased levels of caspase-3, casapse-9 and Bcl-2/Bax protein ratio. Determination of cellular respiratory function was performed with intact PC-12 cells and homogenized hippocampal neuron tissue of rat. Reactive oxygen species (ROS) generation was assessed by membrane permeable fluorescent probe DCFH-DA. The expressions of Akt, Nrf2 and HO-1 were examined by Western blot. PCr pretreatment significantly reduced oxidative stress-induced high LDH, MDA level, and ROS production of PC-12 cells. PCr pretreatment also significantly decreased mitochondrial dysfunction in vitro and in vivo. In addition, PCr pretreatment increased the expression of p-Akt, Nrf2 and HO-1, and reduced the apoptosis. Moreover, the expression of Cleaved caspase3 was partially increased and the p-Akt, Nrf2 and HO-1 was partially reduced by a PI3K inhibitor (LY294002). While, compared with LY294002 groups, pre-treatment with PCr at the concentrations of 20 mM significantly reduced the expression of Cleaved caspase3 and increased the expression of p-Akt, Nrf2 and HO-1. Molecular docking assay showed that PCr possessed powerful affinity towards to Akt with lower binding energy. In conclusion, the neuroprotective effects of PCr in vitro and in vivo rely on normalizing mitochondrial function and reducing oxidative stress via Akt mediated Nrf2/HO-1 pathway, suggesting that PCr may be a novel therapeutic candidate for the treatment of diabetes-associated neurodegenerative diseases.


Assuntos
Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfocreatina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Respiração Celular/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Experimental/fisiopatologia , Heme Oxigenase-1/metabolismo , Masculino , Mitocôndrias/efeitos dos fármacos , Fator 2 Relacionado a NF-E2/metabolismo , Células PC12 , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , Aldeído Pirúvico/toxicidade , Ratos , Ratos Sprague-Dawley
11.
Acta cir. bras ; 33(2): 117-124, Feb. 2018. tab, graf
Artigo em Inglês | LILACS | ID: biblio-886260

RESUMO

Abstract Purpose: To observe the efficacy of phosphocreatine pre-administration (PCr-PA) on X-linked inhibitor of apoptosis protein (XIAP), the second mitochondia-derived activator of caspase (Smac) and apoptosis in the ischemic penumbra of rats with focal cerebral ischemia-reperfusion injury (CIRI). Methods: A total of 60 healthy male Sprague Dawley (SD) rats were randomly divided into three groups (n=20): group A (the sham operation group), group B <intraperitoneally injected with 20 mg/kg (10 mg/ml) of saline before preparing the ischemia-reperfusion (IR) model>, and group C <intraperitoneally injected with 20 mg/kg (10 mg/ml) of PCr immediately before preparing the IR model>. After 24 h for reperfusion, the neurological function was evaluated and the tissue was sampled to detect expression of XIAP, Smac and caspase-3 positive cells in the ischemic penumbra so as to observe the apoptosis. Results: Compared with group B, neurological deficit scores, numbers of apoptotic cells, expression of Smac,caspase-9 and the numbers of Caspase-3 positive cells were decreased while expression of XIAP were increased in the ischemic penumbra of group C. Conclusions: Phosphocreatine pre-administration may elicit neuroprotective effects in the brain by increasing expression of X-linked inhibitor of apoptosis protein, reducing expression of second mitochondia-derived activator of caspase, and inhibiting the apoptosis in the ischemic penumbra.


Assuntos
Humanos , Animais , Masculino , Ratos , Fosfocreatina/farmacologia , Cardiotônicos/farmacologia , Traumatismo por Reperfusão/metabolismo , Isquemia Encefálica/metabolismo , Proteínas Mitocondriais/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Inibidoras de Apoptose Ligadas ao Cromossomo X/metabolismo , Distribuição Aleatória , Isquemia Encefálica/prevenção & controle , Ratos Sprague-Dawley , Apoptose/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Proteínas Reguladoras de Apoptose , Caspase 3/metabolismo
12.
Med Mol Morphol ; 51(2): 96-101, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29282541

RESUMO

Inhibiting endoplasmic reticulum stress (ERS)-induced apoptosis may be a new therapeutic target in cardiovascular diseases. Creatine phosphate disodium salt (CP) has been reported to have cardiovascular protective effect, but its effects on ERS are unknown. The aim of this study was to identify the mechanism by which CP exerts its cardioprotection in doxorubicin (Dox)-induced cardiomyocytes injury. In our study, neonatal rats cardiomyocytes (NRC) was randomly divided into control group, model group, and treatment group. The cell viability and apoptosis were detected. grp78, grp94, and calumenin of the each group were monitored. To investigate the role of calumenin, Dox-induced ERS was compared in control and down-regulated calumenin cardiomyocytes. Our results showed that CP decreased Dox-induced apoptosis and relieved ERS. We found calumenin increased in Dox-induced apoptosis with CP. ERS effector C/EBP homologous protein was down-regulated by CP and it was influenced by calumenin. CP could protect NRC by inhibiting ERS, this mechanisms may be associated with its increasing of calumenin.


Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Cardiotoxicidade/prevenção & controle , Doxorrubicina/efeitos adversos , Miócitos Cardíacos/efeitos dos fármacos , Fosfocreatina/farmacologia , Animais , Animais Recém-Nascidos , Apoptose/efeitos dos fármacos , Proteínas de Ligação ao Cálcio/genética , Cardiotônicos/farmacologia , Cardiotoxicidade/etiologia , Células Cultivadas , Estresse do Retículo Endoplasmático/efeitos dos fármacos , Proteínas de Choque Térmico/genética , Miócitos Cardíacos/patologia , Ratos , Fator de Transcrição CHOP/metabolismo
13.
Med Chem ; 14(4): 387-393, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29165089

RESUMO

BACKGROUND: Adenosine triphosphate (ATP) is the energy currency of the body; it takes part in various and indispensable metabolic processes for the maintenance of cell homeostasis, degrading to its hydrolysis product, adenosine diphosphate (ADP). Efficient ways to restore ATP are therefore necessary in the cells. When the cell lacks energy due to ischemic conditions or high ATP demand, phosphocreatine gives its phosphate group to ADP that converts to ATP, in a reaction catalyzed by the enzyme creatine kinase. For this reason, phosphocreatine is utilized as a pharmacological treatment in human diseases that involve a failure of the cellular energy, most notably in coronary artery disease. OBJECTIVE: Commercially available phosphocreatine is currently synthesized using different methods, each of one characterized by a rather low yield of the final product, probably due to the low reactivity of the guanylating reagent. The aim of this work is to overcome the drawbacks of the synthetic methods currently employed, devising a novel synthetic route to obtain phosphocreatine and phosphocreatine prodrugs in higher yields and purity. METHOD: To obtain a higher yield of the final product and a lower number of sub-products, this method utilizes a new guanylating agent characterized by high reactivity, endowed with a protecting group t-Boc on one of the two nitrogen atoms of the guanidinic function and a protected phosphate on the other one; that compound is then conjugated with an opportune secondary amine. The obtained product is cleaved first with acidic conditions to obtain the phosphocreatine prodrug (phosphocreatine ethyl ester) and then with an enzymatic method to obtain the phosphocreatine. RESULT: Have been obtained in good yield and purity as demonstrated by HPLC and mass spectrometry analysis. CONCLUSION: This novel synthetic route permits to obtain the phosphocreatine molecule in higher yield and purity compared to the methods currently employed with a combination of chemical and enzymatic methods.


Assuntos
Fosfocreatina/análogos & derivados , Fosfocreatina/síntese química , Pró-Fármacos/síntese química , Animais , Hidrolases de Éster Carboxílico/metabolismo , Indicadores e Reagentes , Fosfocreatina/farmacologia , Pró-Fármacos/metabolismo , Pró-Fármacos/farmacologia , Suínos
14.
Vascul Pharmacol ; 91: 26-35, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-27590258

RESUMO

Methylglyoxal (MGO), an active metabolite of glucose, can cause cellular injury which has an affinity for the progression of diabetes-associated atherosclerosis. Phosphocreatine (PCr) is a well-known high-energy phosphate compound. However, its protective effects and mechanism in the formation of a diabetes-associated atherosclerosis have not been clarified. In the present study, we investigated whether PCr could prevent MGO-induced apoptosis in human umbilical vascular endothelial cells (HUVECs) and explored the possible mechanisms. Cells were pre-treated with PCr and then stimulated with MGO. Cell morphology, cytotoxicity and apoptosis were assessed by light microscopy, MTT assay, and Annexin V-FITC respectively. Apoptotic-related proteins were evaluated by Western blotting. Reactive oxygen species (ROS) generation, intracellular calcium and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Our results showed that PCr dose-dependently prevented MGO associated HUVEC cytotoxicity and suppressed MGO activated ROS generation as well as apoptotic biochemical changes such as lactate dehydrogenase, malondialdehyde leakage, loss of MMP, decreased Bcl-2/Bax protein ratio, levels of caspase-3 and 9. In addition, the antiapoptotic effect of PCr enhanced p-Akt/Akt protein ratio, NO synthase (eNOS) activation, NO production and cGMP levels and also was partially suppressed by a PI3K inhibitor (LY294002). Furthermore, PCr also inhibited MGO-induced transcriptional activity of Nuclear factor kappa B (NFκB). In conclusion, our data described that PCr exerts an antiapoptotic effect in HUVECs exposed to oxidative stress by MGO through the mitochondrial pathway and the modulation of PI3K/Akt/eNOS and NF-κB signaling pathway. Thus, it might be a candidate therapeutic agent for diabetic-associated cardiovascular diseases.


Assuntos
Antioxidantes/farmacologia , Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , NF-kappa B/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Fosfatidilinositol 3-Quinase/metabolismo , Fosfocreatina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Aldeído Pirúvico/toxicidade , Proteínas Reguladoras de Apoptose/metabolismo , Células Cultivadas , Citoproteção , Relação Dose-Resposta a Droga , Células Endoteliais da Veia Umbilical Humana/enzimologia , Células Endoteliais da Veia Umbilical Humana/patologia , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos
15.
Eur Rev Med Pharmacol Sci ; 20(12): 2726-33, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27383329

RESUMO

OBJECTIVE: Transforming growth factor ß (TGF-ß) plays crucial roles in Ang II-induced cardiac fibrosis (CF). Phosphocreatine (PCr), one of the important players involved in cellular energy metabolism, is widely used in the treatment of clinical heart failure. However, whether it participates in CF is still unclear. This study aimed to identify the mechanisms involved in PCr and CF. MATERIALS AND METHODS: Rat cardiomyocytes (H9C2) were induced by Ang II followed by treatment of PCr. ERK1 siRNA, ERK2 siRNA and NF-κB siRNA were applied to identify the molecular mechanism. Then CF-related proteins were analyzed by western blot and real-time PCR to confirm the influence of the mechanisms involved in PCr. RESULTS: PCr did protect cardiomyocytes from Ang II-induced fibrosis. Meanwhile, PCr suppressed Ang II-induced up-regulation of TGF-ß. By detecting TGFß-mediated or MAPK pathway associated proteins, PCr inhibited MAPK and NF-κB pathway, thus suppressed Ang II-induced cardiac fibrosis, which was further confirmed by siRNA transfection. CONCLUSIONS: Our study determined that PCr protected cardiomyocytes from Ang II-induced CF through inhibition of MAPK and NF-κB pathway.


Assuntos
Angiotensina II/farmacologia , Miócitos Cardíacos/metabolismo , NF-kappa B/metabolismo , Fosfocreatina/farmacologia , Animais , Sistema de Sinalização das MAP Quinases , Fosfocreatina/metabolismo , RNA Interferente Pequeno , Ratos , Fator de Transcrição RelA/metabolismo
16.
Zhongguo Ying Yong Sheng Li Xue Za Zhi ; 32(6): 514-518, 2016 Jun 08.
Artigo em Chinês | MEDLINE | ID: mdl-29926618

RESUMO

OBJECTIVE: To investigate the effect of creatine phosphate sodium (sodium phosphocreatine) on miRNA378, miRNA378* and calumenin mRNA in adriamycin-injured suckling mouse myocardium. METHODS: The suckling mouse myocardium of primary culture were randomly divided into control group, adriamycin group and treatment group. To identify the suckling mouse myocardium, Smooth muscle actin-α (α-SMA) was monitored by immunohistochemical method. Cardiac function was evaluated by transthoracic echocardiography. The mRNA change of miRNA378, miRNA378* and calumenin mRNA were detected by quantitative real-time PCR. The expression of calumenin and GRP78 were identified by western blot. RESULTS: Mitochondrial damage and vacuolization were found in adriamycin-induced suckling mouse myocardium compared with control group, while creatine phosphate sodium could reduce this phenomenon. Compared with the control group, the mRNA of miRNA378, miRNA378* and calumenin in adriamycin group was reduced, while creatine phosphate sodium could increase this phenomenon. The expression of calumenin and GRP78 were decreased after adriamycin treatment in suckling mouse myocardiums, creatine phosphate sodium increased the expression of calumenin and GRP78. CONCLUSIONS: The results of this experiment might be closely related to the effects of that creatine phosphate sodium reduced the pathological mechanism of suckling mouse myocardium with myocarditis caused by adriamycin.


Assuntos
Proteínas de Ligação ao Cálcio/genética , Doxorrubicina/efeitos adversos , MicroRNAs/genética , Miócitos Cardíacos/efeitos dos fármacos , Fosfocreatina/farmacologia , Actinas/metabolismo , Animais , Células Cultivadas , Estresse do Retículo Endoplasmático , Camundongos , Miocárdio/patologia , Cultura Primária de Células , RNA Mensageiro/genética
17.
Apoptosis ; 21(3): 283-97, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26708229

RESUMO

Phosphocreatine (PCr) is an exogenous energy substance, which provides phosphate groups for adenosine triphosphate (ATP) cycle and promotes energy metabolism in cells. However, it is still unclear whether PCr has influenced on mitochondrial energy metabolism as well as oxidative phosphorylation (OXPHO) in previous studies. Therefore, the aim of the present study was to investigate the regulation of PCr on lipopolsaccharide (LPS)-induced human umbilical vein endothelial cells (HUVECs) and mitochondrial OXPHO pathway. PCr protected HUVECs against LPS-induced apoptosis by suppressing the mitochondrial permeability transition, cytosolic release of cytochrome c (Cyt C), Ca(2+), reactive oxygen species and subsequent activation of caspases, and increasing Bcl2 expression, while suppressing Bax expression. More importantly, PCr significantly improved mitochondrial swelling and membrane potential, enhanced the activities of ATP synthase and mitochondrial creatine kinase (CKmt) in creatine shuttle, influenced on respiratory chain enzymes, respiratory control ratio, phosphorus/oxygen ratio and ATP production of OXPHO. Above PCr-mediated mitochondrial events were effectively more favorable to reduced form of flavin adenine dinucleotide (FADH2) pathway than reduced form of nicotinamide-adenine dinucleotid pathway in the mitochondrial respiratory chain. Our results revealed that PCr protects against LPS-induced HUVECs apoptosis, which probably related to stabilization of intracellular energy metabolism, especially for FADH2 pathway in mitochondrial respiratory chain, ATP synthase and CKmt. Our findings suggest that PCr may play a certain role in the treatment of atherosclerosis via protecting endothelial cell function.


Assuntos
Apoptose/efeitos dos fármacos , Citoproteção , Endotélio Vascular/efeitos dos fármacos , Mitocôndrias/fisiologia , Dilatação Mitocondrial/efeitos dos fármacos , Fosforilação Oxidativa/efeitos dos fármacos , Fosfocreatina/farmacologia , Trifosfato de Adenosina/metabolismo , Aterosclerose/tratamento farmacológico , Caspases/metabolismo , Creatina Quinase Mitocondrial/metabolismo , Citocromos c/metabolismo , Endotélio Vascular/fisiologia , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/fisiologia , Humanos , Lipopolissacarídeos/farmacologia , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/enzimologia , Fosfocreatina/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Proteína X Associada a bcl-2/metabolismo
18.
Apoptosis ; 20(12): 1563-76, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26404526

RESUMO

Endothelial apoptosis triggered by oxidized low-density lipoprotein (oxLDL) can accelerate the progression of endothelial dysfunction atherosclerosis. Phosphocreatine (PCr) is a natural compound, which has been used in cardiac disease and cardiopulmonary resuscitation. However, its protective effects on atherosclerosis and its mechanism have not been clarified. In the present study, we investigated the anti-apoptotic effect of phosphocreatine in human umbilical vein endothelial cells (HUVECs) exposed to oxLDL and explored the possible mechanisms. HUVECs were pre-treated with 10-30 mM PCr and then stimulated with oxLDL. Cell morphology, cytotoxicity and apoptosis were evaluated by light microscopy, CCK assay, and flow cytometry respectively. Levels of Bax, Bcl-2, protein expression of protein kinase B (Akt), eNOS and caspase activities were assessed by Western blotting. Reactive oxygen species (ROS) and mitochondrial membrane potential (MMP) were measured with fluorescent probes. Lactate dehydrogenase (LDH), malondialdehyde (MDA), nitric oxide (NO) and superoxide dismutase (SOD) contents were determined by spectrophotometer. Our results showed that PCr dose-dependently prevented oxLDL associated HUVEC cytotoxicity and apoptotic biochemical changes such as loss of MMP, LDH and MDA leakage and loss of SOD, decrease of Bcl-2/Bax protein ratio, activation of caspase-3 and 9, and ROS generation. In addition, the antiapoptotic effect of PCr was partially inhibited by a PI3K inhibitor (LY294002) and also enhanced p-Akt/Akt protein ratio, eNOS activation and NO production. In conclusion, our data show that the inhibition of oxLDL-induced endothelial apoptosis by PCr is due, at least in part to its anti-oxidant activity and its ability to modulate the PI3K/Akt/eNOS signaling pathway.


Assuntos
Apoptose/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Lipoproteínas LDL/metabolismo , Óxido Nítrico Sintase Tipo III/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Fosfocreatina/farmacologia , Proteínas Proto-Oncogênicas c-akt/metabolismo , Antioxidantes/metabolismo , Caspase 3/metabolismo , Caspase 9/metabolismo , Linhagem Celular , Cromonas/farmacologia , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Morfolinas/farmacologia , Óxido Nítrico/metabolismo , Substâncias Protetoras/farmacologia , Proteínas Proto-Oncogênicas c-akt/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Transdução de Sinais/efeitos dos fármacos , Superóxido Dismutase/metabolismo , Proteína X Associada a bcl-2/metabolismo
19.
Bull Exp Biol Med ; 158(3): 313-4, 2015 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25573357

RESUMO

We studied the effect of phosphocreatine and ethylmethylhydroxypyridine succinate on the expression of Bax and Bcl-2 proteins in left-ventricular cardiomyocytes of spontaneously hypertensive rats (SHR). Both drugs have no effect on the expression of Bcl-2, but significantly reduce the level of Bax protein (phosphocreatine produces more pronounced effect). These data attest to an important role of energy deficit and oxidative stress in the induction of cardiomyocyte apoptosis in genetically determined arterial hypertension.


Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Ventrículos do Coração/efeitos dos fármacos , Hipertensão/metabolismo , Fosfocreatina/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/genética , Piridinas/farmacologia , Proteína X Associada a bcl-2/genética , Animais , Apoptose/efeitos dos fármacos , Masculino , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Picolinas/farmacologia , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Endogâmicos SHR , Proteína X Associada a bcl-2/metabolismo
20.
ASN Neuro ; 6(6)2014.
Artigo em Inglês | MEDLINE | ID: mdl-25424428

RESUMO

Creatine is the substrate for creatine kinase in the synthesis of phosphocreatine (PCr). This energetic system is endowed of antioxidant and neuroprotective properties and plays a pivotal role in brain energy homeostasis. The purpose of this study was to investigate the neuroprotective effect of creatine and PCr against 6-hydroxydopamine (6-OHDA)-induced mitochondrial dysfunction and cell death in rat striatal slices, used as an in vitro Parkinson's model. The possible involvement of the signaling pathway mediated by phosphatidylinositol-3 kinase (PI3K), protein kinase B (Akt), and glycogen synthase kinase-3ß (GSK3ß) was also evaluated. Exposure of striatal slices to 6-OHDA caused a significant disruption of the cellular homeostasis measured as 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide reduction, lactate dehydrogenase release, and tyrosine hydroxylase levels. 6-OHDA exposure increased the levels of reactive oxygen species and thiobarbituric acid reactive substances production and decreased mitochondrial membrane potential in rat striatal slices. Furthermore, 6-OHDA decreased the phosphorylation of Akt (Serine(473)) and GSK3ß (Serine(9)). Coincubation with 6-OHDA and creatine or PCr reduced the effects of 6-OHDA toxicity. The protective effect afforded by creatine or PCr against 6-OHDA-induced toxicity was reversed by the PI3K inhibitor LY294002. In conclusion, creatine and PCr minimize oxidative stress in striatum to afford neuroprotection of dopaminergic neurons.


Assuntos
Corpo Estriado/efeitos dos fármacos , Creatina/farmacologia , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo/efeitos dos fármacos , Fosfocreatina/farmacologia , Adrenérgicos/farmacologia , Animais , Morte Celular/efeitos dos fármacos , Cromonas/farmacologia , Inibidores Enzimáticos/farmacologia , Quinase 3 da Glicogênio Sintase/metabolismo , Glicogênio Sintase Quinase 3 beta , Técnicas In Vitro , L-Lactato Desidrogenase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Morfolinas/farmacologia , Oxidopamina/farmacologia , Fosfatidilinositol 3-Quinase , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Ratos Sprague-Dawley
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