RESUMEN
Tryptanthrin is a potent natural alkaloid with good in vitro pharmacological properties. Herein, we report the synthesis of the compound via a new method involving the reduction of isatin with solid-state-supported sodium borohydride under microwave irradiation. The title compound has been tested for its analgesic and anti-inflammatory activity. The results showed that tryptanthrin dose dependently inhibits oedema and pain formation in all the models used. The agent also exhibited significant higher effects in its anti-inflammatory and analgesic activities better than positive drugs (aspirin and indomethacin) being currently used in the treatment and in the management of acute and chronic forms of pain and inflammatory disorders. The inhibitory potential of the compound was investigated by molecular docking using the software AutoDock Vina. The docking results were used to better rationalize the action and prediction of the binding affinity of tryptanthrin. Density Functional Theory (DFT) calculations at the B3LYP/6-311++G (2df, 2pd) level of theory showed that compared to ascorbic acid, tryptanthrin shows higher antioxidant activity which may be improved upon by functionalizing the aromatic core to enhance its solubility in polar solvents. The calculated electronic and thermodynamic properties obtained for tryptanthrin compete well with the standard ascorbic acid.
RESUMEN
Psychosocial stress has been widely reported to contribute to psychiatric disturbances. Perturbations in the enzymes of GABAergic and cholinergic systems have been implicated as precursors in different stress-related neuropsychiatric diseases. Targeting glutamic acid decarboxylase-67 kDa (GAD67) and acetylcholinesterase (AChE) via oxidative, nitrergic, and neuroinflammatory mechanisms have been recognized as prospective strategies for the prevention of psychosocial stress-induced behavioral impairments. Naringin, a neuro-active flavonoid compound isolated from citrus fruits, has been shown to produce memory-enhancing, antiepileptic, antidepressant, and anti-inflammatory activities similarly to ginseng, a very potent adaptogen. In this communication, we assessed the effect of naringin on social-defeat stress (SDS)-induced behavioral, GABAergic, cholinergic, oxidative, nitrergic, and neuroinflammatory changes in mice using the resident-intruder paradigm. The intruder male mice were culled into six groups. Groups 1 and 2 (normal- and SDS-controls) received sterile saline, groups 3-5 were given naringin (25-100 mg/kg, i.p.) whereas group 6 had ginseng (50 mg/kg, i.p.) daily for 14 days, but followed by 10 min SDS (physical and psychological) exposure to groups 2-6 with aggressor-resident mice. Behavioral effects using Y-maze, elevated-plus maze, sociability, and tail-suspension tests were assessed on day 14. GAD67, AChE enzymes, and biomarkers of oxidative, nitrergic, and neuroinflammatory changes were assayed in the striatum, prefrontal cortex, and hippocampus. Naringin and ginseng reversed all SDS-induced behavioral impairments. Naringin increased the levels of GAD67 and decreased AChE activities in the striatum, prefrontal cortex, and hippocampus. Furthermore, naringin reduced pro-inflammatory cytokines (TNF-α, IL-6), malondialdehyde, nitrite concentrations, and increased glutathione levels in a region-dependent manner. Our study suggests that naringin attenuated SDS-induced behavioral endophenotypes of neuropsychiatric disease through increased GAD67 synthesis, inhibition of AChE activity, oxidative, nitrergic stress, and neuroinflammatory processes in stress-sensitive brain regions.
Asunto(s)
Antiinflamatorios/farmacología , Flavanonas/farmacología , Glutamato Descarboxilasa/metabolismo , Óxido Nítrico/metabolismo , Estrés Psicológico/tratamiento farmacológico , Animales , Antiinflamatorios/uso terapéutico , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Endofenotipos , Flavanonas/uso terapéutico , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Interleucina-6/metabolismo , Masculino , Aprendizaje por Laberinto , Ratones , Estrés Oxidativo , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Derrota Social , Estrés Psicológico/etiología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Psychosocial stress and biological predispositions are linked to mood and personality disorders related to psychiatric behaviors. Targeting neuroinflammation and oxidative stress has been recognized as a potential strategy for the prevention of psychosocial stress-induced psychiatric disorders. Morin, a bioactive compound isolated from mulberry leaf has been shown to produce antiamnesic, antipsychotic and anti-inflammatory effects relative to ginseng, a well-known adaptogen. Hence, the present study investigated the effect of morin on social-defeat stress (SDS)-induced behavioral, neurochemical, neuroimmune and neurooxidative changes in mice using intruder-resident paradigm. The intruder male mice were distributed into 6 groups (n = 10). Groups 1 (normal-control) and 2 (SDS-control) received normal saline, groups 3-5 had morin (25-100 mg/kg) while group 6 received ginseng (50 mg/kg) intraperitoneally daily for 14 days. Thirty minutes after treatment from days 7-14 onwards, mice in groups 2-6 were exposed to SDS for 10 min physical and psychological confrontations respectively with aggressive-resident mice. Neurobehavioral effects (locomotor activity, cognitive performance, anxiety- and depressive-like behavior) were assessed on day 14. Biomarkers of oxidative/nitrergic stress and neuroinflammation; acetylcholinesterase (AChE) and glutamic-acid decarboxylase-67 (GAD67) were measured in the striatum, prefrontal-cortex and hippocampus. Behavioral deficits induced by SDS were attenuated by morin and ginseng. Both morin and ginseng decreasedmalondialdehyde, nitrite levels and increased glutathione concentrations in the brain regions. They also reduced inflammatory mediators (TNF-α, IL-6, COX-2 and NF-κB), AChE activity and Nox-2 expression in the specific brain regions. However, morin increased the levels of GAD67 in the striatum, prefrontal-cortex and hippocampus in contrast to ginseng. Our results suggest that morin mitigates SDS-induced neurobehavioral deficits through enhancement of GAD67, inhibition of AChE activity, oxidative stress, Nox-2 and neuroinflammatory pathways.
Asunto(s)
Antioxidantes/farmacología , Encéfalo/efectos de los fármacos , Flavonoides/farmacología , Estrés Oxidativo/efectos de los fármacos , Estrés Psicológico/metabolismo , Animales , Encéfalo/metabolismo , Glutamato Descarboxilasa/metabolismo , Inflamación/etiología , Inflamación/metabolismo , Mediadores de Inflamación/metabolismo , Masculino , Ratones , NADPH Oxidasas/metabolismo , Estrés Oxidativo/fisiología , Estrés Psicológico/complicacionesRESUMEN
Curcumin shows antiglycemic effects in animals. Curcumin is chemically unstable at physiological pH, and its oxidative degradation products were shown to contribute to its anti-inflammatory effects. Since the degradation products may also contribute to other effects, we analyzed their role in the antiglycemic activity of curcumin. We quantified curcumin-induced release of glucagon-like peptide 1 (GLP-1) from mouse STC-1â¯cells that represent enteroendocrine L-cells as a major source of this anti-diabetic hormone. Curcumin induced secretion of GLP-1 in a dose-dependent manner. Two chemically stable analogues of curcumin that do not readily undergo degradation, were less active while two unstable analogues were active secretagogues. Chromatographically isolated spiroepoxide, an unstable oxidative metabolite of curcumin with anti-inflammatory activity, also induced secretion of GLP-1. Stable compounds like the final oxidative metabolite bicyclopentadione, and the major plasma metabolite, curcumin-glucuronide, were inactive. GLP-1 secretion induced by curcumin and its oxidative degradation products was associated with activation of PKC, ERK, and CaM kinase II. Since activity largely correlated with instability of curcumin and the analogues, we tested the extent of covalent binding to proteins in STC-1â¯cells and found it occurred with similar affinity as N-ethylmaleimide, indicating covalent binding occurred with nucleophilic cysteine residues. These results suggest that oxidative metabolites of curcumin are involved in the antiglycemic effects of curcumin. Our findings support the hypothesis that curcumin functions as a pro-drug requiring oxidative activation to reveal its bioactive metabolites that act by binding to target proteins thereby causing a change in function.
Asunto(s)
Antiinflamatorios no Esteroideos/farmacología , Curcumina/análogos & derivados , Curcumina/farmacología , Péptido 1 Similar al Glucagón/metabolismo , Animales , Línea Celular Tumoral , Hipoglucemiantes/farmacología , Oxidación-ReducciónRESUMEN
l-Arginine-nitric oxide pathway has been reported to be involved in the mediation of the psychopharmacological effects of many psychotropic drugs. Previous studies have shown that morin, a psychotropic compound isolated from mulberry leaf produces functional psychopharmacological effects indicative of antidepressant, antipsychotic, anxiolytic and nootropic properties. However, the role of l-arginine-nitric oxide pathway in the psychotropic effects of morin has not been fully investigated, hence, the need for this study. Male Swiss mice were pretreated individually or in combination with nitric oxide precursor [l-arginine (750 mg/kg, i.p.)], competitive nonselective nitric oxide synthase (NOS) inhibitor [N(G)-nitro-l-arginine methyl ester (l-NAME, i.p) (50 mg/kg)] or selective neuronal NOS inhibitor [methylene blue (3.75 mg/kg, i.p)] prior to morin (100 mg/kg, i.p.) or saline (10 mL/kg, i.p.) treatment. Psychopharmacological activities were then evaluated 30 min later using open field, Y-maze, and forced swim tests. l-Arginine significantly reversed the effects of morin on locomotion, memory and depression in mice. The reduced motor activity and enhanced memory function produced by morin were significantly attenuated by methylene blue but augmented the antimobility activity of morin in the FST. Moreover, l-NAME potentiated the psychopharmacological effects of morin in the open field and forced swim tests but reduced its memory promoting effect. Meanwhile, morin supplementation reversed the effects of l-arginine on l-NAME-treated mice in all behavioral models. The results of this study suggest that l-arginine-nitric oxide pathway might play a role in the modulation of the antidepressant and memory promoting effects of morin in mice.
Asunto(s)
Antidepresivos/administración & dosificación , Arginina/administración & dosificación , Flavonoides/administración & dosificación , Memoria/efectos de los fármacos , Actividad Motora/efectos de los fármacos , Óxido Nítrico/metabolismo , Animales , Antidepresivos/farmacología , Arginina/farmacología , Conducta Animal/efectos de los fármacos , Depresión/tratamiento farmacológico , Depresión/metabolismo , Modelos Animales de Enfermedad , Flavonoides/farmacología , Inyecciones Intraperitoneales , Masculino , Pruebas de Memoria y Aprendizaje , Azul de Metileno/administración & dosificación , Azul de Metileno/farmacología , Ratones , NG-Nitroarginina Metil Éster/administración & dosificación , NG-Nitroarginina Metil Éster/farmacología , Transducción de Señal/efectos de los fármacos , NataciónRESUMEN
This study evaluates the reproductive toxicity of ethyl acetate and butanolic fractions from crude methanolic leaf extract of Ocimum gratissimum in male Wistar rats. Acute toxicity was assessed to determine the safety dose, Sub-chronic reproductive toxicity studies were carried out by administering daily 25, 100 and 400â¯mg/kg body weight doses of the fractions to respective group of animals and 1â¯ml of normal saline daily for the control group for 28 days. Blood, epididymis and testes were harvested for reproductive hormones, sperm parameters, and histopathologic analysis respectively. There was significant (Pâ¯<â¯0.05) increase in serum levels of testosterone, body-weight gain, sperm count. There was also apparent increase in mean-testicular weight and preservation of testicular histology with increase spermatogenesis in both the ethyl acetate and butanolic fraction treated groups compared with control. Serum levels of luteinising hormone was however significantly (Pâ¯<â¯0.05) decrease across the groups compared to control. These effects were more pronounced in the butanolic fraction group compared to the ethyl acetate treated group. Sperm motility was also significantly (Pâ¯<â¯0.05) higher in the ethyl acetate treated group compared to control. Findings from this studies demonstrate that these fractions were non-toxic at the tested doses with regards to male reproduction but, rather, exhibited fertility enhancing effects which was better with the butanolic fraction. Our findings also shows that the ethyl acetate fraction may be safer than the butanolic fraction.
RESUMEN
Neuroinflammation plays a prominent role in the pathophysiology and progression of schizophrenia. Thus, suppression of neuroinflammation may retard the progression of the disease. This study was designed to investigate whether morin, a bioactive compound with antipsychotic-like activity could reduce biomarkers of neuroinflammation and neurodegeneration in lipopolysaccharide (LPS)- and ketamine (KET)-induced schizophrenic-like behavior in mice. Animals were treated once daily intraperitoneally with morin (100â¯mg/kg), haloperidol (1â¯mg/kg), risperidone (0.5â¯mg/kg), or saline (10â¯mL/kg) in combination with LPS (0.1â¯mg/kg) for 14 consecutive days. However, from days 8-14, overt schizophrenia-like episode was produced with i.p. injection of KET (20â¯mg/kg) once daily. Schizophrenic-like behaviors: positive (open-field test), negative (social-interaction and social-memory tests) and cognitive (Y-maze test) symptoms were assessed on day 14. Thereafter, the levels and expressions of biomarkers of neuroinflammation were estimated in the striatum (ST), prefrontal cortex (PFC) and hippocampus (HC) using spectrophotometry, ELISA and immunohistochemistry. The effects of morin on cortical pyramidal neurons were estimated using Golgi-impregnation staining technique. LPS in combination with KET significantly (pâ¯<â¯0.05) induced schizophrenia-like behaviors, which was attenuated by morin. Morin significantly (pâ¯<â¯0.05) decreased tumor necrosis factor-α, interleukine-6 levels and myeloperoxidase activity in the ST, PFC and HC of mice treated with LPSâ¯+â¯KET. Moreover, morin reduced regional brain expressions of cyclooxygenase-2, inducible nitric oxide synthase and nuclear factor kappa-B, and also rescued loss of pyramidal neurons in the PFC. Taken together, these findings suggest that morin reduces schizophrenic-like symptoms induced by LPSâ¯+â¯KET via mechanisms related to inhibition of the release of pro-inflammatory mediators and suppression of degeneration of cortical pyramidal neurons in mice.
Asunto(s)
Antioxidantes/uso terapéutico , Flavonoides/uso terapéutico , Células Piramidales/efectos de los fármacos , Esquizofrenia/tratamiento farmacológico , Animales , Conducta Animal/efectos de los fármacos , Corteza Cerebelosa/citología , Modelos Animales de Enfermedad , Humanos , Mediadores de Inflamación/metabolismo , Interleucina-6/metabolismo , Ketamina/metabolismo , Lipopolisacáridos/metabolismo , Masculino , Ratones , Inflamación Neurogénica , Peroxidasa/metabolismo , Células Piramidales/fisiología , Conducta Social , Degeneraciones Espinocerebelosas , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Flavonoids are naturally occurring bioactive phytochemical metabolites widely known to prevent and suppress several human diseases, and are important sources of therapeutic compounds from plants. Evidence derived from previous studies suggests that naringin, a neuroactive flavonoid possess functional beneficial neurobehavioral effects including anxiolytic, antidepressant and memory enhancing properties. However, literature search revealed that no studies have been carried out to evaluate the possible biochemical mechanisms involved in the neurobehavioral property of naringin alone following repeated treatment. Hence, this study was designed to evaluate the possible neuro-biochemical mechanisms involved in the neurobehavioral property of naringin following repeated administration in mice. The effects of naringin (2.5, 5 and 10 mg/kg), diazepam (2 mg/kg), imipramine (15 mg/kg) and donepezil (1 mg/kg) or vehicle on neurobehavioral and biochemical effects were evaluated in mice following repeated intraperitoneal injection for 7 consecutive days. Neurobehavioral activities consisting of open-field (locomotor), elevated-plus maze (anxiolytic), forced swim and social interaction (antidepressant and social preference), and Y-maze (memory enhancing) tests were assessed. Thereafter, brains levels of biomarkers of oxidative, nitrosative and cholinergic parameters were determined. Repeated treatment with naringin produced increased locomotor activity, and demonstrated antidepressant-like effects evidenced by decreased immobility time in forced swim test and increased % social preference in the social interaction test relative to controls. Also, naringin induced anxiolytic-like effect and increased cognitive performance in mice. Mechanistically, naringin significantly increased the activities of superoxide dismutase and catalase, and glutathione concentration relative to vehicle-controls. However, naringin significantly decreased malondialdehyde and nitrite contents, and reduced brain acetylcholinesterase activity in mice brains in a significant manner relative to controls. Taken together, these findings suggest that treatment with naringin might be useful to produce functional behavioral effects via mechanisms related to enhancement of cholinergic transmission, antioxidant defense systems, inhibition of lipid peroxidation and nitrosative processes.
Asunto(s)
Antioxidantes/farmacología , Flavanonas/farmacología , Locomoción/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Fármacos Neuroprotectores/farmacología , Animales , Relación Dosis-Respuesta a Droga , Peroxidación de Lípido/efectos de los fármacos , Peroxidación de Lípido/fisiología , Locomoción/fisiología , Masculino , Aprendizaje por Laberinto/fisiología , Ratones , Distribución AleatoriaRESUMEN
Evidence derived from preliminary studies suggests that morin, a neuroactive flavonoid with proven antioxidant and antiinflammatory properties possess antipsychotic-like activity. The present study was designed to evaluate the probable mechanisms involve in the antipsychotic-like activity of morin in ketamine model of schizophrenia. The effects of morin, haloperidol and risperidone on neurobehavioral and anti-schizophrenia-like effects were evaluated in mice (nâ¯=â¯7) following intraperitoneal (i.p.) administration of morin (25-100â¯mg/kg), haloperidol (1â¯mg/kg) and risperidone (0.5â¯mg/kg) alone or in combination with ketamine (20â¯mg/kg, i.p.) for 10 days. Neurobehavioral and schizophrenia-like activities consisting of open-field (positive symptoms), Y-maze, novel-object recognition (cognitive symptoms), social interaction (negative symptoms) tests were assessed. Also, wood-block catalepsy and rota-rod tests were employed to evaluate extrapyramidal side effects of morin. Thereafter, brain levels of biomarkers of oxidative, nitrergic and acetylcholinesterase alterations as well as histomorphological changes in the striatum and prefrontal-cortex were determined. Administration of morin and risperidone alone but not haloperidol significantly (p > 0.05) prevented ketamine-induced hyperlocomotion, social withdrawal and cognitive impairments relative to controls, and were devoid of extrapyramidal side effects. Morin alone or in combination with ketamine significantly increased glutathione concentration, superoxide dismutase and catalase activities compared with saline- or ketamine-treated mice. Moreover, morin alone or in combination with ketamine also significantly decreased malondialdehyde, nitrite and acetylcholinesterase alterations in mice brains. Furthermore, morin prevented ketamine-induced brain neuronal alterations in the striatum and prefrontal-cortex. Together, our findings suggest that morin may demonstrate antipsychotic-like therapeutic effect via modulation of oxidative/nitrergic, cholinergic actions and neuroprotection.
Asunto(s)
Antipsicóticos/uso terapéutico , Encéfalo/metabolismo , Flavonoides/uso terapéutico , Esquizofrenia/tratamiento farmacológico , Esquizofrenia/metabolismo , Anestésicos Disociativos/toxicidad , Animales , Antioxidantes/farmacología , Antioxidantes/uso terapéutico , Antipsicóticos/farmacología , Encéfalo/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Flavonoides/farmacología , Ketamina/toxicidad , Masculino , Ratones , Distribución Aleatoria , Esquizofrenia/inducido químicamenteRESUMEN
Previous studies have revealed that morin (MOR), a neuroactive bioflavonoid, with proven psychotropic and neuroprotective properties reduced schizophrenic-like behaviors in mice. This study further evaluated the ability of MOR to prevent and reverse ketamine-induced schizophrenic-like behaviors and the underlying neurochemical changes and increased oxidative/nitrergic stress in mice. In the preventive protocol, mice received intraperitoneal injection of MOR (100 mg/kg), reference antipsychotic drugs [haloperidol (1 mg/kg), risperidone (0.5 mg/kg)], or saline daily for 14 consecutive days prior to i.p. injection of ketamine (KET) (20 mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or saline for 14 days prior to MOR, haloperidol, risperidone, or saline treatments. Schizophrenic-like behaviors: positive (open-field test), negative (social-interaction test) and cognitive (Y-maze test) symptoms were evaluated. Thereafter, the brain levels of dopamine, glutamate, 5-hydroxytryptamine and acetyl-cholinesterase, as well as biomarkers of oxidative/nitrergic stress were measured in the striatum, prefrontal-cortex (PFC) and hippocampus (HC). Morin prevented and reversed KET-induced hyperlocomotion, social and cognitive deficits. Also, MOR or risperidone attenuated altered dopaminergic, glutamatergic, 5-hydroxytryptaminergic and cholinergic neurotransmissions in brain region-dependent manner. The increased malondialdehyde and nitrite levels accompanied by decreased glutathione concentrations in the striatum, PFC and HC in KET-treated mice were significantly attenuated by MOR or risperidone. Taken together, these findings suggest that the anti-schizophrenic-like activity of MOR may be mediated via mechanisms related to attenuation of neurochemical changes and oxidative/nitrergic alterations in mice.
Asunto(s)
Antipsicóticos/farmacología , Flavonoides/farmacología , Ketamina/farmacología , Estrés Oxidativo/efectos de los fármacos , Esquizofrenia/prevención & control , Animales , Antioxidantes/farmacología , Modelos Animales de Enfermedad , Hipocampo/efectos de los fármacos , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Esquizofrenia/inducido químicamenteRESUMEN
OBJECTIVES: This study was carried out to investigate the neurobehavioral properties of naringin, a flavonoid compound formed from naringenin on behavioral models in mice. METHOD: The neurobehavioral property of naringin (2.5, 5 and 10 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced rearing, locomotor behavior using open field test; anxiolytic effect was evaluated using hole-board, light and dark box, and elevated-plus maze paradigms. The anti-depressant-like property was also assessed using forced swim test (FST), tail suspension test (TST) and social interaction test (SIT). The cognitive enhancing effect of naringin was evaluated using Y-maze test. RESULTS: Intraperitoneal administration of naringin (2.5 and 5 mg/kg) demonstrated significant (p<0.05) increase in rearing behavior but not the spontaneous motor activity in comparison to control. In the anti-depressant test, naringin (2.5, 5 and 10 mg/kg, i.p.) significantly decreased the duration of immobility in the FST and TST, and increased the % social interaction preference in the SIT relative to controls, suggesting anti-depressant-like and increased social behaviors. Moreover, naringin also exhibited anxiolytic and memory enhancing properties in mice. CONCLUSION: These findings suggest that naringin possesses anti-depressant- and anxiolytic-like activities as well as memory enhancing effect in mice.
Asunto(s)
Conducta Animal/efectos de los fármacos , Flavanonas/farmacología , Actividad Motora/efectos de los fármacos , Animales , Ansiolíticos/farmacología , Antidepresivos/farmacología , Depresión/tratamiento farmacológico , Flavonoides/farmacología , Suspensión Trasera/métodos , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Pruebas de Estado Mental y Demencia , Ratones , NataciónRESUMEN
GABAergic (Gamma-aminobutyric acid) and neurotrophic derangements have important implication in schizophrenia, a neuropsychiatric disease. Previous studies have shown that nicotinamide adenine dinucleotide phosphate oxidase (NADPH-oxidase) alters GABAergic and neurotrophic activities via inflammatory and oxidative pathways. Thus, it has been proposed that agents with anti-oxidant and anti-inflammatory properties might be beneficial for the treatment of the disease. Morin is neuroactive bioflavonoid compound, which has been reported to demonstrate antipsychotic and anti-oxidant/anti-inflammatory activities. In this study, we further evaluated its effects on the brain markers of GABAergic, neurotrophic and oxidative alterations in the preventive and reversal of schizophrenia-like behavior induced by ketamine (KET). In the prevention protocol, adult mice were treated intraperitoneally with morin (100â¯mg/kg/day), haloperidol (1â¯mg/kg/day), risperidone (0.5â¯mg/kg/day), or saline (10â¯mL/kg/day) for 14 consecutive days. In addition, the animals were administered KET (20â¯mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or saline for 14â¯days. From 8th to 14th days mice were additionally treated with morin, haloperidol, risperidone or saline. Schizophrenic-like behaviors consisting of positive (stereotypy test), negative (behavioral despair in forced swim test) and cognitive (novel-object recognition test) symptoms were evaluated. Afterwards, brain levels of biomarkers of GABAergic (Glutamic acid decarboxylase-67, GAD67), neurotrophic (Brain-derived neurotrophic factor, BDNF) and oxidative [NADPH-oxidase, superoxide dismutase, (SOD) and catalase (CAT)] alterations were determined in the striatum, prefrontal cortex (PFC) and hippocampus, respectively. Morin significantly (pâ¯<â¯0.05) prevented and reversed KET-induced increased stereotypy, behavioral despair and deficit in cognitive functions when compared with KET-treated mice respectively. Also, morin and risperidone but not haloperidol, significantly (pâ¯<â¯0.05) prevented and reversed the decreases in expressions of GAD67 and BDNF immunoreactivity in the striatum, PFC and hippocampus caused by KET. Moreover, morin and risperidone significantly (pâ¯<â¯0.05) decreased regional brain expressions of NADPH-oxidase immunopositive cells and increased endogenous anti-oxidant enzymes (SOD and CAT) in the striatum, PFC and hippocampus relative to KET controls respectively. Taken together, these findings further suggest that the antipsychotic-like activity of morin may be mediated via mechanisms related to enhancement of GABAergic neurotransmission and neurotrophic factor, and suppression of NADPH-oxidase induced oxidative damage in mice.
Asunto(s)
Antioxidantes/uso terapéutico , Síntomas Conductuales/etiología , Síntomas Conductuales/prevención & control , Factor Neurotrófico Derivado del Encéfalo/metabolismo , Flavonoides/uso terapéutico , NADPH Oxidasas/metabolismo , Esquizofrenia/complicaciones , Animales , Antioxidantes/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Catalasa/metabolismo , Modelos Animales de Enfermedad , Antagonistas de Dopamina/farmacología , Antagonistas de Aminoácidos Excitadores/toxicidad , Haloperidol/farmacología , Ketamina/toxicidad , Masculino , Memoria a Corto Plazo/efectos de los fármacos , Ratones , Risperidona/farmacología , Esquizofrenia/inducido químicamente , Conducta Estereotipada/efectos de los fármacos , Superóxido Dismutasa/metabolismo , Natación/psicologíaRESUMEN
The involvement of oxidative, nitrergic, cholinergic and inflammatory alterations have been reported to contribute to the pathophysiology of schizophrenia, a debilitating neuropsychiatric disorder. Our previous studies have shown that doxycycline (DOX), a notable member of tetracyclines with proven antioxidant and anti-inflammatory properties, attenuated psychotic-like behaviors induced by apomophine and ketamine (KET) in mice. This present study was designed to further evaluate in detail the ability of DOX and its combination with risperidone (RIS) to prevent and reverse KET-induced schizophrenic-like behaviors and the role of oxidative/nitrergic and cholinergic pathways in mice. In the prevention protocol, mice were treated orally with DOX (25, 50 or 100â¯mg/kg), RIS (0.5â¯mg/kg), DOX (50â¯mg/kg) in combination with RIS, or vehicle for 14 consecutive days. In addition, the animals received intraperitoneal injection of KET (20â¯mg/kg/day) from the 8th to the 14th day. In the reversal protocol, the animals received KET or vehicle for 14â¯days prior to DOX, RIS, DOX in-combination with RIS or vehicle treatments. Schizophrenic-like behaviors consisting of positive, negative and cognitive symptoms were evaluated using open field, social interaction, Y-maze and novel object recognition tests. Thereafter, the brain levels of biomarkers of oxidative stress, nitrite and acetylcholinesterase activity were determined. DOX given alone or in combination with RIS attenuated schizophrenic-like behaviors induced by chronic injection of KET in both preventive and reversal treatment protocols. DOX significantly increased glutathione, superoxide dismutase and catalase levels in the brain of chronic KET-treated mice. However, it decreased malonyladehyde, nitrite levels and acetylcholinesterase activity when given alone or in-combination with RIS in both protocols. Taken together, these findings showed that doxycycline ameliorated schizophrenic-like behaviors induced by ketamine in both preventive and reversal treatment protocols in mice via inhibition of oxidative and nitrergic alterations, and acetylcholinesterase activity. Our data further suggests that adjunctive oral administration of doxycycline may augment the therapeutic efficacy of risperidone particularly for the treatment of negative and cognitive symptoms associated with schizophrenia.
Asunto(s)
Acetilcolinesterasa/metabolismo , Antipsicóticos/uso terapéutico , Doxiciclina/uso terapéutico , Nitroprusiato/metabolismo , Estrés Oxidativo/efectos de los fármacos , Esquizofrenia/prevención & control , Transducción de Señal/efectos de los fármacos , Animales , Catalasa/metabolismo , Modelos Animales de Enfermedad , Antagonistas de Aminoácidos Excitadores/toxicidad , Conducta Exploratoria/efectos de los fármacos , Glutatión/metabolismo , Ketamina/toxicidad , Masculino , Malondialdehído/metabolismo , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Reconocimiento en Psicología/efectos de los fármacos , Risperidona/uso terapéutico , Esquizofrenia/inducido químicamente , Superóxido Dismutasa/metabolismoRESUMEN
OBJECTIVES: Morin is a naturally occurring flavonoid with strong anti-oxidant and anti-inflammatory properties. Studies have shown that flavones modulate neurotransmission through enhancement of gamma amino butyric acid activity in the central nervous system; which led to the hypothesis that they could exert tranquilizing effects in rodents. Hence, this study was designed to evaluate the antipsychotic effect of morin on experimental animal models. METHODS: The antipsychotic effect of morin (25, 50 and 100 mg/kg) administered intraperitoneally (i.p.) was assessed on novelty-induced locomotion, apomorphine-induced stereotypy, ketamine-induced stereotypy, ketamine-induced hyperlocomotion and ketamine-enhanced immobility in forced swim test (FST). Catalepsy and rota rod tests were also carried out to evaluate the extrapyramidal side effects of morin. RESULTS: Morin (25, 50 and 100 mg/kg, i.p.) pretreatments significantly (p<0.05) demonstrated anti-schizophrenia-like behavior by inhibiting ketamine-induced hyperlocomotion in mice. Moreover, morin (50 and 100 mg/kg, i.p.) significantly (p<0.05) reduced spontaneous locomotor activity. Also, morin suppressed apomorphine-induced stereotypy and ketamine-induced stereotypy. The increase in immobility in FST due to ketamine administration was reduced by morin in a significant dose-dependent manner. Furthermore, the antipsychotic activity of morin was not associated with extrapyramidal side effects, as evidenced by decreased decent latency and increased motoric coordination and performance in mice. CONCLUSION: The results of the study revealed that morin demonstrated antipsychotic-like property devoid of extrapyramidal side effects in experimental animal models and may be beneficial in the treatment of schizophrenia-like behaviors; particularly in patients with behavioral hyperactivity and negative symptoms.
Asunto(s)
Antipsicóticos/farmacología , Catalepsia/prevención & control , Flavonoides/farmacología , Pérdida de Tono Postural/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Animales , Apomorfina/antagonistas & inhibidores , Apomorfina/farmacología , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Ketamina/antagonistas & inhibidores , Ketamina/farmacología , Locomoción/efectos de los fármacos , Masculino , Ratones , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: The leaf and fruit of Uvaria chamae P. Beauv (Annonaceae) are used in antimalarial ethnomedical preparations. Therefore, they were investigated for antimalarial activities as well as possible herb-drug interaction with amodiaquine (AQ). MATERIALS AND METHODS: The methanol extracts of the leaf (UCL) and fruit (UCF) were administered orally at 100-800mg/kg/day in mice infected with chloroquine (CQ)-sensitive Plasmodium berghei NK65 using the four-day, curative and prophylactic antimalarial test models. The UCL was further evaluated at 100-800mg/kg as twice-daily doses and combinations of UCL+AQ using the four-day test. Mice infected with CQ-resistant P. berghei ANKA were treated with UCL at 400mg/kg and AQ at 10mg/kg - [UCL400+AQ10]mg/kg - in the four-day and curative test models. RESULT: At 800mg/kg/day, UCL, UCF gave chemosuppression of 42, 28% (four-day test), parasite clearance of 36.3, 49.5% on day 5 (curative test) and 64.3, 82.6% (prophylactic test), respectively. The twice-daily dose of UCL at 800mg/kg showed activity of 51.50% while the combination of [UCL200+AQ5]mg/kg exhibited chemosuppression of 91.66%, which was not significantly different (p>0.05) from AQ at 10mg/kg (85.41%). In the CQ-resistant P. berghei experiment, the combination gave a chemosuppression of 45.80%, significantly lower (p<0.05) than AQ (78.40%) while the parasite clearance was not significantly different from AQ (curative test). CONCLUSION: The leaf extract showed moderate chemosuppressive activity. The lower-dose combination of the leaf extract and amodiaquine had better antimalarial activity in CQ-sensitive murine malaria. However, the tested combination had no beneficial antimalarial effect in CQ-resistant murine malaria.
Asunto(s)
Amodiaquina/uso terapéutico , Preparaciones de Plantas/uso terapéutico , Uvaria , Animales , Antimaláricos/farmacología , Interacciones de Hierba-Droga , Malaria/tratamiento farmacológico , Ratones , Plasmodium berghei/efectos de los fármacosRESUMEN
OBJECTIVES: Over the past years, there has been a growing number of knee osteoarthritis (KOA) patients who are not willing to comply with long-term non-steroidal anti-inflammatory drugs (NSAID) treatment and wish to use herbal anti- rheumatic medicine. This study assessed the clinical effects of Garcinia kola (GK) in KOA patients. PATIENTS AND METHODS: Prospective randomized, placebo controlled, double blind, clinical trial approved by the institutional medical ethics review board and written informed consent obtained from each patient. All KOA patients presenting at the Obafemi Awolowo University Teaching Hospital complex were recruited into the study. The patients were grouped into four (A = Placebo, B = Naproxen, C = Garcinia kola, D = Celebrex). The drugs and placebo were given twice a day per oral route. Each dose consisted of 200 mg of G. kola, Naproxen (500 mg), Celebrex (200 mg) and Ascorbic acid (100 mg). The primary outcome measure over six weeks study period was the change in mean WOMAC pain visual analogue scales (VAS). Secondary outcome measures included the mean change in joint stiffness and physical function (mobility/walking). RESULTS: 143 patients were recruited, 84 (58.7%, males--24, females--60) satisfied the selection criteria and completed the study. The effect of knee osteoarthritis bilateralism among the subjects was not significant on their outcome (p > 0.05). The change in the mean WOMAC pain VAS after six weeks of G. kola was significantly reduced compared to the placebo (p < 0.001). Multiple comparisons of the mean VAS pain change of G. kola group was not lowered significantly against the naproxen and celebrex groups (p > 0.05). The onset of G. kola symptomatic pain relief was faster than the placebo (p < 0.001). However, it was slower than the active comparators (p > 0.05). The duration of therapeutic effect of Garcinia kola was longer than the placebo (p > 0.001). G. kola period of effect was less than naproxen and celebrex (p < 0.001). G. kola subjects had improved mean change mobility/walking after six weeks better than the control group(p < 0.001). The mean change in mobility of the G. kola group when compared to the active comparators was not significantly better (p < 0.05). The mean change of knee joint stiffness (p < 0.001) and the change of mean WOMAC score (p < 0.001) were improved on Garcinia kola as compared to the placebo. The mid term outcome of eleven Garcinia kola subjects after cessation of use had a mean pain relief period of 17.27 +/- 5.15 days (range: 9-26 days). There was no significant cardiovascular, renal or drug induced adverse reaction to Garcinia kola. CONCLUSION: Garcinia kola appeared to have clinically significant analgesic/anti-inflammatory effects in knee osteoarthritis patients. Garcinia kola is a potential osteoarthritis disease activity modifier with good mid term outcome. Further studies are required for standardization of dosages and to determine long-term effects.
RESUMEN
In this study, we evaluated the effects of air-dried Spondias mombin leaves extracted with aqueous, methanol and ethanol solvents on hexobarbital-induced sleeping time and novelty-induced rearing (NIR) behaviours in mice and rats. We also studied the effect of the extracts on amphetamine- and apomorphine-induced stereotyped and picrotoxin-induced convulsive behaviour in rats. All residues from different extractions were dissolved in normal saline and administered intraperitoneally (i.p.). The methanolic and ethanolic extracts (12.5-100mg/kg i.p.) prolonged the hexobarbital-induced sleeping time and reduced the NIR in both mice and rat in a dose-dependent manner. The aqueous extract prolonged the hexobarbital-induced sleeping time and reduced (NIR) at doses of 50 and 100mg/kg. The inhibitory effect of the extracts on NIR was not reversed by atropine, yohimbine, naltrexone and flumazenil. However, the extracts blocked the facilitating effect of flumazenil. This suggests that NIR inhibitory effects of extracts of Spondia mombin are not mediated via muscarinic, alpha(2) adrenergic, and mu-opioid receptors, whereas, the extracts appear to facilitate GABAergic transmission. In addition the extracts blocked picrotoxin-induced convulsions. Phenolic compound(s) were present in the ethanolic and methanolic extracts, which exhibited anticonvulsant properties in the picrotoxin-induced convulsions model. The extracts decreased the amphetamine/apomorphine-induced stereotyped behaviour, which suggest that these extracts possess antidopaminergic activity. The effect of the extracts on hexobarbitone-induced sleeping time was blocked by flumazenil a GABA(A) antagonist, indicating that the extracts contain GABA(A) agonists. These results suggest that the leaves extracts of Spondias mombin possess sedative and antidopaminergic effects.
Asunto(s)
Anacardiaceae , Anticonvulsivantes/uso terapéutico , Antipsicóticos/farmacología , Actividad Motora/efectos de los fármacos , Extractos Vegetales/farmacología , Convulsiones/tratamiento farmacológico , Sueño/efectos de los fármacos , Conducta Estereotipada/efectos de los fármacos , Animales , Anticonvulsivantes/aislamiento & purificación , Antipsicóticos/aislamiento & purificación , Interacciones Farmacológicas , Femenino , Masculino , Ratones , Extractos Vegetales/aislamiento & purificación , Extractos Vegetales/toxicidad , Hojas de la Planta , Ratas , Ratas WistarRESUMEN
The aqueous extract of Calotropis procera was evaluated for its spasmolytic effect using in vitro trachea smooth muscle chain of Guinea-pig. The extract (50, 100 and 200 microg/ml) showed a dose-dependent relaxant activity probably exhibited through the direct relaxant action on the smooth muscle.