RESUMEN
Phenytoin is one of the most well-known antiepileptic drugs that cause cognitive impairment which is closely related to cAMP response element-binding protein (CREB) brain-derived neurotrophic factor (BDNF) signaling pathway. Moreover, vascular endothelial growth factor (VEGF), an endothelial growth factor, has a documented role in neurogenesis and neuronal survival and cognitive impairment. Therefore, this study aimed to investigate the influence of powerful antioxidants: α-Toc and CoQ10 alone or combined in the preservation of brain tissues and the maintenance of memory formation in phenytoin-induced cognitive impairment in rats. The following behavioral test novel object recognition and elevated plus maze were assessed after 14 days of treatment. Moreover, VEGF, BDNF, TrkB, and CREB gene expression levels in the hippocampus and prefrontal cortex were estimated using RT-PCR. Both α-Toc and CoQ10 alone or combined with phenytoin showed improvement in behavioral tests compared to phenytoin. Mechanistically, α-Toc and/or CoQ10 decreases the VEGF mRNA expression, while increases BDNF-TrKB-CREB mRNA levels in hippocampus and cortex of phenytoin-treated rats. Collectively, α-Toc and/or CoQ10 alleviated the phenytoin-induced cognitive impairment through suppressing oxidative damage. The underlying molecular mechanism of the treating compounds is related to the VEGF and enhancing BDNF-TrkB-CREB signaling pathway. Our study indicated the usefulness α-Toc or CoQ10 as an adjuvant to antiepileptic drugs with an advantage of preventing cognitive impairment and oxidative stress.
Asunto(s)
Disfunción Cognitiva/metabolismo , Fenitoína/toxicidad , Transducción de Señal/efectos de los fármacos , Ubiquinona/análogos & derivados , Factor A de Crecimiento Endotelial Vascular/metabolismo , alfa-Tocoferol/administración & dosificación , Animales , Antioxidantes/administración & dosificación , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Disfunción Cognitiva/inducido químicamente , Disfunción Cognitiva/tratamiento farmacológico , Proteína de Unión a Elemento de Respuesta al AMP Cíclico/metabolismo , Quimioterapia Combinada , Masculino , Ratas , Ratas Wistar , Receptor trkB/metabolismo , Transducción de Señal/fisiología , Resultado del Tratamiento , Ubiquinona/administración & dosificación , Factor A de Crecimiento Endotelial Vascular/antagonistas & inhibidoresRESUMEN
Current anticonvulsant therapies are principally aimed at suppressing neuronal hyperexcitability to prevent or control the incidence of seizures. However, the role of oxidative stress processes in seizures led to the proposition that antioxidant compounds may be considered as promising candidates for limiting the progression of epilepsy. Accordingly, the aim of this study is to determine if coenzyme Q10 (CoQ10) and alpha-tocopherol (α-Toc) have a neuroprotective effect in rats against the observed oxidative stress and inflammation during seizures induced by pentylenetetrazole (PTZ) in rats, and to study their interactions with the conventional antiseizure drug phenytoin (PHT), either alone or in combination. Overall, the data revealed that α-Toc and CoQ10 supplementation can ameliorate PTZ-induced seizures and recommended that nuclear factor erythroid 2-related factor 2 (NRF2) and silencing information regulator 1 (Sirt1) signaling pathways may exemplify strategic molecular targets for seizure therapies. The results of the present study provide novel mechanistic insights regarding the protective effects of antioxidants and suggest an efficient therapeutic strategy to attenuate seizures. Additionally, concurrent supplementation of CoQ10 and α-Toc may be more effective than either antioxidant alone in decreasing inflammation and oxidative stress in both cortical and hippocampal tissues. Also, CoQ10 and α-Toc effectively reverse the PHT-mediated alterations in the brain antioxidant status when compared to PHT only.
Asunto(s)
Anticonvulsivantes , Antioxidantes , Fármacos Neuroprotectores , Pentilenotetrazol , Fenitoína , Convulsiones , Ubiquinona , alfa-Tocoferol , Animales , Masculino , alfa-Tocoferol/administración & dosificación , Anticonvulsivantes/administración & dosificación , Antioxidantes/administración & dosificación , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Inflamación/inducido químicamente , Inflamación/metabolismo , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Neuronas/patología , Fármacos Neuroprotectores/administración & dosificación , Estrés Oxidativo , Pentilenotetrazol/administración & dosificación , Fenitoína/administración & dosificación , Ratas Wistar , Convulsiones/inducido químicamente , Convulsiones/metabolismo , Convulsiones/prevención & control , Transducción de Señal , Sirtuina 1/metabolismo , Ubiquinona/administración & dosificación , Ubiquinona/análogos & derivados , Factor 2 Relacionado con NF-E2/metabolismoRESUMEN
Estrogenic compounds have been documented in literature to exert neuroprotective effects. This study investigated the potential neuroprotective effect of genistein; a phytoestrogen at doses of 5, 10, 20, and 40 mg/kg p.o. in ovariectomized rats challenged with pentylenetetrazole (PTZ) 90 mg/kg i.p. Systemic acute administration of PTZ induced seizures, increased oxidative stress, and caused apoptosis and histological abnormalities. Pretreatment with genistein delayed seizure onset, reduced the seizure duration, improved oxidative stress profile, decreased estrogen receptor expression, reduced apoptosis, and improved the histopathological pattern. Overall, the genistein doses (10 and 20 mg/kg) showed the strongest protective effects. In conclusion, the current study suggests that genistein exhibits neuroprotective effects against PTZ-induced seizures. Such effects might be attributed to its estrogenic, antioxidant, and/or anti-apoptotic properties.
Asunto(s)
Química Encefálica/efectos de los fármacos , Genisteína/uso terapéutico , Ovariectomía/efectos adversos , Pentilenotetrazol/toxicidad , Convulsiones/tratamiento farmacológico , Convulsiones/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Química Encefálica/fisiología , Relación Dosis-Respuesta a Droga , Femenino , Genisteína/farmacología , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Ovariectomía/tendencias , Fitoestrógenos/farmacología , Fitoestrógenos/uso terapéutico , Ratas , Ratas Wistar , Convulsiones/inducido químicamenteRESUMEN
Benign prostate hyperplasia (BPH) is a common age-related health problem affecting almost 3 out of 4 men in their sixties. Chrysin is a dietary phytoestrogen found naturally in bee propolis and various plant extracts. It possesses antioxidant, anti-inflammatory and anti-proliferative properties. The current study was conducted to explore the role chrysin plays in protection against testosterone-induced BPH in rats. On grounds of a preliminary experiment, a dose of chrysin (50â¯mg/kg) was chosen for further investigation. Testosterone significantly depleted glutathione, suppressed superoxide dismutase and catalase activities, and elevated lipid peroxidation. Moreover, it markedly scaled down the level of cleaved caspase-3 enzyme, reduced Bax/Bcl-2 ratio and mRNA expression of p53 and p21; conversely, protein expression of proliferating cell nuclear antigen was enhanced. Chrysin alleviated testosterone-induced oxidative stress and restored cleaved caspase-3 level, Bax/Bcl-2 ratio and mRNA expression of p53 and p21 to almost control levels. Chrysin prevented the increase in binding activity of nuclear factor kappa B (NF-κB) p65 subunit, mRNA expression of insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 1 receptor (IGF-1R). These data highlight the protective role of chrysin against experimentally-induced BPH. This is attributed - at least partly - to its antioxidant, antiproliferative and proapoptotic properties.
Asunto(s)
Flavonoides/administración & dosificación , Hiperplasia Prostática/tratamiento farmacológico , Testosterona/efectos adversos , Animales , Caspasa 3/genética , Caspasa 3/metabolismo , Glutatión/metabolismo , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , FN-kappa B/genética , FN-kappa B/metabolismo , Antígeno Nuclear de Célula en Proliferación/genética , Antígeno Nuclear de Célula en Proliferación/metabolismo , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/genética , Hiperplasia Prostática/metabolismo , Ratas , Ratas Sprague-Dawley , Receptores de Somatomedina/genética , Receptores de Somatomedina/metabolismo , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismoRESUMEN
Huntington's disease (HD) is a neurodegenerative disorder, characterized by selective atrophy in the striatum, particularly the medium spiny GABAergic efferent neurons. This results in striatal sensorimotor gating deficits. Systemic administration of 3-nitropropionic acid (3-NPA) produces selective lesions mimicking those of HD. Males were found to be more susceptible to 3-NPA-induced neurotoxicity than females, suggesting neuroprotective effects of estrogens. Phytoestrogens, including genistein, are good estrogenic alternatives that keep their beneficial effects on non-reproductive organs and lack the potential hazardous side effects. The current study was designed to investigate the potential beneficial effects of genistein in 3-NPA-induced HD in ovariectomized rats. Results showed that 3-NPA (20 mg/kg) administration caused significant disruption of the rats' locomotor activity and prepulse inhibition. In addition, it decreased striatal ATP levels and increased oxidative stress, inflammatory and apoptotic markers with striatal focal hemorrhage and gliosis. Pretreatment with 17ß-estradiol (2.5 mg/kg) or genistein (20 mg/kg) led to a significant improvement of behavioral parameters, increased ATP production, decreased oxidative stress, attenuated inflammation and apoptosis. Therefore, this study suggests potential neuroprotective effects of genistein in ovariectomized rats challenged with 3-NPA.
Asunto(s)
Cuerpo Estriado/efectos de los fármacos , Genisteína/administración & dosificación , Enfermedad de Huntington/prevención & control , Enfermedad de Huntington/fisiopatología , Fármacos Neuroprotectores/administración & dosificación , Fitoestrógenos/administración & dosificación , Inhibición Prepulso/efectos de los fármacos , Adenosina Trifosfato/metabolismo , Animales , Antioxidantes/metabolismo , Apoptosis/efectos de los fármacos , Cuerpo Estriado/metabolismo , Cuerpo Estriado/patología , Dinoprostona/metabolismo , Modelos Animales de Enfermedad , Estradiol/administración & dosificación , Estrógenos/administración & dosificación , Femenino , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/metabolismo , Mediadores de Inflamación/metabolismo , Locomoción , Nitrocompuestos , Estrés Oxidativo , Propionatos , Ratas , Ratas Sprague-DawleyRESUMEN
Propolis, a honey bee product, has been used in folk medicine for centuries for the treatment of abscesses, canker sores and for wound healing. Caffeic acid phenethyl ester (CAPE) is one of the most extensively investigated active components of propolis which possess many biological activities, including antibacterial, antiviral, antioxidant, anti-inflammatory, and anti-cancer effects. CAPE is a polyphenolic compound characterized by potent antioxidant and cytoprotective activities and protective effects against ischemia-reperfusion (I/R)-induced injury in multiple tissues such as brain, retina, heart, skeletal muscles, testis, ovaries, intestine, colon, and liver. Furthermore, several studies indicated the protective effects of CAPE against chemotherapy-induced adverse drug reactions (ADRs) including several antibiotics (streptomycin, vancomycin, isoniazid, ethambutol) and chemotherapeutic agents (mitomycin, doxorubicin, cisplatin, methotrexate). Due to the broad spectrum of pharmacological activities of CAPE, this review makes a special focus on the recently published data about CAPE antioxidant activity as well as its protective effects against I/R-induced injury and many adverse drug reactions.
Asunto(s)
Antioxidantes , Ácidos Cafeicos/uso terapéutico , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/prevención & control , Alcohol Feniletílico/análogos & derivados , Própolis/química , Daño por Reperfusión/prevención & control , Animales , Antibacterianos/efectos adversos , Antineoplásicos/efectos adversos , Ácidos Cafeicos/química , Humanos , Alcohol Feniletílico/química , Alcohol Feniletílico/uso terapéuticoRESUMEN
Aluminum is the most widely used non-ferrous metal. However, recently it is reported to be a neurotoxic agent that could induce biochemical defects in brain by affecting levels of neurotransmitters and generating reactive oxygen species resulting in oxidative stress. This study aimed at evaluating neuroprotective effect of Ginkgo biloba extract(2) (GBE) (200 mg/kg for 28 days) in antagonizing aluminum-induced neurotoxicity through investigating certain parameters such as serum aluminum level, brain aluminum content, brain regional distribution of aluminum, brain oxidative stress biomarkers' content, and brain acetylcholinesterase(3) (AChE) activity. Passive avoidance paradigm was used to assess memory retrieval of rats. Rats' activities were studied using open field test. Results showed that administration of aluminum (10 mg/kg for 28 days) impaired rats' memory retrieval associated with marked elevation of aluminum brain content, serum aluminum level and AChE activity. In addition, aluminum treatment induced significant elevation in its brain content in all tested regions. GBE treatment attenuated neurotoxic effects of aluminum as evidenced by improving rats' performance in passive avoidance and lowering brain AChE activity. Moreover, marked elevation in brain content of oxidized glutathione(4) (GSSG) and malonedialdehyde(5) (MDA) as well as depletion of reduced glutathione(6) (GSH) demonstrated following aluminum administration were reversed reaching normal levels after GBE treatment. Open field test, demonstrated no changes in latency period, number of ambulation, rearing, and grooming following aluminum or other treatments. Therefore, GBE may be a promising therapy ameliorating neurotoxicity of aluminum as an environmental toxic agent.
Asunto(s)
Aluminio/toxicidad , Trastornos de la Memoria/inducido químicamente , Trastornos de la Memoria/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Fitoterapia/métodos , Extractos Vegetales/uso terapéutico , Acetilcolinesterasa/metabolismo , Aluminio/metabolismo , Animales , Reacción de Prevención/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Modelos Animales de Enfermedad , Conducta Exploratoria/efectos de los fármacos , Masculino , Estrés Oxidativo/efectos de los fármacos , Ratas , Ratas Sprague-Dawley , Tiempo de Reacción/efectos de los fármacos , Estadísticas no ParamétricasRESUMEN
Caffeic acid phenethyl ester (CAPE) is an important active component of honey bee propolis that possesses a plethora of biological activities. Propolis is used safely in traditional medicine as a dietary supplement for its therapeutic benefits. This review highlights the recently published data about CAPE bioavailability, anti-inflammatory, neuroprotective; hepatoprotective and cardioprotective activities. CAPE showed promising efficacy both in vitro and in vivo studies in animal models with minimum adverse effects. Its effectiveness was demonstrated in multiple target organs. Despite this fact, it has not been yet investigated as a protective agent or a potential therapy in humans. Investigation of CAPE efficacy in clinical trials is strongly encouraged to elucidate its therapeutic benefit for different human diseases after performing full preclinical toxicological studies and gaining more insights into its pharmacokinetics.
Asunto(s)
Antiinflamatorios/farmacología , Ácidos Cafeicos/farmacología , Cardiotónicos/farmacología , Fármacos Neuroprotectores/farmacología , Alcohol Feniletílico/análogos & derivados , Animales , Antioxidantes/farmacología , Abejas , Disponibilidad Biológica , Ácidos Cafeicos/metabolismo , Ácidos Cafeicos/farmacocinética , Hígado/efectos de los fármacos , Alcohol Feniletílico/metabolismo , Alcohol Feniletílico/farmacocinética , Alcohol Feniletílico/farmacologíaRESUMEN
The hepatoprotective activity of the ethanol extract of Astragalus kahiricus (Fabaceae) roots against ethanol-induced liver apoptosis was evaluated and it showed very promising hepatoprotective actions through different mechanisms. The extract counteracted the ethanol-induced liver enzymes leakage and glutathione depletion. In addition, it demonstrated anti-apoptotic effects against caspase-3 activation and DNA fragmentation that were confirmed by liver histopathological examination. Moreover, the phytochemical study of this extract led to the isolation of four cycloartane-type triterpenes identified as astrasieversianin II (1), astramembrannin II (2), astrasieversianin XIV (3), and cycloastragenol (4). The structures of these isolates were established by HRESI-MS and 1D and 2D NMR experiments. The antimicrobial, antimalarial, and cytotoxic activities of the isolates were further evaluated, but none of them showed any activity.
Asunto(s)
Apoptosis/efectos de los fármacos , Planta del Astrágalo/química , Enfermedad Hepática Inducida por Sustancias y Drogas/prevención & control , Etanol/toxicidad , Hígado/citología , Extractos Vegetales/administración & dosificación , Sustancias Protectoras/administración & dosificación , Animales , Caspasa 3/metabolismo , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Enfermedad Hepática Inducida por Sustancias y Drogas/genética , Enfermedad Hepática Inducida por Sustancias y Drogas/fisiopatología , Fragmentación del ADN/efectos de los fármacos , Femenino , Humanos , Hígado/efectos de los fármacos , Hígado/enzimología , Raíces de Plantas/química , Ratas , Ratas Sprague-DawleyRESUMEN
Liquorice extract was reported to have nootropic and/or antiamnestic effects. Prepulse inhibition (PPI) of startle response is a multimodal, cross-species phenomenon used as a measure of sensorimotor gating. Previous studies indicated that liquorice/its constituents augmented mouse brain monoamine levels. Increased brain monoamines' transmission was suggested to underlie PPI disruption. However, the effect of antiamnestic dose(s) of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. The effect of administration of the antiamnestic dose of the extract (150 mg/kg for 7 days) was tested on PPI of acoustic startle response in mice. It resulted in PPI disruption and therefore its effect on monoamines' levels was investigated in a number of mouse brain areas involved in PPI response mediation. Results demonstrated that the extract antiamnestic dose augmented cortical, hippocampal and striatal monoamine levels. It was therefore concluded that liquorice extract (150 mg/kg)-induced PPI deficit was mediated through augmenting monoaminergic transmission in the cortex, hippocampus and striatum. These findings can be further investigated in experimental models for autism, psychosis and Huntington's disease to decide the safety of using liquorice extract in ameliorating memory disturbance in disorders manifesting PPI deficit.
Asunto(s)
Amnesia/metabolismo , Amnesia/prevención & control , Monoaminas Biogénicas/metabolismo , Encéfalo/metabolismo , Glycyrrhiza/química , Inhibición Neural/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Animales , Encéfalo/efectos de los fármacos , Masculino , Memoria/efectos de los fármacos , Ratones , Fármacos Neuroprotectores/administración & dosificación , Resultado del TratamientoRESUMEN
Androgen and estrogen play an important role in the pathogenesis of benign prostatic hyperplasia (BPH). Estrogen exerts its action through two distinct estrogen receptors (ERs) either ER-α or ER-ß. The phytoestrogenic property of silymarin (SIL) has been previously characterized. Thus, this study examined the protective effect of SIL against testosterone-induced BPH in rats. In an initial dose-response study, SIL in a dose of 50mg/kg was the most effective in preventing the rise in prostate weight, prostate weight/body weight ratio and histopathologic changes induced by testosterone. Testosterone significantly decreased ER-ß and increased ER-α and AR expressions as compared to the control group and these effects were significantly ameliorated by SIL. Furthermore, SIL significantly protected against testosterone-provoked decline in mRNA expression of P21(WAF1/Cip1) and Bax/Bcl-xl ratio as well as caspase-3 activity. SIL minimized the number of proliferating cell nuclear antigen (PCNA) positive cells as compared to testosterone-treated group. Moreover, SIL significantly blunted the inducible NF-κB expression and restored the oxidative status to within normal values in the prostatic tissues. Collectively these findings elucidate the effectiveness of SIL in preventing testosterone-induced BPH in rats. This could be attributed, at least partly, to its phytoestrogenic, pro-apoptotic and anti-oxidative properties.
Asunto(s)
Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Fitoestrógenos/farmacología , Hiperplasia Prostática/prevención & control , Silimarina/farmacología , Animales , Peso Corporal/efectos de los fármacos , Caspasa 3/metabolismo , Proliferación Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Inmunohistoquímica , Masculino , FN-kappa B/biosíntesis , Tamaño de los Órganos/efectos de los fármacos , Estrés Oxidativo/efectos de los fármacos , Antígeno Nuclear de Célula en Proliferación/biosíntesis , Próstata/patología , Hiperplasia Prostática/inducido químicamente , Hiperplasia Prostática/patología , ARN Mensajero/biosíntesis , ARN Mensajero/genética , Ratas , Ratas Sprague-Dawley , Receptores Androgénicos/biosíntesis , Receptores Androgénicos/efectos de los fármacos , Receptores de Estrógenos/biosíntesis , Receptores de Estrógenos/efectos de los fármacos , Testosterona/farmacologíaRESUMEN
Huntington's disease (HD) is a progressive neurodegenerative disorder with a spectrum of cognitive, behavioral, and motor abnormalities. The mitochondrial toxin 3-nitropropionic acid (3-NP) effectively induces specific behavioral changes, primarily manifested as prepulse inhibition (PPI) deficit of acoustic startle stimuli, and selective striatal lesions in rats and primates mimicking those in HD. The implications of nitric oxide in a variety of neurodegenerative diseases attract attention to study the possible role of flavonoids in interaction with nitric oxide pathways involved in HD. The present study investigates the potential effect of hesperidin, a flavanone group member, on 3-NP-induced behavioral, neurochemical, histopathological and cellular changes. Systemic administration of 3-NP to rats for 5 days (20 mg/kg) caused reduction of locomotor activity by days 2 and 5, 55% deficit of PPI response, elevation of cortical, striatal and hippocampal malondialdehyde (MDA) levels by 63%, 41% and 56%, reduction of respective catalase activity by 50%. Immunohistochemical staining of cortices, striata and hippocampi showed patches of iNOS positive cells. Electron microscopic ultrastructural examination showed marked mitochondrial swelling, perivascular edema and shrunken nerve cells. Pretreatment with hesperidin (100 mg/kg) ahead of 3-NP prevented any changes of locomotor activity or PPI response, slightly increased cortical, striatal and hippocampal MDA levels by 10% and reduced respective catalase activity by 22%, 20% and 5%. Only few iNOS positive cells were detected in sections from rats pretreated with hesperidin which also reduced cellular abnormalities induced by 3-NP. This study suggests a potential neuroprotective role of hesperidin against 3-NP-induced Huntington's disease-like manifestations. Such neuroprotection can be referred to its antioxidant and anti-inflammatory activities.
Asunto(s)
Convulsivantes/toxicidad , Hesperidina/uso terapéutico , Fármacos Neuroprotectores/uso terapéutico , Síndromes de Neurotoxicidad/tratamiento farmacológico , Síndromes de Neurotoxicidad/etiología , Nitrocompuestos/toxicidad , Propionatos/toxicidad , Estimulación Acústica , Análisis de Varianza , Animales , Encéfalo/patología , Encéfalo/ultraestructura , Catalasa/metabolismo , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Inhibición Psicológica , Peroxidación de Lípido/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Síndromes de Neurotoxicidad/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Ratas , Ratas Wistar , Reflejo de Sobresalto/efectos de los fármacos , Factores de TiempoRESUMEN
3-Nitropropionic acid (3-NP), an irreversible inhibitor of succinate dehydrogenase enzyme (SDH), induces neurodegeneration similar to that observed in Huntington's disease (HD). Reduction of prepulse inhibition (PPI) of acoustic startle response, locomotor hypoactivity, bilateral striatal lesions as well as brain oxidative stress are major features of HD. The present study was designed to investigate neuroprotective effect of Ginkgo biloba extract (EGb 761) on 3-NP induced neurobehavioral changes and striatal lesions. Rats administered 3-NP (20mg/kg, s.c.) for five consecutive days exhibited PPI deficits and locomotor hypoactivity whereas, pretreatment of animals with EGb 761 (100mg/kg, i.p. for 15 days) ahead of and during the induction of HD by 3-NP (20mg/kg for 5 days starting at day 8) ameliorated 3-NP-induced neurobehavioral deficits. Administration of 3-NP increased the level of striatal malondialdehyde (MDA). This effect was prevented in animals pre-treated with EGb 761. Changes in the level of apoptotic regulatory gene expressions, following 3-NP treatment, were demonstrated as both an up-regulation and a down-regulation of the expression levels of striatal Bax and Bcl-xl genes, respectively. In addition, an up-regulation of the expression level of striatal glyceraldehyde-3-phosphate dehydrogenase (GAPDH) was also observed. Pre-treatment with EGb 761 caused a down-regulation in striatal GAPDH and Bax together with an up-regulation of striatal Bcl-xl expression level as compared to the 3-NP treated group. Histochemical examination of striatal tissue showed that EGb 761 significantly prevented 3-NP induced inhibition of SDH activity. Histopathological examination further affirmed the neuroprotective effect of EGb 761 against 3-NP toxicity. Taken together, these results suggest that EGb 761 has a neuroprotective role in the current HD paradigm, which may be related to improvement of energy metabolism, antioxidant properties and antiapoptotic effects.
Asunto(s)
Antioxidantes/uso terapéutico , Enfermedad de Huntington/tratamiento farmacológico , Fármacos Neuroprotectores/uso terapéutico , Neurotoxinas/antagonistas & inhibidores , Neurotoxinas/toxicidad , Nitrocompuestos/antagonistas & inhibidores , Nitrocompuestos/toxicidad , Extractos Vegetales/uso terapéutico , Propionatos/antagonistas & inhibidores , Propionatos/toxicidad , Animales , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Regulación hacia Abajo/fisiología , Ginkgo biloba/química , Enfermedad de Huntington/inducido químicamente , Enfermedad de Huntington/fisiopatología , Masculino , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Ratas , Ratas Wistar , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/fisiologíaRESUMEN
OBJECTIVES: Rubus sanctus Schreb., known from the Bible as 'holy thorn bush', grows wild in Egypt. Rubus sanctus aqueous alcoholic extract (RE) contains a complicated phenolic mixture (ellagitanins, flavonoids and caffeic acid derivatives). In this study, the phytochemical investigation of the plant was re-evaluated. Herein, we report on the isolation and identification of three galloylated flavonoids, namely kaempferol-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside, quercetin-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside and myricetin-3-O-(6''-O-galloyl)-(4)C(1)-beta-d-galactopyranoside for the first time from the Rubus genus. We further aimed at evaluating the potential protective effects of RE against carbon tetrachloride (CCl(4))-induced toxicity in isolated rat hepatocytes. METHODS: Based on an initial concentration-response experiment, a concentration of 100 mug/ml was selected to investigate the hepatoprotective activity of RE. KEY FINDINGS: Pretreatment with RE afforded protection as indicated by counteracting CCl(4)-induced cell death, and reduced glutathione depletion. In addition, RE ameliorated CCl(4)-induced enzyme leakage by 40% for lactate dehydrogenase, 30% for alanine aminotransferase and 20% for aspartate aminotransferase as compared with CCl(4)-treated cells. Moreover, RE counteracted CCl(4)-induced lipid peroxidation and inhibited spontaneous lipid peroxidation in the control group. CONCLUSIONS: In conclusion, RE protects against CCl(4)-induced toxicity in isolated rat hepatocytes.
Asunto(s)
Intoxicación por Tetracloruro de Carbono/prevención & control , Enfermedad Hepática Inducida por Sustancias y Drogas/tratamiento farmacológico , Flavonoides/uso terapéutico , Hepatocitos/efectos de los fármacos , Fitoterapia , Extractos Vegetales/uso terapéutico , Rosaceae/química , Alanina Transaminasa/metabolismo , Animales , Aspartato Aminotransferasas/metabolismo , Tetracloruro de Carbono/toxicidad , Intoxicación por Tetracloruro de Carbono/metabolismo , Muerte Celular/efectos de los fármacos , Enfermedad Hepática Inducida por Sustancias y Drogas/metabolismo , Flavonoides/aislamiento & purificación , Flavonoides/farmacología , Glutatión/metabolismo , Hepatocitos/metabolismo , L-Lactato Deshidrogenasa/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/farmacología , Ratas , Ratas Sprague-DawleyRESUMEN
Prepulse inhibition (PPI) of acoustic startle response is a valuable paradigm for sensorimotor gating processes. Previous research showed that acute administration of St. John's wort extract (500 mg/kg, p.o.) to rats caused significant disruption of PPI while elevating monoamines levels in some brain areas. The cause-effect relationship between extract-induced PPI disruption and augmented monoaminergic transmission was studied using different serotoninergic, adrenergic and dopaminergic antagonists. The effects of hypericin and hyperforin, as the main active constituents of the extract, on PPI response were also tested. PPI disruption was prevented after blocking the serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors. Results also demonstrated a significant PPI deficit after acute treatment of rats with hyperforin, and not hypericin. In some conditions manifesting disrupted PPI response, apoptosis coexists. Electrophoresis of DNA isolated from brains of hyperforin-treated animals revealed absence of any abnormal DNA fragmentation patterns. It is concluded that serotoninergic 5-HT1A and 5-HT2A, alpha-adrenergic and dopaminergic D1 receptors are involved in the disruptive effect of St. John's wort extract on PPI response in rats. We can also conclude that hyperforin, and not hypericin, is one of the active ingredients responsible for St. John's wort-induced PPI disruption with no relation to apoptotic processes.
Asunto(s)
Medicamentos Herbarios Chinos/efectos adversos , Hypericum/toxicidad , Inhibición Psicológica , Perileno/análogos & derivados , Floroglucinol/análogos & derivados , Receptores Adrenérgicos alfa/efectos de los fármacos , Receptores de Dopamina D1/antagonistas & inhibidores , Antagonistas del Receptor de Serotonina 5-HT1 , Antagonistas del Receptor de Serotonina 5-HT2 , Terpenos/farmacología , Animales , Antracenos , Apoptosis/efectos de los fármacos , Compuestos Bicíclicos con Puentes/farmacología , Fragmentación del ADN/efectos de los fármacos , Masculino , Ratones , Perileno/farmacología , Floroglucinol/farmacología , Ratas , Ratas Wistar , Reflejo Acústico/efectos de los fármacos , Reflejo de Sobresalto/efectos de los fármacosRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: St. John's wort extract is commonly used as a wound healing, anti-inflammatory, anxiolytic, diuretic, antibiotic, antiviral and cancer chemoprotective agent. It also has nootropic and/or antiamnestic effects. AIM OF THE STUDY: Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes. A previous study indicated that single administration of St. John's wort extract (500 mg/kg) caused PPI disruption in rats. The effect of antiamnestic doses of the extract on PPI has not been investigated despite the coexistence of impaired memory and PPI deficit in some neurological disorders. MATERIALS AND METHODS: The effects of acute (500 mg/kg) and chronic (200mg/kg for 3 days) administration of St. John's wort extract were investigated for its antiamnestic activity. The effects of administration of the antiamnestic dose of the extract and hyperforin, its main active component, were tested on PPI of an acoustic startle response in rats. This study also investigated the proapoptotic effect of hyperforin in animals, demonstrating PPI deficit, by electrophoresis of DNA isolated from selected brain areas. RESULTS: Disruption of PPI resulted after treatment of rats with an antiamnestic dose of the extract (200mg/kg for 3 days) and with hyperforin. Gel electrophoresis showed DNA fragmentation of the cortices of hyperforin-treated animals exhibiting PPI deficit. CONCLUSIONS: The exacerbating effect of St. John's wort extract on PPI deficit may provide a limitation for using the extract to manage cognitive disturbance in psychotic and Huntington's disease patients manifesting PPI deficit.
Asunto(s)
Amnesia/prevención & control , Apoptosis/efectos de los fármacos , Corteza Cerebral/efectos de los fármacos , Hypericum , Extractos Vegetales/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Filtrado Sensorial/efectos de los fármacos , Amnesia/inducido químicamente , Animales , Compuestos Bicíclicos con Puentes/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Corteza Cerebral/citología , Antagonistas Colinérgicos , Fragmentación del ADN/efectos de los fármacos , Masculino , Floroglucinol/análogos & derivados , Floroglucinol/farmacología , Fitoterapia , Componentes Aéreos de las Plantas , Ratas , Ratas Wistar , Escopolamina , Terpenos/farmacologíaRESUMEN
Prepulse inhibition (PPI) of startle response is a valuable paradigm for sensorimotor gating processes by which an organism filters sensory information. Disruption of PPI is evident in schizophrenia and Huntington's disease among other neuropsychiatric disorders characterized by sensorimotor gating deficit. In such disorders, increased brain monoamines' transmission was suggested to underlie PPI disruption. The effect of St. John's wort extract on PPI of startle response is yet to be investigated despite research findings indicating augmented levels of brain monoaminergic function after acute administration of the extract. In this study, the effect of acute oral administration of St. John's wort extract (62.5, 125, 250 and 500 mg/kg) was tested on PPI of an acoustic startle response in rats. A disruption of PPI resulted after the administration of the highest dose of the extract and therefore its effect on dopaminergic, serotonergic and noradrenergic neurotransmission was investigated in a number of rat brain areas involved in mediation of PPI response. Results demonstrated that 500 mg/kg of the extract augmented dopaminergic transmission in the thalamus together with elevating noradrenergic transmission in both brainstem and hippocampus. In addition, increased serotonin levels in brainstem, thalamus, cortex and hippocampus were evident after administration of the same dose of the extract. It was therefore concluded that St. John's wort extract (500 mg/kg) reduced PPI response possibly through enhancing monoaminergic transmission in brainstem, thalamus, cortex and/or hippocampus. Clinical investigations are therefore needed to determine whether St. John's wort extract may affect sensorimotor gating in both schizophrenia and Huntington's disease.
Asunto(s)
Monoaminas Biogénicas/fisiología , Hypericum/química , Inhibición Neural/efectos de los fármacos , Extractos Vegetales/farmacología , Reflejo de Sobresalto/efectos de los fármacos , Estimulación Acústica/métodos , Administración Oral , Análisis de Varianza , Animales , Monoaminas Biogénicas/análisis , Tronco Encefálico/química , Tronco Encefálico/efectos de los fármacos , Corteza Cerebral/química , Corteza Cerebral/efectos de los fármacos , Cuerpo Estriado/química , Cuerpo Estriado/efectos de los fármacos , Dopamina/análisis , Relación Dosis-Respuesta a Droga , Fluorometría/métodos , Hipocampo/química , Hipocampo/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Inhibición Neural/fisiología , Plasticidad Neuronal/efectos de los fármacos , Plasticidad Neuronal/fisiología , Norepinefrina/análisis , Extractos Vegetales/química , Extractos Vegetales/aislamiento & purificación , Ratas , Ratas Wistar , Reflejo de Sobresalto/fisiología , Serotonina/análisis , Tálamo/química , Tálamo/efectos de los fármacosRESUMEN
Jojoba [Simmondsia chinensis (Link 1822) Schneider 1907] is an arid perennial shrub grown in several American and African countries. Jojoba seeds, which are rich in liquid wax, were used in folk medicine for diverse ailments. In the current study, the potential anti-inflammatory activity of jojoba liquid wax (JLW) was evaluated in a number of experimental models. Results showed that JLW caused reduction of carrageenin-induced rat paw oedema in addition to diminishing prostaglandin E2 (PGE2) level in the inflammatory exudates. In a test for anti-inflammatory potential utilizing the chick's embryo chroioallantoic membrane (CAM), JLW also caused significant lowering of granulation tissue formation. Topical application of JLW reduced ear oedema induced by croton oil in rats. In the same animal model, JLW also reduced neutrophil infiltration, as indicated by decreased myeloperoxidase (MPO) activity. In addition, JLW ameliorated histopathological changes affected by croton oil application. In the lipopolysaccharide (LPS)-induced inflammation in air pouch in rats, JLW reduced nitric oxide (NO) level and tumor necrosis factor-alpha (TNF-alpha) release. In conclusion, this study demonstrates the effectiveness of JLW in combating inflammation in several experimental models. Further investigations are needed to identify the active constituents responsible for the anti-inflammatory property of JLW.
Asunto(s)
Antiinflamatorios no Esteroideos/uso terapéutico , Modelos Animales de Enfermedad , Edema/tratamiento farmacológico , Ceras/uso terapéutico , Animales , Antiinflamatorios no Esteroideos/aislamiento & purificación , Edema/metabolismo , Edema/patología , Masculino , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/uso terapéutico , Ratas , Ratas Sprague-Dawley , Semillas , Ceras/aislamiento & purificaciónRESUMEN
This study was designed to investigate if the impairment of learning and memory induced by acute administration of scopolamine (1.4 mg/kg ip) in rats is associated with altered brain oxidative stress status. The passive avoidance paradigm was used to assess retrieval memory of rats after scopolamine treatment. Following retrieval testing, biochemical assessments of malondialdehyde (MDA), glutathione peroxidase (GSHPx), glutathione (GSH), and superoxide dismutase (SOD) levels/activities as oxidative stress indices were performed. This study also investigated the effect of acute administration of Hypericum perforatum extract (4.0, 8.0, 12.0, and 25.0 mg/kg ip), containing flavonoids with documented antioxidant activity, on brain oxidative status of nai;ve rats treated with amnestic dose of scopolamine. Results showed that administration of 1.4 mg/kg of scopolamine impaired retrieval memory of rats and that such amnesia was associated with elevated MDA and reduced GSH brain levels. In nai;ve rats, which have not been exposed to conditioned fear, scopolamine administration also increased MDA and reduced GSH levels, although with an increase in brain GSHPx activity. Pretreatment of the animals with Hypericum extract (4, 8, and 12 mg/kg) resulted in an antioxidant effect through altering brain MDA, GSHPx, and/or GSH level/activity. Since oxidative stress is implicated in the pathophysiology of dementia, the findings of this study may substantiate the value of scopolamine-induced amnesia in rats as a valid animal model to screen for drugs with potential therapeutic benefit in dementia. Exposure of animals to conditioned fear may be suggested to impair the balance between the rate of lipid peroxidation and the activation of GSHPx as a compensatory antioxidant protective mechanism. It is also concluded that low doses of Hypericum extract, demonstrating antioxidant activity, may be of value for demented patients exhibiting elevated brain oxidative status. Since depression commonly coexists with dementia, Hypericum extract as a drug with documented antidepressant action may also be a better alternative than several other antidepressant medications that have not been evaluated to test their effect on brain oxidative status during amnesia.
Asunto(s)
Amnesia/inducido químicamente , Amnesia/metabolismo , Antioxidantes/farmacología , Química Encefálica/efectos de los fármacos , Hypericum/química , Antagonistas Muscarínicos , Escopolamina , Animales , Glutatión/metabolismo , Glutatión Peroxidasa/metabolismo , Masculino , Malondialdehído/metabolismo , Oxidación-Reducción , Extractos Vegetales/farmacología , Ratas , Ratas Wistar , Superóxido Dismutasa/metabolismoRESUMEN
Oxidative stress is believed to be implicated in the pathogenesis of postischaemic cerebral injury. Many antioxidants were shown to be neuroprotective in experimental models of cerebral ischaemia/reperfusion (I/R). The present study was designed to investigate the potential protective effects of curcumin (CUR) against I/R insult in rat forebrain. The model adopted was that of surgically-induced forebrain ischaemia, performed by means of bilateral common carotid artery occlusion (BCCAO) for 1 h, followed by reperfusion for another 1h. The effects of a single i.p. dose of CUR (50, 100 or 200 mg kg(-1)), administered 0.5 h after the onset of ischaemia, were investigated by assessing oxidative stress-related biochemical parameters in rat forebrain. CUR, at the highest dose level (200 mg kg(-1)), decreased the I/R-induced elevated xanthine oxidase (XO) activity, superoxide anion (O(2)*(-)) production, malondialdehyde (MDA) level and glutathione peroxidase (GPx), superoxide dismutase (SOD), and lactate dehydrogenase (LDH) activities. On the other hand, CUR did not affect the declined reduced glutathione (GSH) content due to I/R insult. Worth mentioning is that the activity of catalase (CAT) did not change in response to either I/R insult or drug treatment. In conclusion, CUR was found to protect rat forebrain against I/R insult. These protective effects may be attributed to its antioxidant properties and/or its inhibitory effects on xanthine dehydrogenase/xanthine oxidase (XD/XO) conversion and resultant O(2)*(-) production.