RESUMEN
Benzodiazepines are highly effective in combating anxiety; however, they have considerable adverse effects, so it is important to discover new safe anxiolytic agents. This study was designed to investigate the effect of the natural product 2-hydroxy-3,4,6-trimethoxyacetophenone (HTMCX) on anxiety and seizure behavior in adult zebrafish and its possible mechanisms of action. The acute toxicity of 96 h of HTMCX was analyzed, and the open and light/dark field tests (n = 6 animals/group) were used to assess the anxiety behavior of animals treated with HTMCX. In addition, the mechanisms of action were investigated with antagonists of the GABAA, 5-HT receptors, and molecular anchorage study. Pentylenetetrazole (PTZ) was used to induce seizure by immersion. As a result, acetophenone HTMCX (1, 3 and 10 mg/kg; v.o.) was non-toxic and affected locomotor activity. The higher doses (3 and 10 mg/kg; v.o.) produced signs of anxiolytic action in the light/dark test, and this effect was reversed by the pizotifen (antagonist 5HTR1 and 5HTR2A/2C), having the potential to form a complex with 5HTR1B. However, the anxiolytic effect of HTMCX has not been abolished by flumazenil (antagonist GABAA), cyproheptadine (antagonist 5HTR2A), and granisetron (antagonist 5HTR3A/3B). Therefore, HTMCX demonstrated an anxiolytic effect, suggesting that the 5HTR1 and 5HTR2C receptors may be involved in the pharmacological performance of this acetophenone in the central nervous system.
Asunto(s)
Acetofenonas/uso terapéutico , Ansiolíticos/uso terapéutico , Ansiedad/tratamiento farmacológico , Productos Biológicos/uso terapéutico , Croton , Neurotransmisores/uso terapéutico , Acetofenonas/farmacología , Acetofenonas/toxicidad , Animales , Ansiolíticos/farmacología , Ansiolíticos/toxicidad , Ansiedad/metabolismo , Productos Biológicos/farmacología , Productos Biológicos/toxicidad , Femenino , Masculino , Simulación del Acoplamiento Molecular , Neurotransmisores/farmacología , Neurotransmisores/toxicidad , Pentilenotetrazol , Receptores de Serotonina/metabolismo , Convulsiones/inducido químicamente , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Serotonina/metabolismo , Pez CebraRESUMEN
We investigated whether hypertension induced by maternal lipopolysaccharide (LPS) administration during gestation is linked to peripheral vascular and renal hemodynamic regulation, through angiotensin IIâ¯ââ¯NADPH-oxidase signalling, and whether these changes are directly linked to intrauterine oxidative stress. Female Wistar rats were submitted to LPS, in the absence or presence of α-tocopherol during pregnancy. Malondialdehyde in placenta and in livers from dams and foetuses was enhanced by LPS. Tail-cuff systolic blood pressure (tcSBP) was elevated in the 16-week-old LPS offspring. Renal malondialdeyde and protein expression of NADPH oxidase isoform 2 were elevated in these animals at 20â¯weeks of age. Maternal α-tocopherol treatment prevented the elevation in malondialdehyde induced by LPS on placenta and livers from dams and foetuses, as well as prevented the elevation in tcSBP and the elevation in renal malondialdehyde in adult life. LPS offspring presented impairment of endothelium-dependent relaxation in aorta and mesenteric rings, which was blunted by angiotensin type 1 receptor (AT1R) blockade and NADPH oxidase inhibition. At age of 32â¯weeks, renal hemodynamic parameters were unchanged in anaesthetised LPS offspring, but angiotensin II infusion led to an increased glomerular filtration rate paralleled by filtration fraction elevation. The renal haemodynamic changes provoked by angiotensin II was prevented by early treatment with α-tocopherol and by late treatment with NADPH oxidase inhibitor. These results point to oxidative stress as a mediator of offspring hypertension programmed by maternal inflammation and to the angiotensin IIâ¯ââ¯NADPH oxidase signalling pathway as accountable for vascular and renal dysfunctions that starts and maintains hypertension.
Asunto(s)
Antioxidantes/uso terapéutico , Hemodinámica/efectos de los fármacos , Hipertensión/prevención & control , Lipopolisacáridos/metabolismo , Estrés Oxidativo/efectos de los fármacos , Complicaciones Cardiovasculares del Embarazo/prevención & control , alfa-Tocoferol/uso terapéutico , Acetofenonas/uso terapéutico , Angiotensina II/metabolismo , Animales , Presión Sanguínea/efectos de los fármacos , Femenino , Hipertensión/metabolismo , Riñón/irrigación sanguínea , Riñón/efectos de los fármacos , Riñón/metabolismo , Riñón/fisiopatología , Malondialdehído/metabolismo , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/metabolismo , Embarazo , Complicaciones Cardiovasculares del Embarazo/metabolismo , Ratas WistarRESUMEN
Ventricular arrhythmias are a common cause of sudden cardiac death, and their occurrence is higher in obese subjects. Abnormal gating of ryanodine receptors (RyR2), the calcium release channels of the sarcoplasmic reticulum, can produce ventricular arrhythmias. Since obesity promotes oxidative stress and RyR2 are redox-sensitive channels, we investigated whether the RyR2 activity was altered in obese mice. Mice fed a high fat diet (HFD) became obese after eight weeks and exhibited a significant increase in the occurrence of ventricular arrhythmias. Single RyR2 channels isolated from the hearts of obese mice were more active in planar bilayers than those isolated from the hearts of the control mice. At the molecular level, RyR2 channels from HFD-fed mice had substantially fewer free thiol residues, suggesting that redox modifications were responsible for the higher activity. Apocynin, provided in the drinking water, completely prevented the appearance of ventricular arrhythmias in HFD-fed mice, and normalized the activity and content of the free thiol residues of the protein. HFD increased the expression of NOX4, an isoform of NADPH oxidase, in the heart. Our results suggest that HFD increases the activity of RyR2 channels via a redox-dependent mechanism, favoring the appearance of ventricular arrhythmias.
Asunto(s)
Arritmias Cardíacas/etiología , Dieta Alta en Grasa/efectos adversos , Obesidad/complicaciones , Canal Liberador de Calcio Receptor de Rianodina/metabolismo , Disfunción Ventricular/etiología , Acetofenonas/uso terapéutico , Animales , Antiarrítmicos/uso terapéutico , Arritmias Cardíacas/tratamiento farmacológico , Masculino , Ratones , Ratones Endogámicos C57BL , Miocardio/metabolismo , NADPH Oxidasa 4/metabolismo , Obesidad/etiología , Especies Reactivas de Oxígeno/metabolismo , Disfunción Ventricular/tratamiento farmacológicoRESUMEN
Chronic ethanol consumption is a risk factor for cardiovascular diseases. We studied whether NAD(P)H oxidase-derived reactive oxygen species (ROS) play a role in ethanol-induced hypertension, vascular dysfunction, and protein expression in resistance arteries. Male Wistar rats were treated with ethanol (20 % v/v) for 6 weeks. Ethanol treatment increased blood pressure and decreased acetylcholine-induced relaxation in the rat mesenteric arterial bed (MAB). These responses were attenuated by apocynin (30 mg/kg/day; p.o. gavage). Ethanol consumption increased superoxide anion (O2-) generation and decreased nitrate/nitrite (NO x ) concentration in the rat MAB and apocynin prevented these responses. Conversely, ethanol did not affect the concentration of hydrogen peroxide (H2O2) and reduced glutathione (GSH) or the activity of superoxide dismutase (SOD) and catalase (CAT) in the rat MAB. Ethanol increased interleukin (IL)-10 levels in the rat MAB but did not affect the levels of tumor necrosis factor (TNF)-α, IL-6, or IL-1ß. Ethanol increased the expression of Nox2 and the phosphorylation of SAPK/JNK, but reduced eNOS expression in the rat MAB. Apocynin prevented these responses. However, ethanol treatment did not affect the expression of Nox1, Nox4, p38MAPK, ERK1/2, or SAPK/JNK in the rat MAB. Ethanol increased plasma levels of TBARS, TNF-α, IL-6, IL-1ß, and IL-10, whereas it decreased NO x levels. The major finding of our study is that NAD(P)H oxidase-derived ROS play a role on ethanol-induced hypertension and endothelial dysfunction in resistance arteries. Moreover, ethanol consumption affects the expression and phosphorylation of proteins that regulate vascular function and NAD(P)H oxidase-derived ROS play a role in such responses.
Asunto(s)
Modelos Animales de Enfermedad , Endotelio Vascular/metabolismo , Hipertensión/metabolismo , Arterias Mesentéricas/metabolismo , NADPH Oxidasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Acetofenonas/uso terapéutico , Alcoholismo/fisiopatología , Animales , Enfermedades Cardiovasculares/etiología , Enfermedades Cardiovasculares/inmunología , Enfermedades Cardiovasculares/prevención & control , Citocinas/sangre , Endotelio Vascular/efectos de los fármacos , Endotelio Vascular/inmunología , Endotelio Vascular/fisiopatología , Inhibidores Enzimáticos/uso terapéutico , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Hipertensión/etiología , Hipertensión/fisiopatología , Hipertensión/prevención & control , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Masculino , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Arterias Mesentéricas/efectos de los fármacos , Arterias Mesentéricas/inmunología , Arterias Mesentéricas/fisiopatología , NADPH Oxidasa 2 , NADPH Oxidasas/antagonistas & inhibidores , NADPH Oxidasas/genética , Óxido Nítrico Sintasa de Tipo III/genética , Óxido Nítrico Sintasa de Tipo III/metabolismo , Estrés Oxidativo/efectos de los fármacos , Fosforilación/efectos de los fármacos , Distribución Aleatoria , Ratas Wistar , Especies Reactivas de Oxígeno/antagonistas & inhibidores , Resistencia Vascular/efectos de los fármacosRESUMEN
4-Hydroxy-3-methoxy-acetophenone (apocynin) is a naturally occurring methoxy-substitute catechol that is isolated from the roots of Apocynin cannabinum (Canadian hemp) and Picrorhiza kurroa (Scrophulariaceae). It has been previously shown to have antioxidant and neuroprotective properties in several models of neurodegenerative disease, including cerebral ischemia. The present study investigates the effects of apocynin on transient global cerebral ischemia (TGCI)-induced retrograde memory deficits in rats. The protective effects of apocynin on neurodegeneration and the glial response to TGCI are also evaluated. Rats received a single intraperitoneal injection of apocynin (5 mg/kg) 30 min before TGCI and were tested 7, 14, and 21 days later in the eight-arm aversive radial maze (AvRM). After behavioral testing, the hippocampi were removed for histological evaluation. The present results confirm that TGCI causes memory impairment in the AvRM and that apocynin prevents these memory deficits and attenuates hippocampal neuronal death in a sustained way. Apocynin also decreases OX-42 and glial fibrillary acidic protein immunoreactivity induced by TGCI. These findings support the potential role of apocynin in preventing neurodegeneration and cognitive impairments following TGCI in rats. The long-term protective effects of apocynin may involve inhibition of the glial response.
Asunto(s)
Acetofenonas/uso terapéutico , Hipocampo/metabolismo , Ataque Isquémico Transitorio/metabolismo , Trastornos de la Memoria/metabolismo , Neuroglía/metabolismo , Fármacos Neuroprotectores/uso terapéutico , Acetofenonas/farmacología , Animales , Muerte Celular/efectos de los fármacos , Muerte Celular/fisiología , Hipocampo/efectos de los fármacos , Ataque Isquémico Transitorio/tratamiento farmacológico , Ataque Isquémico Transitorio/psicología , Masculino , Trastornos de la Memoria/tratamiento farmacológico , Trastornos de la Memoria/psicología , Neuroglía/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Ratas , Ratas WistarRESUMEN
A monomeric basic PLA2 (PhTX-II) of 14149.08 Da molecular weight was purified to homogeneity from Porthidium hyoprora venom. Amino acid sequence by in tandem mass spectrometry revealed that PhTX-II belongs to Asp49 PLA2 enzyme class and displays conserved domains as the catalytic network, Ca²âº-binding loop and the hydrophobic channel of access to the catalytic site, reflected in the high catalytic activity displayed by the enzyme. Moreover, PhTX-II PLA2 showed an allosteric behavior and its enzymatic activity was dependent on Ca²âº. Examination of PhTX-II PLA2 by CD spectroscopy indicated a high content of alpha-helical structures, similar to the known structure of secreted phospholipase IIA group suggesting a similar folding. PhTX-II PLA2 causes neuromuscular blockade in avian neuromuscular preparations with a significant direct action on skeletal muscle function, as well as, induced local edema and myotoxicity, in mice. The treatment of PhTX-II by BPB resulted in complete loss of their catalytic activity that was accompanied by loss of their edematogenic effect. On the other hand, enzymatic activity of PhTX-II contributes to this neuromuscular blockade and local myotoxicity is dependent not only on enzymatic activity. These results show that PhTX-II is a myotoxic Asp49 PLA2 that contributes with toxic actions caused by P. hyoprora venom.
Asunto(s)
Venenos de Crotálidos/enzimología , Modelos Animales de Enfermedad , Fosfolipasas A2 Grupo II/toxicidad , Músculo Esquelético/efectos de los fármacos , Miositis/etiología , Neurotoxinas/toxicidad , Mordeduras de Serpientes/fisiopatología , Acetofenonas/uso terapéutico , Secuencia de Aminoácidos , Animales , Quelantes del Calcio/farmacología , Dominio Catalítico , Pollos , Secuencia Conservada , Venenos de Crotálidos/antagonistas & inhibidores , Venenos de Crotálidos/toxicidad , Edema/etiología , Edema/prevención & control , Inhibidores Enzimáticos/farmacología , Inhibidores Enzimáticos/uso terapéutico , Fosfolipasas A2 Grupo II/química , Fosfolipasas A2 Grupo II/aislamiento & purificación , Fosfolipasas A2 Grupo II/metabolismo , Técnicas In Vitro , Ratones , Datos de Secuencia Molecular , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Miositis/prevención & control , Neurotoxinas/antagonistas & inhibidores , Neurotoxinas/química , Neurotoxinas/aislamiento & purificación , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Mordeduras de Serpientes/tratamiento farmacológico , Mordeduras de Serpientes/patología , ViperidaeRESUMEN
BACKGROUND: Sepsis- associated encephalopathy (SAE) is an early and common feature of severe infections. Oxidative stress is one of the mechanisms associated with the pathophysiology of SAE. The goal of this study was to investigate the involvement of NADPH oxidase in neuroinflammation and in the long-term cognitive impairment of sepsis survivors. METHODS: Sepsis was induced in WT and gp91(phox) knockout mice (gp91(phox-/-)) by cecal ligation and puncture (CLP) to induce fecal peritonitis. We measured oxidative stress, Nox2 and Nox4 gene expression and neuroinflammation in the hippocampus at six hours, twenty-four hours and five days post-sepsis. Mice were also treated with apocynin, a NADPH oxidase inhibitor. Behavioral outcomes were evaluated 15 days after sepsis with the inhibitory avoidance test and the Morris water maze in control and apocynin-treated WT mice. RESULTS: Acute oxidative damage to the hippocampus was identified by increased 4-HNE expression in parallel with an increase in Nox2 gene expression after sepsis. Pharmacological inhibition of Nox2 with apocynin completely inhibited hippocampal oxidative stress in septic animals. Pharmacologic inhibition or the absence of Nox2 in gp91(phox-/-) mice prevented glial cell activation, one of the central mechanisms associated with SAE. Finally, treatment with apocynin and inhibition of hippocampal oxidative stress in the acute phase of sepsis prevented the development of long-term cognitive impairment. CONCLUSIONS: Our results demonstrate that Nox2 is the main source of reactive oxygen species (ROS) involved in the oxidative damage to the hippocampus in SAE and that Nox2-derived ROS are determining factors for cognitive impairments after sepsis. These findings highlight the importance of Nox2-derived ROS as a central mechanism in the development of neuroinflammation associated with SAE.
Asunto(s)
Proteínas Bacterianas/metabolismo , Trastornos del Conocimiento/etiología , NADH NADPH Oxidorreductasas/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Sepsis/complicaciones , Acetofenonas/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/uso terapéutico , Reacción de Prevención/efectos de los fármacos , Quimiocina CCL2/metabolismo , Modelos Animales de Enfermedad , Hipocampo/metabolismo , Hipocampo/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , NADPH Oxidasas/metabolismo , Receptores Inmunológicos/deficiencia , Sepsis/tratamiento farmacológico , Sepsis/patología , Tiflitis/complicaciones , Tiflitis/etiologíaRESUMEN
In this study, the antioxidant and antidepressant-like effects of α-(phenylselanyl) acetophenone (PSAP), an organoselenium compound, were investigated. To assess the in vitro antioxidant properties, PSAP was evaluated in four test systems (DPPH, ABTS, FRAP and inhibition of lipid peroxidation). PSAP (100-500 µM) showed potent antioxidant activity and protected against lipid peroxidation. Additionally, we investigated whether PSAP, when administered in mice (100, 200 and 400mg/kg, per oral, p.o.), could cause acute toxicity. Our results demonstrated that PSAP did not cause the death of any animal, significantly reduce body weight or cause any oxidative tissue stress following treatment. This study also evaluated the effect of PSAP (0.1-10 mg/kg, p.o) on mice in a forced swim test (FST) and tail suspension test (TST), assays that are predictive of depressant activity and motor activity in the open-field. PSAP (5-10 mg/kg) significantly reduced immobility time in the FST and TST without affecting motor activity. In addition, the antidepressant-like effect caused by PSAP (5m/kg, p.o) in mice during the TST was dependent on an interaction with the serotonergic system (5-HT(1A) receptors), but not with the noradrenergic, dopaminergic or adenosinergic system. Together, these results suggest that PSAP possesses antioxidant and antidepressant-like properties and may be of interest as a therapeutic agent for the treatment of depressive disorders.
Asunto(s)
Acetofenonas/química , Acetofenonas/uso terapéutico , Antidepresivos/química , Antidepresivos/uso terapéutico , Antioxidantes/química , Antioxidantes/farmacología , Compuestos de Organoselenio/química , Compuestos de Organoselenio/uso terapéutico , Acetofenonas/administración & dosificación , Animales , Antidepresivos/administración & dosificación , Antioxidantes/uso terapéutico , Depresión/tratamiento farmacológico , Depresión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/fisiología , Masculino , Ratones , Compuestos de Organoselenio/administración & dosificación , Distribución Aleatoria , Resultado del TratamientoRESUMEN
In pathological conditions, such as hypertension, there is impairment in the autonomic control of blood pressure resulting in changes in baroreflex sensitivity. In the present study we tested the hypothesis that acute superoxide scavenging would restore the depressed baroreflex sensitivity (BRS) in spontaneously hypertensive rats (SHR). Male 10-week-old SHR (n = 14) and their controls (Wistar-Kyoto (WKY) rats; n = 14) underwent femoral artery and vein catheterization for conscious blood pressure recording and drug administration. The BRS was obtained by the drug-induced method using phenylephrine (8 µg/kg, i.v.) and sodium nitroprusside (25 µg/kg, i.v.) before and after the administration of tiron (30 mg/kg, i.v.), a superoxide dismutase mimetic, or apocynin (30 µg/kg), an NADPH oxidase inhibitor. Spontaneously hypertensive rats was significantly hypertensive compared with WKY rats (160 ± 7 vs 105 ± 2 mmHg, respectively). However, there was no significant difference in heart rate between the two groups (388 ± 10 vs 370 ± 20 b.p.m.). In addition, SHR exhibited a diminished BRS compared with WKY rats (-1.34 ± 0.11 vs -2.91 ± 0.20 b.p.m./mmHg, respectively). Administration of tiron improved BRS in SHR (from -1.34 ± 0.11 to 2.26 ± 0.21 b.p.m./mmHg), as did apocynin (to -2.14 ± 0.23 b.p.m./mmHg). Serum samples from SHR (n = 20) and WKY rats (n = 20) were collected for thiobarbituric acid-reactive substances assays before and after tiron or apocynin to confirm the reduction in oxidative stress. There was considerably greater oxidative stress in SHR compared with WKY rats (36.2 ± 3.0 vs 13.3 ± 2.6 nmol/L, respectively). Both apocynin and tiron treatment reduced the oxidative stress in SHR (from 36.2 ± 3.0 to 21.5 ± 3.0 nmol/L and from 37.2 ± 3.9 to 21.9 ± 1.6 nmol/L, respectively). The data suggest that acute scavenging of NADPH oxidase-derived superoxide improves baroreflex sensitivity in SHR.
Asunto(s)
Barorreflejo/fisiología , Depuradores de Radicales Libres/metabolismo , Hipertensión/metabolismo , NADPH Oxidasas/metabolismo , Superóxidos/metabolismo , Sal Disódica del Ácido 1,2-Dihidroxibenceno-3,5-Disulfónico/farmacología , Sal Disódica del Ácido 1,2-Dihidroxibenceno-3,5-Disulfónico/uso terapéutico , Acetofenonas/farmacología , Acetofenonas/uso terapéutico , Animales , Barorreflejo/efectos de los fármacos , Hipertensión/tratamiento farmacológico , Hipertensión/enzimología , Masculino , Estrés Oxidativo/fisiología , Ratas , Ratas Endogámicas SHR , Ratas Endogámicas WKYRESUMEN
BACKGROUND: Two-kidney-one-clip (2K-1C) rats develop renovascular hypertension associated with endothelial dysfunction and elevated levels of oxidative stress. The role of oxidative damage is unknown in vascular dysfunction coupled with 2K-1C hypertension. The aims of this study were to evaluate the effects of chronic treatment with a superoxide dismutase (SOD) mimetic (tempol) and an inhibitor of nicotinamide adenine dinucleotide phosphate (NADPH)-dependent oxidase (apocynin) on the development of hypertension, endothelial dysfunction, and oxidative damage in 2K-1C rats. METHODS: 2K-1C rats and sham-operated rats were treated with tempol or apocynin for 40 days, while the corresponding nontreated groups received tap water. Blood pressure (BP), mesenteric arterial reactivity, plasma and mesentery oxidative damage, mesenteric protein expression, and antioxidant activities were compared among the four groups. RESULTS: Chronic treatment with tempol (1 mmol/l) or apocynin (33 microg/kg/day) impaired the development of hypertension in 2K-1C rats and did not change the BP in control animals. The reduction in vasodilatory effect induced by acetylcholine (ACh) in the mesenteric arterial beds (MABs) of 2K-1C rats was restored by tempol and apocynin. Plasma and mesentery levels of malondialdehyde (MDA) were higher in 2K-1C rats, and these levels were significantly reduced by the administration of tempol and apocynin. Mesenteric SOD activity and expression were higher in 2K-1C rats than in the controls, and treatment with tempol resulted in a reduction in SOD activity. CONCLUSIONS: The data suggest that a compromised mechanism of antioxidant defense and an increase in oxidative damage contribute to the development of hypertension and associated vascular dysfunction in 2K-1C rats, and that tempol and apocynin prevent these effects.
Asunto(s)
Acetofenonas/uso terapéutico , Antioxidantes/uso terapéutico , Óxidos N-Cíclicos/uso terapéutico , Hipertensión Renovascular/tratamiento farmacológico , Hipertensión Renovascular/prevención & control , Animales , Presión Sanguínea/efectos de los fármacos , Catalasa/metabolismo , Hipertensión Renovascular/fisiopatología , Masculino , Ratas , Ratas Wistar , Marcadores de Spin , Superóxido Dismutasa/metabolismoRESUMEN
Cis-diamminedichloroplatinum (II) (cisplatin) is an effective chemotherapeutic agent successfully used in the treatment of a wide range of tumors; however, nephrotoxicity has restricted its clinical use. Several studies have shown that reactive oxygen species are involved in cisplatin-induced nephrotoxicity, including hydrogen peroxide, hydroxyl radical and superoxide anion (O(2)(-)). The source of O(2)(-) in cisplatin-induced renal damage has not been established. The aim of this study was to investigate if NADPH oxidase is involved in cisplatin-induced nephrotoxicity using apocynin, a widely used NADPH oxidase inhibitor. Rats were studied 3 days after a single injection of cisplatin (7.5mg/kg, i.p.). Apocynin was given in the drinking water (2g/L) 7 days before and 3 days after cisplatin injection. Apocynin treatment was able to ameliorate the renal histological damage and the increase in blood urea nitrogen, serum creatinine, and urinary excretion of total protein, N-acetyl-beta-d-glucosaminidase and glutathione-S-transferase induced by cisplatin. In addition, the protective effect of apocynin was associated with the amelioration of cisplatin-induced oxidative and nitrosative stress. Our data suggest that O(2)(-) derived from NADPH oxidase triggers some of the side effects due to cisplatin administration.
Asunto(s)
Acetofenonas/uso terapéutico , Antioxidantes/uso terapéutico , Cisplatino/efectos adversos , Enfermedades Renales/prevención & control , Riñón/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Acetofenonas/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Riñón/metabolismo , Riñón/patología , Enfermedades Renales/inducido químicamente , Enfermedades Renales/metabolismo , Enfermedades Renales/patología , Pruebas de Función Renal , Peróxidos Lipídicos/metabolismo , Masculino , Malondialdehído/metabolismo , Ratas , Ratas WistarAsunto(s)
Acetofenonas/farmacología , Antifúngicos/farmacología , Extractos Vegetales/farmacología , Acetofenonas/aislamiento & purificación , Acetofenonas/uso terapéutico , Animales , Antifúngicos/aislamiento & purificación , Antifúngicos/uso terapéutico , Aspergillus/efectos de los fármacos , Aspergillus/metabolismo , Brasil , Candida/efectos de los fármacos , Candida/metabolismo , Epidermophyton/efectos de los fármacos , Epidermophyton/metabolismo , Microsporidios/efectos de los fármacos , Microsporidios/metabolismo , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Hojas de la Planta , Tallos de la Planta , Plantas Medicinales , Trichophyton/efectos de los fármacos , Trichophyton/metabolismoRESUMEN
A new model of active anaphylactic reaction in mice was developed. The edematogenic reaction appeared 5 min after the intraplantar injection of ovalbumin, peaked at 30 min after the antigenic challenge, and decreased thereafter. Using the non-steroidal, anti-inflammatory agents indomethacin and aspirin, we found that cyclooxygenase products do not participate in the reaction. In contrast, vasoactive amines appear to be involved, because meclizine and methysergide reduced the edema. Dexamethasone, BW755C, LY 171883 and WEB 2170 effectively interfered with the edematogenic reaction, which suggests that lipid mediators such as leukotrienes and PAF play a role in the active anaphylactic response.