RESUMO
The present study was aimed to evaluate the antioxidant potential and inhibitory effect of Cannabis sativa and Morus nigra against lipid peroxidation in goat brain and liver homogenates. The formation of free radicals, highly reactive oxygen species (ROS) and reactive nitrogen species (RNS) is a normal metabolic process for cellular signaling and countering the antigens. However, they may cause serious damage if they produced at amplified tolls. In addition, metabolic disorders also serve as sources of these reactive species. Although the issue can be addressed through supplements and other phytochemicals. In this study, two plant species were evaluated for their biological potential by employing a spectrum of antioxidant assays. The antioxidant activity was performed by lipid peroxidation assay. The water extract prepared from leaves of Cannabis sativa and Morus nigra showed significant (P<0.05) inhibition as compared to control i.e., 522.6±0.06 and 659.97±0.03 µg/mL against iron-induced lipid peroxidation in goat brain homogenate while the inhibitions were 273.54±0.04 and 309.18±0.05 µg/mL against nitroprusside induced lipid peroxidation of the brain. The iron and nitroprusside induced lipid peroxidation was also significantly inhibited by leaf extracts of Cannabis sativa and Morus nigra in liver homogenates such as 230.63±0.52 and 326.91±0.01 µg/mL (iron-induced) while 300.47±0.07 and 300.47±0.07 µg/mL (nitroprusside induced), respectively. The extracts of Cannabis sativa extract showed promising activity (96.04±0.060%) against DPPH radicals while Morus nigra showed a moderate activity (34.11±0.120%). The results suggest that different accessions of Cannabis sativa and Morus nigra are a potential source of antioxidants and have a therapeutic effect against disease induced by oxidative stress and hence can be used for novel drug discovery and development.
O presente estudo teve como objetivo avaliar o potencial antioxidante e o efeito inibitório de Cannabis sativa e Morus nigra contra a peroxidação lipídica em homogenatos de cérebro e fígado de cabras. A formação de radicais livres, espécies altamente reativas de oxigênio (ROS) e espécies reativas de nitrogênio (RNS), é um processo metabólico normal para sinalização celular e combate aos antígenos. No entanto, eles podem causar sérios danos se forem produzidos em portagens ampliadas. Além disso, distúrbios metabólicos também servem como fontes dessas espécies reativas, embora o problema possa ser resolvido por meio de suplementos e outros fitoquímicos. Neste estudo, duas espécies de plantas foram avaliadas quanto ao seu potencial biológico, empregando um espectro de ensaios antioxidantes. A atividade antioxidante foi realizada por ensaio de peroxidação lipídica. O extrato de água preparado a partir de folhas de Cannabis sativa e Morus nigra mostrou inibição significativa (P < 0,05) em comparação com o controle, ou seja, 522,6 ± 0,06 e 659,97 ± 0,03 µg / mL contra peroxidação lipídica induzida por ferro em homogenato de cérebro de cabra, enquanto as inibições foram 273,54 ± 0,04 e 309,18 ± 0,05 µg / mL contra a peroxidação lipídica do cérebro induzida por nitroprussiato. A peroxidação lipídica induzida por ferro e nitroprussiato também foi significativamente inibida por extratos de folhas de Cannabis sativa e Morus nigra em homogenatos de fígado, como 230,63 ± 0,52 e 326,91 ± 0,01 µg / mL (induzida por ferro), enquanto 300,47 ± 0,07 e 300,47 ± 0,07 µg / mL (induzida por nitroprussiato), respectivamente. Os extratos do extrato de Cannabis sativa apresentaram atividade promissora (96,04 ± 0,060%) contra os radicais DPPH enquanto Morus nigra apresentou atividade moderada (34,11 ± 0,120%). Os resultados sugerem que diferentes acessos de Cannabis sativa e Morus nigra são uma fonte potencial de antioxidantes e têm efeito terapêutico [...].
Assuntos
Animais , Antioxidantes/farmacologia , Cabras , Cannabis/química , Cérebro/efeitos dos fármacos , Fígado/efeitos dos fármacos , Morus/químicaRESUMO
In this work, diffuse near-infrared light reflectance spectroscopy based on a single optical probe, contains central single collection fiber surrounded by a circular array of illumination fibers, was used to quantify cerebral tissue properties in ApoE knockout mice following Sarcopoterium spinosum treatment. Sarcopoterium spinosum, also known as Thorny burnet, is a Mediterranean plant widely used as a traditional therapy for the treatment of a variety of pathologies, primarily type 2 diabetes mellitus (T2D). While it's efficacy in the treatment of T2D, and of other components of metabolic syndrome, have already been validated by us, the aim of this study was to investigate the effects of Sarcopoterium spinosum extract (SSE) on dyslipidemia and vascular functions. We utilized ApoE deficient mice (ApoE-/- , Atherosclerosis-prone apolipoprotein E-deficient), who have a severe impairment in plasma lipoprotein clearance and thus develop alterations in blood lipid profile and are highly susceptible to atherogenic plaque formation. A total of 34 male mice were divided into five groups representing various genetic, dietary, and treatment configurations. Optical measurements were used to assess changes in diffused reflectance spectra, optical properties (absorption and scattering), and cerebral tissue chromophore contents. Specifically, significant improvement in cerebral hemoglobin level was observed in ApoE KO mice, fed an artherogenic diet (ATD), upon SSE treatment. Biochemical and histological analyses of ApoE-/- ATD mice showed elevated body weight and a high level of blood triglycerides, free fatty acids and cholesterol. In contrast, in SSE treated mice improvement was observed, suggesting beneficial effects of SSE. In ApoE-/- ATD mice group a higher levels of deoxyhemoglobin was monitored indicating that the rate of oxygen release to the tissue is low. This was supported by decrease in oxygen saturation. It was also shown a reduction in water content in the brain of ApoE KO. Mice fed with the atherogenic diet demonstrated increased water content as compared to STD-fed ApoE KO mice, while SSE administration reversed the effect of the diet. To our knowledge, no such study has been reported before.
Assuntos
Cérebro/efeitos dos fármacos , Extratos Vegetais/farmacologia , Animais , Diabetes Mellitus Tipo 2 , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout para ApoE , Rosaceae , Análise EspectralRESUMO
Tramadol is an opioid used as an analgesic for treating moderate or severe pain. The long-term use of tramadol can induce several adverse effects. The toxicological mechanism of tramadol abuse is unclear. Metabolomics is a very useful method for investigating the toxicology of drug abuse. We investigated the impact of chronic tramadol administration on the cerebrum of mice, focusing on the metabolites after tramadol administration. The mice received 20 or 50 mg/kg body weight tramadol dissolved in physiological saline daily for 5 weeks via oral gavage. Compared with the control group, the low dose tramadol group showed seven potential biomarkers, including gamma-hydroxybutyric acid, succinate semialdehyde, and methylmalonic acid, which were either up- or down-regulated. Compared with the control group, the high dose tramadol group showed ten potential biomarkers, including gamma-hydroxybutyric acid, glutamine, and O-phosphorylethanolamine, which were either up- or down-regulated. The up-regulated gamma-hydroxybutyric acid and the down-regulated succinate semialdehyde revealed that the neurotransmitter system was disrupted after tramadol abuse. Compared with the low dose tramadol group, there were twenty-nine potential biomarkers in the high dose tramadol group, mainly related to the pentose phosphate pathway and glycerophospholipid metabolism. In conclusion, metabolomics in the tramadol abuse group demonstrated that long-term tramadol abuse can result in oxidative damage, inflammation, and disruption of the GABA neurotransmitter system, which will help to elucidate the toxicology of tramadol abuse.
Assuntos
Analgésicos Opioides/toxicidade , Cérebro/efeitos dos fármacos , Tramadol/toxicidade , Analgésicos Opioides/administração & dosagem , Animais , Biomarcadores/análise , Cérebro/química , Cérebro/metabolismo , Masculino , Malondialdeído/análise , Metabolômica , Camundongos , Superóxido Dismutase/metabolismo , Tramadol/administração & dosagemRESUMO
Ketamine acts as a rapid clinical antidepressant at 25 min after injection with effects sustained for 7 days. As dissociative effects emerging acutely after injection are not entirely discernible from therapeutic action, we aimed to dissect the differences between short-term and long-term response to ketamine to elucidate potential imaging biomarkers of ketamine's antidepressant effect. We used a genetical model of depression, in which we bred depressed negative cognitive state (NC) and non-depressed positive cognitive state (PC) rat strains. Four parallel rat groups underwent stress-escape testing and a week later received either S-ketamine (12 NC, 13 PC) or saline (12 NC, 12 PC). We acquired resting-state functional magnetic resonance imaging time series before injection and at 30 min and 48 h after injection. Graph analysis was used to calculate brain network properties. We identified ketamine's distinct action over time in a qualitative manner. The rapid response entailed robust and strain-independent topological modifications in cognitive, sensory, emotion, and reward-related circuitry, including regions that exhibited correlation of connectivity metrics with depressive behavior, and which could explain ketamine's dissociative and antidepressant properties. At 48 h ketamine had mainly strain-specific action normalizing habenula, midline thalamus, and hippocampal connectivity measures in depressed rats. As these nodes mediate cognitive flexibility impaired in depression, action within this circuitry presumably reflects ketamine's procognitive effects induced only in depressed patients. This finding is especially valid, as our model represents cognitive aspects of depression. These empirically defined circuits explain ketamine's distinct action over time and might serve as translational imaging correlates of antidepressant response in preclinical testing.
Assuntos
Antidepressivos/farmacologia , Cérebro/efeitos dos fármacos , Conectoma , Depressão/tratamento farmacológico , Ketamina/farmacologia , Rede Nervosa/efeitos dos fármacos , Animais , Comportamento Animal/efeitos dos fármacos , Córtex Cerebral/diagnóstico por imagem , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/fisiopatologia , Cérebro/diagnóstico por imagem , Cérebro/fisiopatologia , Modelos Animais de Doenças , Habenula/diagnóstico por imagem , Habenula/efeitos dos fármacos , Habenula/fisiopatologia , Hipocampo/diagnóstico por imagem , Hipocampo/efeitos dos fármacos , Hipocampo/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiopatologia , Ratos , Ratos Sprague-Dawley , Tálamo/diagnóstico por imagem , Tálamo/efeitos dos fármacos , Tálamo/fisiopatologiaRESUMO
OBJECTIVE: To investigate free fatty acid levels and histopathological changes in the brain of rats fed a high fructose diet (HFrD) and to evaluate the effects of Mucuna pruriens, known to have antidiabetic activity, on these changes. MATERIALS AND METHODS: The study comprised 28 mature female Wistar rats. The rats were divided into 4 groups, each included 7 rats. Group 1: control; group 2: fed an HFrD; group 3: fed normal rat chow and M. pruriens; group 4: fed an HFrD and M. pruriens for 6 weeks. At the end of 6 weeks, the rats were decapitated, blood and brain tissues were obtained. Serum glucose and triglyceride levels were measured. Free fatty acid levels were measured in 1 cerebral hemisphere of each rat and histopathological changes in the other. The Mann-Whitney U test was used to compare quantitative continuous data between 2 independent groups, and the Kruskal-Wallis test was used to compare quantitative continuous data between more than 2 independent groups. RESULTS: Arachidonic acid and docosahexaenoic acid levels were significantly higher in group 2 than in group 1 (p < 0.05). Free arachidonic acid and docosahexaenoic acid levels in group 4 were significantly less than in group 2 (p < 0.05). Histopathological examination of group 2 revealed extensive gliosis, neuronal hydropic degeneration, and edema. In group 4, gliosis was much lighter than in group 2, and edema was not observed. Neuronal structures in group 4 were similar to those in group 1. CONCLUSIONS: The HFrD increased the levels of free arachidonic acid and docosahexaenoic acid probably due to membrane degradation resulting from possible oxidative stress and inflammation in the brain. The HFrD also caused extensive gliosis, neuronal hydropic degeneration, and edema. Hence, M. pruriens could have therapeutic effects on free fatty acid metabolism and local inflammatory responses in the brains of rats fed an HFrD.
Assuntos
Ácidos Graxos não Esterificados/biossíntese , Frutose/farmacologia , Mucuna , Extratos Vegetais/farmacologia , Animais , Ácido Araquidônico/biossíntese , Glicemia , Cérebro/efeitos dos fármacos , Cérebro/patologia , Ácidos Docosa-Hexaenoicos/biossíntese , Feminino , Gliose/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Triglicerídeos/sangueRESUMO
OBJECTIVE: Hypobaric hypoxia, frequently encountered at high altitude, may lead to lung and cerebrum injury. Our study aimed to investigate whether puerarin could exert ameliorative effects on rats exposed to hypobaric hypoxia via regulation of aquaporin (AQP) and NF-κB signaling pathway in lung and cerebrum. MATERIALS AND METHODS: 40 Sprague Dawley rats were divided into four groups (normal control group, hypobaric hypoxia group, puerarin group and dexamethasone group). Wet/dry ratio, blood gas, pathological changes of lung and cerebrum and spatial memory were observed in each group. Inflammatory cytokines in bronchoalveolar lavage fluid (BALF) were determined with ELISA and expression of AQP1, AQP4, NF-κB signaling pathway in lung and cerebrum with western blot RESULTS: Puerarin showed significant preventative effects on tissue injury and behavioral changes, as evidenced by histopathological findings and Morris water maze. In addition, levels of inflammatory cytokines in BALF decreased in the two preventative groups compared with those of hypobaric hypoxia group. AQP in lung and cerebrum increased under the condition of hypobaric hypoxia while was down regulated in both two preventative groups. NF-κB and IκB was also inhibited by puerarin. CONCLUSION: Our study suggested that lung and cerebrum injury, increased inflammatory cytokines in BALF and increased AQP1, AQP4 and NF-κB signaling pathway occurred under the condition of hypobaric hypoxia. Moreover, puerarin could prevent lung and cerebrum injury of rats exposed to hypobaric hypoxia via down-regulation of inflammatory cytokines, AQP1 and AQP4 expression and NF-κB signaling pathway.
Assuntos
Lesão Pulmonar Aguda/tratamento farmacológico , Lesões Encefálicas/tratamento farmacológico , Hipóxia/complicações , Isoflavonas/uso terapêutico , Substâncias Protetoras/uso terapêutico , Lesão Pulmonar Aguda/etiologia , Lesão Pulmonar Aguda/imunologia , Lesão Pulmonar Aguda/metabolismo , Animais , Aquaporina 1/metabolismo , Aquaporina 4/metabolismo , Lesões Encefálicas/etiologia , Lesões Encefálicas/imunologia , Lesões Encefálicas/metabolismo , Líquido da Lavagem Broncoalveolar/imunologia , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Citocinas/imunologia , Isoflavonas/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Medicina Tradicional Chinesa , NF-kappa B/metabolismo , Substâncias Protetoras/farmacologia , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacosRESUMO
Cyclophosphamide (CPA) is a widely used anticancer chemotherapeutic agent and its toxicity has been associated with its toxic metabolites phosphormide mustard. Therefore, the ameliorative effect of Gallic acid against neurotoxicity was examined in this study. Sixty rats were grouped into 10 rats per group. Group 1 received saline orally. Group 2 received CPA at 100 mg/kg single dose intraperitoneally on day 1. Groups 3 and 4 were treated with Gallic acid (GA) at 60 and 120 mg/kg body weight only for 10 days and also received a single dose of CPA (100 mg/kg) intraperitoneally on day 1, respectively. Rats in groups 5 and 6 received GA at 60 and 120 mg/kg body weight only for 10 days. Groups 3, 4, 5, and 6 received GA orally. The cerebellar and cerebral malondialdehyde (MDA) contents and hydrogen peroxide generation were significantly (p < .05) elevated. The cerebellar and cerebral catalase (CAT), superoxide dismutase and glutathione-S-transferase (GST) activities were significantly (p < .05) reduced in CPA treated group. The activity of glutathione peroxidase (GPx) was significantly increased in rats that were treatment with CPA. Also, nitrite content was significantly elevated in the brain of rats that received the toxic dose of CPA. All these findings suggest that treatment with GA (60 and 120 mg/kg) ameliorated the neurotoxicity induced by CPA via reduction of oxidative stress and increase in antioxidant defense system. Combining all, chemotherapeutic agents with structure/function similar to GA could be of potential benefit to the pharmaceutical industries as an adjuvant in chemotherapy with little or no side effects.
Assuntos
Antioxidantes/farmacologia , Ciclofosfamida/toxicidade , Ácido Gálico/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Catalase/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Glutationa Peroxidase/metabolismo , Glutationa Transferase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismoRESUMO
Cinnabar, an important traditional Chinese mineral medicine, has been widely used as a Chinese patent medicine ingredient for sedative therapy. Nevertheless, the neurotoxic effects of cinnabar have also been noted. In this study, (1)H NMR-based metabolomics, combined with multivariate pattern recognition, were applied to investigate the neurotoxic effects of cinnabar after intragastrical administration (dosed at 2 and 5 g/kg body weight) on male Wistar rats. The metabolite variations induced by cinnabar were characterized by increased levels of glutamate, glutamine, myo-inositol, and choline, as well as decreased levels of GABA, taurine, NAA, and NAAG in tissue extracts of the cerebellum and cerebrum. These findings suggested that cinnabar induced glutamate excitotoxicity, neuronal cell loss, osmotic state changes, membrane fluidity disruption, and oxidative injury in the brain. We also show here that there is a dose- and time-dependent neurotoxicity of cinnabar, and that cerebellum was more sensitive to cinnabar induction than cerebrum. This work illustrates the utility and reliability of (1)H NMR-based metabolomics approach for examining the potential neurotoxic effects of cinnabar and other traditional Chinese medicines.
Assuntos
Cerebelo/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Compostos de Mercúrio/toxicidade , Metabolômica , Neurônios/efeitos dos fármacos , Animais , Ácido Aspártico/análogos & derivados , Ácido Aspártico/metabolismo , Morte Celular/efeitos dos fármacos , Cerebelo/metabolismo , Cérebro/metabolismo , Colina/metabolismo , Relação Dose-Resposta a Droga , Ácido Glutâmico/metabolismo , Glutamina/metabolismo , Inositol/metabolismo , Masculino , Medicina Tradicional Chinesa , Fluidez de Membrana/efeitos dos fármacos , Neurônios/citologia , Neurônios/metabolismo , Especificidade de Órgãos , Ratos , Ratos Wistar , Taurina/metabolismo , Ácido gama-Aminobutírico/metabolismoRESUMO
Aluminium (Al), a ubiquitous element in nature is associated with the onset of Alzheimer's disease. On the other hand, zinc (Zn) is an essential trace element that regulates large number of physiological processes in the human body. The present study was conducted to explore the role of zinc, if any, in regulating apoptotic machinery during Al induced neurodegeneration in rat. Male sprague dawley rats weighing 140-160 g were divided into four different groups viz: Normal control, Al treated (100 mg/kg b.wt./day), Zn treated (227 mg/l) and combined Al and Zn treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment resulted in a significant increase in the protein expressions of cytochrome c, Bax, Apaf-1, caspase 9, caspase 3 (p17), caspase 8, caspase 6, caspase 7 but decreased the Bcl-2 in both the cerebrum and cerebellum. However, Zn supplementation to Al treated rats resulted in a reduction in the protein expressions of cytochrome c, Bax, Apaf-1, caspase 9, caspase 3 (p17), caspase 8, caspase 6 and caspase 7 whereas it elevated the Bcl-2 in both the regions. Further, gene expressions of caspase 3 and caspase 9 were also found to be elevated after Al treatment, which however were reduced following Zn co-treatment. The electron-microscopic analysis of brain revealed that Al intoxication resulted in a number of degenerative signs at ultrastructural level, which were appreciably improved upon Zn supplementation. The present study suggests that Zn provides protection against Al induced neurotoxicity by triggering anti-apoptotic machinery.
Assuntos
Alumínio/toxicidade , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Zinco/farmacologia , Proteína X Associada a bcl-2/metabolismo , Animais , Apoptose/efeitos dos fármacos , Caspase 3/metabolismo , Caspase 6/metabolismo , Caspase 7/metabolismo , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Ativação Enzimática/efeitos dos fármacos , Masculino , Microscopia Eletrônica de Transmissão , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo RealRESUMO
OBJECTIVE: Achillea millefolium (A. millefolium) is widely used as an anti-inflammatory remedy in traditional and herbal medicine. In this study, we investigated the effect of an aqueous extract from A. millefolium on experimental autoimmune encephalomyelitis (EAE) and on the serum cytokine levels in C57BL/6 mice. MATERIALS AND METHODS: EAE was induced in 63 C57BL/6 mice weighing 20-25 g (8 weeks old). Following immunization, the treatment protocol was initiated by using different doses of an aqueous extract from A. millefolium (1, 5, and 10 mg/mouse/day). Histopathologic assessments were performed by hematoxylin and eosin (H and E) and luxol fast blue (LFB) staining. Behavioral disabilities were recorded by a camera. Serum levels of interleukin (IL)-10, IL-12, and transforming growth factor (TGF)-ß were measured using enzyme-linked immunosorbent assay (ELISA). RESULTS: On average, mice developed classical behavioral disabilities of EAE, 13.2 ± 1.9 days following immunization. Treatment of mice with A. millefolium led to delay the appearance of behavioral disabilities along with reduced severity of the behavioral disabilities. Treatment with A. millefolium prevented weight loss and increased serum levels of TGF-ß in immunized mice with MOG35-55. EAE-induced mice, which were treated with A. millefolium, had less cerebral infiltration of inflammatory cells. CONCLUSION: The results demonstrated that treatment with aqueous extract of A. millefolium may attenuate disease severity, inflammatory responses, and demyelinating lesions in EAE-induced mice. In addition, following treatment with A. millefolium, serum levels of TGF-ßwere increased in EAE-induced mice.
Assuntos
Achillea , Anti-Inflamatórios/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Fármacos Neuroprotetores/uso terapêutico , Extratos Vegetais/uso terapêutico , Animais , Anti-Inflamatórios/farmacologia , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Cérebro/patologia , Citocinas/sangue , Encefalomielite Autoimune Experimental/sangue , Encefalomielite Autoimune Experimental/etiologia , Encefalomielite Autoimune Experimental/patologia , Adjuvante de Freund , Masculino , Camundongos Endogâmicos C57BL , Glicoproteína Mielina-Oligodendrócito , Fármacos Neuroprotetores/farmacologia , Fragmentos de Peptídeos , Toxina Pertussis , Fitoterapia , Componentes Aéreos da Planta , Extratos Vegetais/farmacologiaRESUMO
BACKGROUND & OBJECTIVES: Sidh Makardhwaj (SM) is a mercury based Ayurvedic formulation used in rheumatoid arthritis and neurological disorders. However, toxicity concerns due to mercury content are often raised. Therefore, the present study was carried out to evaluate the effect of SM on brain cerebrum, liver and kidney in rats. METHODS: Graded doses of SM (10, 50, 100 mg/kg), mercuric chloride (1 mg/kg) and normal saline were administered orally to male Wistar rats for 28 days. Behavioural parameters were assessed on days 1, 7, 14 and 28 using Morris water maze, passive avoidance, elevated plus maze and rota rod. Liver and kidney function tests were done on day 28. Animals were sacrificed and brain cerebrum acetylcholinesterase activity, levels of malondialdehyde (MDA), reduced glutathione (GSH) in brain cerebrum, liver, kidney were estimated. The levels of mercury in brain cerebrum, liver and kidney were estimated and histopathology of these tissues was also performed. RESULTS: SM in the doses used did not cause significant change in neurobehavioural parameters, brain cerebrum AChE activity, liver (ALT, AST, ALP bilirubin) and kidney (serum urea and creatinine) function tests as compared to control. The levels of mercury in brain cerebrum, liver, and kidney were found to be raised in dose dependent manner. However, the levels of MDA and GSH in these tissues did not show significant changes at doses of 10 and 50 mg/kg. Also, there was no histopathological change in cytoarchitecture of brain cerebrum, liver, and kidney tissues at doses of 10 and 50 mg/kg. INTERPRETATION & CONCLUSIONS: The findings of the present study suggest that Sidh Makardhwaj upto five times the equivalent human dose administered for 28 days did not show any toxicological effects on rat brain cerebrum, liver and kidney.
Assuntos
Cérebro/efeitos dos fármacos , Rim/efeitos dos fármacos , Fígado/efeitos dos fármacos , Ayurveda , Cloreto de Mercúrio/farmacocinética , Cloreto de Mercúrio/toxicidade , Acetilcolinesterase/metabolismo , Administração Oral , Análise de Variância , Animais , Glutationa/efeitos dos fármacos , Masculino , Malondialdeído/metabolismo , Aprendizagem em Labirinto/efeitos dos fármacos , Cloreto de Mercúrio/administração & dosagem , Ratos , Teste de Desempenho do Rota-Rod , Fatores de TempoRESUMO
ETHNOPHARMACOLOGICAL RELEVANCE: Rhynchophylline (Rhy) is a major ingredient of Uncaria rhynchophylla (UR) used to reduce blood pressure and ameliorate brain ailments. This study was to examine the role of Rho kinase (ROCK) in the inhibition of Rhy on contraction of cerebral arterioles caused by endothelin 1 (ET-1). MATERIALS AND METHODS: Cerebral arterioles of male Wistar rats were constricted with ET-1 for 10 min followed by perfusion of Rhy for 20 min. Changes in the diameters of the arterioles were recorded. The effects of Rhy on contraction of middle cerebral arteries (MCAs) were determined by a Multi-Myograph. Western blotting and immunofluorescent staining were used to examine the effects of Rhy on RhoA translocation and myosin phosphatase target subunit 1 (MYPT1) phosphorylation. RESULTS: In vivo, Rhy (30-300 µM) relaxed cerebral arterioles constricted with ET-1 dose-dependently. In vitro, Rhy at lower concentrations (1-100 µM) caused relaxation of rat MCAs constricted with KCl and Bay-K8644 (an agonist of L-type voltage-dependent calcium channels (L-VDCCs)). Rhy at higher concentrations (>100 µM) caused relaxation of rat MCAs constricted with ET-1, which was inhibited by Y27632, a ROCK׳s inhibitor. Western blotting of rat aortas showed that Rhy inhibited RhoA translocation and MYPT1 phosphorylation. Immunofluorescent staining of MCAs confirmed that phosphorylation of MYPT1 caused by ET-1 was inhibited by Rhy. CONCLUSIONS: These results demonstrate that Rhy is a potent inhibitor of contraction of cerebral arteries caused by ET-1 in vivo and in vitro. The effect of Rhy was in part mediated by inhibiting RhoA-ROCK signaling.
Assuntos
Arteríolas/efeitos dos fármacos , Endotelina-1/metabolismo , Alcaloides Indólicos/farmacologia , Uncaria/química , Animais , Arteríolas/metabolismo , Cérebro/irrigação sanguínea , Cérebro/efeitos dos fármacos , Relação Dose-Resposta a Droga , Alcaloides Indólicos/administração & dosagem , Alcaloides Indólicos/isolamento & purificação , Masculino , Oxindóis , Fosforilação/efeitos dos fármacos , Proteína Fosfatase 1/metabolismo , Ratos , Ratos Wistar , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Quinases Associadas a rho/metabolismoRESUMO
Metals perform important functions in the normal physiological system, and alterations in their levels may lead to a number of diseases. Aluminium (Al) has been implicated as a major risk factor, which is linked to several neurodegenerative diseases including Alzheimer's disease and Parkinson's disease. On the other hand, zinc (Zn) is considered as a neuromodulator and an essential dietary element that regulates a number of biological activities in our body. The aim of the present study was to investigate the effects of Zn supplementation, if any, in ameliorating the changes induced by Al on calcium signalling pathway. Male Sprague Dawley rats weighing 140-160 g were divided into four different groups viz.: normal control, aluminium treated (100 mg/kg b.wt./day via oral gavage), zinc treated (227 mg/l in drinking water) and combined aluminium and zinc treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment decreased the Ca(2+) ATPase activity whereas increased the levels of 3', 5'-cyclic adenosine monophosphate, intracellular calcium and total calcium content in both the cerebrum and cerebellum, which, however, were modulated upon Zn supplementation. Al treatment exhibited a significant elevation in the protein expressions of phospholipase C, inositol triphosphate and protein kinase A but decreased the expression of protein kinase C, which, however, was reversed upon Zn co-treatment. Al treatment also revealed alterations in neurohistoarchitecture in the form of calcium deposits, which were improved upon zinc co-administration. The present study, therefore, suggests that zinc regulates the intracellular calcium signalling pathway during aluminium-induced neurodegeneration.
Assuntos
Alumínio/farmacologia , Sinalização do Cálcio/efeitos dos fármacos , Cálcio/metabolismo , Cerebelo/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Zinco/farmacologia , Animais , Cerebelo/metabolismo , Cérebro/metabolismo , Masculino , Doenças Neurodegenerativas/induzido quimicamente , Estresse Oxidativo/efeitos dos fármacos , Ratos Sprague-Dawley , Zinco/metabolismoRESUMO
Niemann-Pick disease type C is a rare lipid trafficking disorder characterized by the accumulation of cholesterol and glycosphingolipids in the brain and viscera. Perinatal, early infantile, late infantile, juvenile and adult forms are distinguished based on the age of manifestation. In the juvenile form, patients in their early years are usually, but not always, symptom free, but present with neurodegeneration later in their lives. These include clumsiness, ataxia, seizures, motor and intellectual decline. Psychiatric manifestations may occur at any stage of the disease. These manifestations include schizophrenia, presenile dementia, depression or psychosis. In 2009, miglustat was approved for the therapy of the disease. We present a case of a patient with juvenile Niemann-Pick C disease whose psychosis was reversed completely by miglustat treatment. Based on our clinical experience we suggest considering Niemann-Pick C in cases of therapy-resistant psychosis and encourage the introduction of miglustat in Niemann-Pick C patients even in the most advanced cases, with respect to psychiatric illness.
Assuntos
1-Desoxinojirimicina/análogos & derivados , Cérebro/patologia , Doença de Niemann-Pick Tipo C/tratamento farmacológico , Transtornos Psicóticos/etiologia , 1-Desoxinojirimicina/administração & dosagem , 1-Desoxinojirimicina/uso terapêutico , Adolescente , Idade de Início , Atrofia , Cérebro/efeitos dos fármacos , Cérebro/fisiopatologia , Humanos , Masculino , Doença de Niemann-Pick Tipo C/complicações , Doença de Niemann-Pick Tipo C/diagnóstico , Doença de Niemann-Pick Tipo C/genética , Transtornos Psicóticos/tratamento farmacológico , Resultado do TratamentoRESUMO
The present study was designed to understand the influence of zinc (Zn) if any, on the biokinetics of (65)Zn in brain as well as whole body and its bio-distribution following aluminium (Al) treatment to rats. Male Sprague-Dawley rats weighing 140-160 g were divided into four different groups viz: normal control, aluminium treated (100 mg/kg b.wt./day via oral gavage), zinc treated (227 mg/L in drinking water) and combined aluminium and zinc treated. All the treatments were carried out for a total duration of 8 weeks. Al treatment showed a significant increase in fast component (Tb1) but revealed a significant decrease in slow component (Tb2) of biological half-life in brain as well as in whole body. However, Zn supplementation to Al-treated rats reversed the trend in both brain and whole body, which indicates a significant decrease in Tb1 component while the Tb2 component was significantly increased. Further, Al treatment showed an increased percent uptake value of (65)Zn in cerebrum, cerebellum, heart, liver and lungs whereas a decrease in uptake was found only in blood. On the other hand, there was a significant decline in (65)Zn activity in nuclear and mitochondrial fractions of brain of Al-treated rats. However, Zn treatment reversed the altered (65)Zn uptake values in different organs as well as in various subcellular fractions. The study demonstrates that Zn shall prove to be effective in regulating the biokinetics of (65)Zn in brain and whole body and its distribution at the tissue and subcellular levels in Al-treated rats.
Assuntos
Alumínio/toxicidade , Encéfalo/metabolismo , Zinco/farmacologia , Zinco/farmacocinética , Animais , Encéfalo/efeitos dos fármacos , Cerebelo/efeitos dos fármacos , Cerebelo/metabolismo , Cerebelo/patologia , Cérebro/efeitos dos fármacos , Cérebro/metabolismo , Cérebro/patologia , Meia-Vida , Masculino , Ratos , Ratos Sprague-Dawley , Frações Subcelulares/efeitos dos fármacos , Frações Subcelulares/metabolismo , Distribuição Tecidual/efeitos dos fármacosRESUMO
Iron chelators, such as the intracellular ferrous chelator 2,2'-bipyridine, are a potential means of ameliorating iron-induced injury after intracerebral hemorrhage (ICH). We evaluated bipyridine against the collagenase and whole-blood ICH models and a simplified model of iron-induced damage involving a striatal injection of FeCl2 in adult rats. First, we assessed whether bipyridine (25 mg/kg beginning 12 h post-ICH and every 12 h for 3 days) would attenuate non-heme iron levels in the brain and lessen behavioral impairments (neurological deficit scale, corner turn test, and horizontal ladder) 7 days after collagenase-induced ICH. Second, we evaluated bipyridine (20 mg/kg beginning 6 h post-ICH and then every 24 h) on edema 3 days after collagenase infusion. Body temperature was continually recorded in a subset of these rats beginning 24 h prior to ICH until euthanasia. Third, bipyridine was administered (as per experiment 2) after whole-blood infusion to examine tissue loss, neuronal degeneration, and behavioral impairments at 7 days post-stroke, as well as body temperature for 3 days post-stroke. Finally, we evaluated whether bipyridine (25 mg/kg given 2 h prior to surgery and then every 12 h for 3 days) lessens tissue loss, neuronal death, and behavioral deficits after striatal FeCl2 injection. Bipyridine caused a significant hypothermic effect (maximum drop to 34.6 °C for 2-5 h after each injection) in both ICH models; however, in all experiments bipyridine-treated rats were indistinguishable from vehicle controls on all other measures (e.g., tissue loss, behavioral impairments, etc.). These results do not support the use of bipyridine against ICH.
Assuntos
2,2'-Dipiridil/farmacologia , Hemorragia Cerebral/tratamento farmacológico , Cérebro/efeitos dos fármacos , Quelantes/farmacologia , Acidente Vascular Cerebral/tratamento farmacológico , 2,2'-Dipiridil/administração & dosagem , Animais , Comportamento/efeitos dos fármacos , Temperatura Corporal/efeitos dos fármacos , Edema Encefálico/tratamento farmacológico , Estudos de Casos e Controles , Morte Celular/efeitos dos fármacos , Quelantes/administração & dosagem , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos/métodos , Ferro/metabolismo , Masculino , Degeneração Neural/tratamento farmacológico , Neurônios/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Falha de TratamentoRESUMO
Recently, the pharmaceutical industry has shifted to pursuing combination therapies that comprise more than one active ingredient. Interestingly, combination therapies have been used for more than 2500 years in traditional Chinese medicine (TCM). Understanding optimal proportions and synergistic mechanisms of multi-component drugs are critical for developing novel strategies to combat complex diseases. A new multi-objective optimization algorithm based on least angle regression-partial least squares was proposed to construct the predictive model to evaluate the synergistic effect of the three components of a novel combination drug Yi-qi-jie-du formula (YJ), which came from clinical TCM prescription for the treatment of encephalopathy. Optimal proportion of the three components, ginsenosides (G), berberine (B) and jasminoidin (J) was determined via particle swarm optimum. Furthermore, the combination mechanisms were interpreted using PLS VIP and principal components analysis. The results showed that YJ had optimal proportion 3(G): 2(B): 0.5(J), and it yielded synergy in the treatment of rats impaired by middle cerebral artery occlusion induced focal cerebral ischemia. YJ with optimal proportion had good pharmacological effects on acute ischemic stroke. The mechanisms study demonstrated that the combination of G, B and J could exhibit the strongest synergistic effect. J might play an indispensable role in the formula, especially when combined with B for the acute stage of stroke. All these data in this study suggested that in the treatment of acute ischemic stroke, besides restoring blood supply and protecting easily damaged cells in the area of the ischemic penumbra as early as possible, we should pay more attention to the removal of the toxic metabolites at the same time. Mathematical system modeling may be an essential tool for the analysis of the complex pharmacological effects of multi-component drug. The powerful mathematical analysis method could greatly improve the efficiency in finding new combination drug from TCM.
Assuntos
Isquemia Encefálica/tratamento farmacológico , Infarto da Artéria Cerebral Média/tratamento farmacológico , Fármacos Neuroprotetores/farmacologia , Algoritmos , Animais , Berberina/farmacologia , Berberina/uso terapêutico , Cérebro/irrigação sanguínea , Cérebro/efeitos dos fármacos , Cérebro/patologia , Combinação de Medicamentos , Composição de Medicamentos , Avaliação Pré-Clínica de Medicamentos , Sinergismo Farmacológico , Medicamentos de Ervas Chinesas/farmacologia , Medicamentos de Ervas Chinesas/uso terapêutico , Ginsenosídeos/farmacologia , Ginsenosídeos/uso terapêutico , Infarto da Artéria Cerebral Média/patologia , Infarto da Artéria Cerebral Média/fisiopatologia , Iridoides/farmacologia , Iridoides/uso terapêutico , Análise dos Mínimos Quadrados , Masculino , Medicina Tradicional Chinesa , Potencial da Membrana Mitocondrial , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Dilatação Mitocondrial , Fármacos Neuroprotetores/uso terapêutico , Análise de Componente Principal , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/efeitos dos fármacosRESUMO
OBJECTIVE: To investigate the dynamic changes and relationship of inducible nitric oxide synthase (iNOS) and apoptosis in endotoxin shock rats, as well as the effects of Sini injection. METHODS: In total, 102 Sprague-Dawley (SD) rats were randomly divided into a normal group (n = 6, NG), sham operation group (n = 24, OG), model group (n = 24, MG), dexamethasone group (n = 24, DG), and Sini group (n = 24, SG). The endotoxin shock model was induced by an intravenous injection of lipopolysaccharide (LPS) (8 mg/kg). Rats in the OG, MG, DG, and SG groups were further divided into 4 groups: 1, 2, 3 and 6 h after shock groups (n = 6 per group). iNOS expression was detected by immunohistochemistry. Terminal Deoxynucleotidyl Transferase Mediated Deoxyuridine Triphosphate-biotin Nick End Labeling was employed to measure apoptosis. RESULTS: No iNOS expression was found in the OG group. Compared with the OG group, iNOS expression in the MG group was markedly elevated, reached a peak at 1 h (P < 0.01), decreased at 2 and 3 h, and rebounded at 6 h. Compared with the MG group, iNOS expression decreased significantly in both the DG (P < 0.05) and SG (P < 0.01) groups at 6 h. The number of apoptotic cells in the MG group was markedly increased than that in the NG and OG (P < 0.01) groups, and reached a peak at 6 h. The number of apoptotic cells in the DG group at 1 and 2 h (P < 0.01) and SG group at 2, 3 and 6 h (P < 0.01) decreased when compared with the MG group. CONCLUSION: Sini injection can significantly inhibit NO generation, which decreases apoptosis and subsequently protects the brain from endotoxic shock.
Assuntos
Apoptose/efeitos dos fármacos , Cérebro/efeitos dos fármacos , Medicamentos de Ervas Chinesas/administração & dosagem , Óxido Nítrico Sintase Tipo II/genética , Choque Séptico/tratamento farmacológico , Animais , Cérebro/citologia , Feminino , Humanos , Masculino , Óxido Nítrico Sintase Tipo II/metabolismo , Ratos , Ratos Sprague-Dawley , Choque Séptico/enzimologia , Choque Séptico/genética , Choque Séptico/fisiopatologiaRESUMO
Apoptosis is believed to play important roles in neuronal cell death associated with cerebral ischemia. We now provided evidence that imperatorin (IMp), the main composition of the dried root or rhizome of R Radix Angelicae Dahuricae, took advantage on oxygen glucose deprivated/reperfusion (OGD-R) SH-SY5Y cell line through neuronal apoptosis inhibition. Our data had shown that imperatorin reduced the number of apoptosis cells after OGD-R, this effect was associated with the inhibition of the apoptosis factors Bax and caspase-3, and the upregulation of anti-apoptosis factor Bcl-2. In the meantime, the protective factor BDNF was upregulated significantly by imperatorin treatment. In our experiment in vivo, imperatorin decreased the infract volume significantly in dose of 5 mg/kg and 10 mg/kg, and the behavior ability was increased in the 10mg/kg of imperatorin. Our observations show that imperatorin exerted protective effect on cerebral ischemia both in vitro and in vivo, this effect is associated with its anti-apoptosis function.
Assuntos
Angelica/química , Apoptose/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Cérebro/efeitos dos fármacos , Furocumarinas/uso terapêutico , Fitoterapia , Traumatismo por Reperfusão/prevenção & controle , Animais , Comportamento Animal/efeitos dos fármacos , Isquemia Encefálica/metabolismo , Isquemia Encefálica/patologia , Caspase 3/metabolismo , Linhagem Celular , Infarto Cerebral/metabolismo , Infarto Cerebral/prevenção & controle , Cérebro/citologia , Cérebro/metabolismo , Cérebro/patologia , Furocumarinas/farmacologia , Glucose/metabolismo , Hipóxia , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oxigênio/metabolismo , Extratos Vegetais/farmacologia , Extratos Vegetais/uso terapêutico , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Traumatismo por Reperfusão/patologia , Rizoma , Regulação para Cima , Proteína X Associada a bcl-2/metabolismoRESUMO
This study investigated the effect of penehyclidine hydrochloride (PHC) on regulatory mediators during the neuroinflammatory response and cerebral cell apoptosis following cardiopulmonary bypass (CPB). Forty-eight rats were randomly divided among 4 groups as follows: sham-operation, vehicle, low-dose PHC (0.6 mg·(kg body mass)(-1)), and high-dose PHC (2.0 mg·(kg body mass)(-1)). CPB was performed in the latter 3 groups. The plasma levels of neuron specific enolase (NSE) and S-100B were tested with ELISA. Real-time PCR and Western blotting were used to evaluate the expression levels of matrix metalloproteinase-9 (MMP-9), IL-10, caspase-3, Bcl-2, and p38 in brain tissue. The ultrastructure of hippocampus tissue was examined under an electron microscope. PHC attenuated the increase of plasma NSE and S-100B following CPB. MMP-9, cleaved caspase-3, and phosphorylated p38 expression were substantially increased in the vehicle group compared with the sham-operation group and gradually diminished with increasing doses of PHC. IL-10 and Bcl-2 expression were markedly lower in the vehicle group than in the sham-operation group and gradually recovered with increasing doses of PHC. PHC attenuated the histopathological changes of cerebral injury following CPB. PHC favorably regulates the inflammatory response and reduces markers of neuronal injury following CPB, potentially by reducing p38 and caspase-3 activation.