ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Scrophularia buergeriana has been used for traditional medicine as an agent for reducing heat in the blood and for nourishing kidney 'Yin'. Therefore, S. buergeriana might be a potential treatment for mental illness, especially schizophrenia, which may be attenuated by supplying kidney Yin and reducing blood heat. In a pilot study, we found that S. buergeriana alleviated sensorimotor gating dysfunction induced by MK-801. AIM OF THE STUDY: In the present study, we attempted to reveal the active component(s) of S. buergeriana as a candidate for treating sensorimotor gating dysfunction, and we identified 4-methoxycinnamic acid. We explored whether 4-methoxycinnamic acid could affect schizophrenia-like behaviors induced by hypofunction of the glutamatergic neurotransmitter system. MATERIALS AND METHODS: Mice were treated with 4-methoxycinnamic acid (3, 10, or 30 mg/kg, i.g.) under MK-801-induced schizophrenia-like conditions. The effect of 4-methoxycinnamic acid on schizophrenia-like behaviors were explored using several behavioral tasks. We also used Western blotting to investigate which signaling pathway(s) is involved in the pharmacological activities of 4-methoxycinnamic acid. RESULTS: 4-Methoxycinnamic acid ameliorated MK-801-induced prepulse inhibition deficits, social interaction disorders and cognitive impairment by regulating the phosphorylation levels of PI3K, Akt and GSK-3ß signaling in the prefrontal cortex. And there were no adverse effects in terms of catalepsy and motor coordination impairments. CONCLUSION: Collectively, 4-methoxycinnamic acid would be a potential candidate for treating schizophrenia with fewer adverse effects, especially the negative symptoms and cognitive dysfunctions.
Subject(s)
Cinnamates/therapeutic use , Dizocilpine Maleate/toxicity , Schizophrenia/chemically induced , Animals , Behavior, Animal/drug effects , Blotting, Western , Catalepsy/chemically induced , Catalepsy/drug therapy , Cinnamates/chemistry , Glycogen Synthase Kinase 3 beta/genetics , Glycogen Synthase Kinase 3 beta/metabolism , Male , Medicine, Traditional , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Phosphatidylinositol 3-Kinases/genetics , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Schizophrenia/drug therapy , Scrophularia/chemistry , Signal Transduction/drug effectsABSTRACT
In the suited rat-models, we focused on the stable pentadecapeptide BPC 157, L-NAME, NOS-inhibitor, and L-arginine, NOS-substrate, relation, the effect on schizophrenia-like symptoms. Medication (mg/kg intraperitoneally) was L-NAME (5), L-arginine (100), BPC 157 (0.01), given alone and/or together, at 5 min before the challenge for the acutely disturbed motor activity (dopamine-indirect/direct agonists (amphetamine (3.0), apomorphine (2.5)), NMDA-receptor non-competitive antagonist (MK-801 (0.2)), or catalepsy, (dopamine-receptor antagonist haloperidol (2.0)). Alternatively, BPC 157 10 µg/kg was given immediately after L-NAME 40 mg/kg intraperitoneally. To induce or prevent sensitization, we used chronic methamphetamine administration, alternating 3 days during the first 3 weeks, and challenge after next 4 weeks, and described medication (L-NAME, L-arginine, BPC 157) at 5 min before the methamphetamine at the second and third week. Given alone, BPC 157 or L-arginine counteracted the amphetamine-, apomorphine-, and MK-801-induced effect, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization. L-NAME did not affect the apomorphine-, and MK-801-induced effects, haloperidol-induced catalepsy and chronic methamphetamine-induced sensitization, but counteracted the acute amphetamine-induced effect. In combinations (L-NAME + L-arginine), as NO-specific counteraction, L-NAME counteracts L-arginine-induced counteractions in the apomorphine-, MK-801-, haloperidol- and methamphetamine-rats, but not in amphetamine-rats. Unlike L-arginine, BPC 157 maintains its counteracting effect in the presence of the NOS-blockade (L-NAME + BPC 157) or NO-system-over-stimulation (L-arginine + BPC 157). Illustrating the BPC 157-L-arginine relationships, BPC 157 restored the antagonization (L-NAME + L-arginine + BPC 157) when it had been abolished by the co-administration of L-NAME with L-arginine (L-NAME + L-arginine). Finally, BPC 157 directly inhibits the L-NAME high dose-induced catalepsy. Further studies would determine precise BPC 157/dopamine/glutamate/NO-system relationships and clinical application.
Subject(s)
Amphetamine/pharmacology , Apomorphine/pharmacology , Arginine/pharmacology , Catalepsy , Dizocilpine Maleate/pharmacology , Dopamine Agents/pharmacology , Enzyme Inhibitors/pharmacology , Haloperidol/pharmacology , NG-Nitroarginine Methyl Ester/pharmacology , Neuroprotective Agents/pharmacology , Nitric Oxide Synthase , Peptide Fragments/pharmacology , Proteins/pharmacology , Schizophrenia , Amphetamine/administration & dosage , Animals , Apomorphine/administration & dosage , Arginine/administration & dosage , Behavior, Animal/drug effects , Catalepsy/chemically induced , Catalepsy/drug therapy , Catalepsy/physiopathology , Disease Models, Animal , Dizocilpine Maleate/administration & dosage , Dopamine Agents/administration & dosage , Enzyme Inhibitors/administration & dosage , Haloperidol/administration & dosage , Male , NG-Nitroarginine Methyl Ester/administration & dosage , Neuroprotective Agents/administration & dosage , Nitric Oxide Synthase/antagonists & inhibitors , Peptide Fragments/administration & dosage , Proteins/administration & dosage , Rats , Rats, Wistar , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Schizophrenia/physiopathologyABSTRACT
We determined anti-Parkinson's activity of M. chamomilla L. tea in chlorpromazine (CPZ) developed investigational animal model. In this research, effects of M. chamomilla L. tea 2.14ml/ kg P.O were studied on cataleptic behavior and its effect on brain histopathological changes and immunohistochemistry (IHC) in rats. The experimental design was developed by administering CPZ (3mg/kg, I/P) for twenty-one days to produce Parkinson's disease-like symptoms to 4 animal groups. We observed that chlorpromazine significantly produced motor dysfunctions (catalepsy) in a time period of twenty-one days. The M. chamomilla L. significantly (P<0.005) minimized/shorten/taper down catalepsy in rats just like standard group (Levodopa/carbidopa treated group). The maximum reduction was observed from both treated and standard groups on the 21st day. M. chamomilla L. treated rats mid brain sections showed presence of proliferative blood vessels, increase cellularity with reactive glial cells as compared to CPZ group. Furthermore, immunostaining CD68 & CD21 of M. chamomilla L. treated rats mid brain region showed few CD68 cells & no polymorphs neutrophils after CD21 staining. Thus, this research work disclosed the neuroprotective effect of M. chamomilla L. tea against Parkinson's disease-like symptoms or anti-Parkinson's activity induced by CPZ.
Subject(s)
Antiparkinson Agents/pharmacology , Behavior, Animal/drug effects , Brain/drug effects , Catalepsy/prevention & control , Matricaria , Motor Activity/drug effects , Neuroprotective Agents/pharmacology , Parkinsonian Disorders/prevention & control , Plant Extracts/pharmacology , Animals , Antiparkinson Agents/isolation & purification , Brain/metabolism , Brain/pathology , Brain/physiopathology , Catalepsy/chemically induced , Catalepsy/pathology , Catalepsy/physiopathology , Chlorpromazine , Disease Models, Animal , Male , Matricaria/chemistry , Neuroprotective Agents/isolation & purification , Parkinsonian Disorders/chemically induced , Parkinsonian Disorders/pathology , Parkinsonian Disorders/physiopathology , Plant Extracts/isolation & purification , Rats, WistarABSTRACT
INTRODUCTION: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. OBJECTIVE: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. MATERIALS AND METHODS: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. RESULTS: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. CONCLUSION: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.
Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.
Subject(s)
Antiparkinson Agents/therapeutic use , Monoamine Oxidase Inhibitors/therapeutic use , Parkinson Disease, Secondary/drug therapy , Animals , Antiparkinson Agents/administration & dosage , Carbidopa/administration & dosage , Catalepsy/chemically induced , Coumarins , Disease Models, Animal , Drug Combinations , Drug Evaluation, Preclinical , Haloperidol , Levodopa/administration & dosage , Locomotion/drug effects , Male , Mice , Mice, Inbred ICR , Monoamine Oxidase Inhibitors/administration & dosage , Parkinson Disease, Secondary/chemically induced , Reserpine/administration & dosageABSTRACT
Abstract Introduction: Parkinson's disease is the second most common neurodegenerative disease. Monoamine oxidase B inhibitors are used in the treatment of this disease concomitantly with levodopa or as monotherapy. Several substituted coumarins have shown activity as inhibitors of monoamine oxidase B. Objective: To evaluate the possible antiparkinsonian effects of the coumarin analogue FCS005 (3-methyl-7H-furo[3,2-g]chromen-7-one) in mouse models, as well as its inhibitory activity towards monoamine oxidases (MAO) and its antioxidant activity. Materials and methods: FCS005 was synthesized and the reversal of hypokinesia was evaluated in the reserpine and levodopa models. Moreover, in the haloperidol model, its anticataleptic effects were evaluated. Additionally, the monoamine oxidase inhibitory activity and antioxidant activity of FCS005 were evaluated using in vitro and ex vivo studies, respectively. Results: FCS005 (100 mg/kg) caused the reversal of hypokinesia in the reserpine and levodopa models. This furocoumarin also presented anti-cataleptic effects at the same dose. Besides, it showed selective inhibitory activity towards the MAO-B isoform and antioxidant activity. Conclusion: These results attribute interesting properties to the compound FCS005. It is important to continue research on this molecule considering that it could be a potential antiparkinsonian agent.
Resumen Introducción. El segundo trastorno neurodegenerativo más común es la enfermedad de Parkinson. Los inhibidores de la monoamino oxidasa B se emplean en el tratamiento de esta enfermedad en monoterapia o concomitantemente con levodopa. Varios compuestos cumarínicos han mostrado actividad como inhibidores de la monoamino oxidasa B. Objetivo. Evaluar los posibles efectos antiparkinsonianos del análogo de la cumarina FCS005 (3-methyl-7H-furo [3,2-g ] chromen-7-one) en modelos de ratones, la actividad inhibitoria frente a las monoamino oxidasas (MAO) y la actividad antioxidante. Materiales y métodos. Se sintetizó la furanocumarina FCS005 y, en los modelos de reserpina y levodopa, se evaluó si producía reversión de la hipocinesia; en el modelo de haloperidol se evaluaron sus efectos anticatalépticos. Además, se evaluó in vitro la actividad inhibidora de MAO y, ex vivo, la actividad antioxidante del compuesto FCS005. Resultados. El compuesto FCS005 en dosis de 100 mg/kg produjo la remisión de la hipocinesia en los modelos de reserpina y de levodopa. Esta furanocumarina presentó efectos anticatalépticos con la misma dosis. Además, mostró tener actividad inhibitoria selectiva sobre la MAO B, así como efectos antioxidantes. Conclusión. Los resultados evidenciaron propiedades interesantes del compuesto FCS005. Es importante continuar investigando esta molécula porque puede ser un potencial agente antiparkinsoniano.
Subject(s)
Animals , Male , Mice , Parkinson Disease, Secondary/drug therapy , Monoamine Oxidase Inhibitors/therapeutic use , Antiparkinson Agents/therapeutic use , Parkinson Disease, Secondary/chemically induced , Reserpine/administration & dosage , Carbidopa/administration & dosage , Catalepsy/chemically induced , Levodopa/administration & dosage , Coumarins , Disease Models, Animal , Drug Combinations , Drug Evaluation, Preclinical , Haloperidol , Locomotion/drug effects , Mice, Inbred ICR , Monoamine Oxidase Inhibitors/administration & dosage , Antiparkinson Agents/administration & dosageABSTRACT
Haloperidol-induced catalepsy is an animal model of a psychotic disorder that may be associated with neurodegeneration and free radical damage. Auricularia polytricha is effective in both prevention and treatment of numerous types of neurological disorders. In the present study, anticataleptic activity of aqueous extract of A polytricha (AEAP) at different doses (400 and 600 mg/kg, respectively, p.o.) was studied using haloperidol-induced (1 mg/ kg, i.p.) catalepsy in rats. Repeated treatment with haloperidol (1 mg/kg, i.p.) on each other day for 15 days (days 5, 10, and 15) significantly induced catalepsy in rats. The effect of AEAP at different doses (400 and 600 mg/kg, p.o.) on levels of superoxide dismutase, catalase, and glutathione reductase as well as inhibition of lipid peroxidation in the forebrain region was assessed. After 15 days of treatment, AEAP (400 and 600 mg/kg) significantly inhibited haloperidol-induced catalepsy. Treatment with AEAP (400 and 600 mg/kg) exhibited significant elevation in the levels of superoxide dismutase, catalase, and glutathione reductase as well as lipid peroxidation in the forebrain region compared to the haloperidol-treated group. The study concludes that AEAP (400 and 600 mg/kg) significantly protects animals against haloperidol-induced catalepsy.
Subject(s)
Basidiomycota/chemistry , Catalepsy/drug therapy , Plant Extracts/pharmacology , Protective Agents/pharmacology , Animals , Antipsychotic Agents/adverse effects , Catalepsy/chemically induced , Disease Models, Animal , Fruiting Bodies, Fungal/chemistry , Haloperidol/adverse effects , Lipid Peroxidation/drug effects , Male , Oxidative Stress/drug effects , Rats , Rats, Wistar , WaterABSTRACT
Zizyphus jujuba Mill, a famous oriental traditional medicine, has been reported to exhibit diverse activities in biological systems including the respiratory system. However, a little information is available on its antiasthmatic activity. Jujuboside B (JB) is a natural saponin and one of the active constituent of fruits of Zizyphus jujuba. In the present investigation, JB was isolated from ethanolic extracts of fruits of Zizyphus jujuba (EZJF). EZJF and JB were then evaluated for anti-asthmatic activity using various screening methods. JB was additionally evaluated using ovalbumin (OVA) -induced allergic asthma in mice. Results obtained in the present study showed that EZJF and JB significantly inhibited clonidine-induced catalepsy, milk-induced leucocytosis and eosinophilia, clonidine-induced mast cell degranulation, and passive paw anaphylaxis. The number of inflammatory cells in bronchoalveolar lavage (BAL) fluid was considerably lowered and the severity of pulmonary inflammation was alleviated in the mice pretreated with JB. The high-level expression of T-helper type 2 (TH2) cytokines was markedly reduced in the serum, BAL fluid, and lung homogenates. Thus EZJF and JB showed potent anti-asthmatic activity. Hence EZJF and JB possess a potential role in the treatment of asthma.
Subject(s)
Anti-Asthmatic Agents/therapeutic use , Asthma/drug therapy , Plant Extracts/therapeutic use , Saponins/therapeutic use , Ziziphus/chemistry , Animals , Anti-Asthmatic Agents/pharmacology , Asthma/chemically induced , Catalepsy/chemically induced , Catalepsy/drug therapy , Clonidine/pharmacology , Clonidine/therapeutic use , Cytokines/metabolism , Disease Models, Animal , Eosinophilia/drug therapy , Leukocytosis/chemically induced , Leukocytosis/drug therapy , Lung/pathology , Mast Cells/drug effects , Medicine, Chinese Traditional , Mice , Milk/toxicity , Ovalbumin/toxicity , Plant Extracts/pharmacology , Rats , Rats, Wistar , Saponins/pharmacologyABSTRACT
BACKGROUND: The root extract of Albizia zygia (DC.) J.F. Macbr. (Leguminosae) is used to manage mental disorders in African traditional medicine. However, its value, particularly, against negative and cognitive symptoms of schizophrenia have not been evaluated. AIM: The aim of this study was to evaluate the antipsychotic properties of the hydroethanolic root extract of Albizia zygia (AZE) against positive, negative and cognitive symptoms of schizophrenia in animal models. MATERIALS AND METHODS: The effects of AZE (30-300â¯mgâ¯kg-1) were evaluated against apomorphine-induced cage climbing as well as ketamine -induced hyperlocomotion, -enhanced immobility, -impaired social interaction and novel object recognition. The propensity of AZE to induce catalepsy and to attenuate haloperidol-induced catalepsy were also investigated. RESULTS: AZE 30-300â¯mgâ¯kg-1 significantly reduced apomorphine-induced climbing behaviour as well as ketamine-induced hyperlocomotion, immobility and object recognition deficits (at least Pâ¯<â¯0.05). Moreover, the extract showed no cataleptic effect but significantly inhibited haloperidol-induced catalepsy at a dose of 30â¯mgâ¯kg-1 (Pâ¯<â¯0.05). CONCLUSION: The root extract of Albizia zygia exhibited an antipsychotic-like activity in mice with potential to alleviate positive, negative and cognitive symptoms of schizophrenia.
Subject(s)
Albizzia , Antipsychotic Agents/pharmacology , Behavior, Animal/drug effects , Plant Extracts/pharmacology , Plant Roots , Schizophrenia/drug therapy , Schizophrenic Psychology , Albizzia/chemistry , Animals , Antipsychotic Agents/isolation & purification , Antipsychotic Agents/toxicity , Catalepsy/chemically induced , Catalepsy/physiopathology , Catalepsy/prevention & control , Catalepsy/psychology , Cognition/drug effects , Disease Models, Animal , Exploratory Behavior/drug effects , Haloperidol , Male , Mice, Inbred ICR , Motor Activity/drug effects , Phytotherapy , Plant Extracts/isolation & purification , Plant Extracts/toxicity , Plant Roots/chemistry , Plants, Medicinal , Schizophrenia/physiopathology , Social BehaviorABSTRACT
Due to the high prevalence of psychiatric disorders and the prevalent side effects produced by the antipsychotic drugs available, it is necessary to search for new therapeutic options. Galphimia glauca has been used for many years in Mexican traditional medicine for treating mental diseases. From this plant, some compounds, denominated galphimines, have been discovered and have shown to possess the ability of modifying the frequency of discharge of dopaminergic neurons in the Ventral tegmental area. The objective of the present work was to evaluate the effect produced by the G. glauca extract, a Galphimine rich fraction (GRF), as well as the pure galphimines (G-A, G-B, and G-E) on behavioral models in mice. Products obtained from G. glauca were evaluated in the Haloperidol-induced catalepsy test and in the acute schizophrenia-like symptoms-induced with Ketamine (KET) in mice. Catalepsy was evaluated through the bar test, and schizophrenia-like symptoms, by means of the Open Field Test (OFT), Passive Avoidance Test (PAT), and the Forced Swimming Test (FST). The methanolic extract from G. glauca, GRF, and the pure galphimines were able to interact with the dopaminergic pathway and modify the behavioral response such as to potentiate the cataleptic effect induced with Haloperidol and to inhibit the behavior induced by KET in mice exposed to OFT, and FST. Moreover, the G. glauca extract and GRF were capable of blocking the cognitive decline that was induced with KET in mice (evaluated by PAT). Based on these results, it is possible to assume that part of the effect of G. glauca is due to the interaction of Galphimines with the dopaminergic and glutamatergic systems in vivo. It can be concluded that the products obtained from G. glauca potentiate the cataleptic effect induced with Haloperidol and show a protector effect on some of the symptoms generated by KET in mice (KET is capable of provoking halucinations in humans and psychosis-like behaviour in mice). With this basis, the metanolic extract from G. glauca, and the GRF are capable of blocking positive and cognitive symptoms associated with psychosis induced by KET. In addition, it could be suggested that the galphimines are responsible for the inhibition of the positive symptoms observed.
Subject(s)
Antipsychotic Agents/adverse effects , Catalepsy/chemically induced , Galphimia/adverse effects , Haloperidol/adverse effects , Ketamine/adverse effects , Plant Extracts/adverse effects , Triterpenes/adverse effects , Animals , Antipsychotic Agents/administration & dosage , Avoidance Learning/drug effects , Behavior, Animal/drug effects , Catalepsy/psychology , Dose-Response Relationship, Drug , Haloperidol/administration & dosage , Herb-Drug Interactions , Ketamine/administration & dosage , Male , Mice, Inbred ICR , Plant Extracts/administration & dosage , Swimming , Triterpenes/administration & dosageABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Seed kernel of the plant Ceasalpinia bonducella Linn (Caesalpiniacaeae) are used for the treatment of asthma in folk medicine and ancient books. AIM OF STUDY: To assess the pharmacological efficacy of the plant in asthma and to confine and describe the synthetic constituents from the seeds that are in charge of the action. MATERIAL AND METHODS: The viability of petroleum ether, ethanol extract and ethyl acetate fraction from ethanol extract of C. bonducella seeds were screened for the treatment of asthma by various methods viz. effect of test drug on clonidine and haloperidol induced catalepsy, milk-induced leukocytosis and eosinophilia, mast cell stabilizing activity in mice and studies on smooth muscle preparation of guinea pig ileum (in-vitro). Column chromatography of active extract was done to pinpoint the active compound followed by structure elucidation by FTIR, GCMS and NMR spectroscopic methods. RESULTS: Ethyl acetate fraction from ethanol extract of C. bonducella seeds exhibited antihistaminic activity at the dose of 50 and 100â¯mg/kg, inhibited clonidine-induced catalepsy but not haloperidol-induced catalepsy. Ethyl acetate fraction from ethanol extract significantly inhibited increased leukocyte and eosinophil count due to milk allergen and showed maximum protection against mast cell degranulation by clonidine. The results of guinea pig ileum indicated that the compound 2 methyl, 1 hexadecanol isolated from ethyl acetate fraction of ethanol extract relaxed significantly the ileum muscle strips pre-contracted by which suggests the involvement of ß2-agonists on the relaxation of the tissue. All the results are dose dependent. Active ethyl acetate fraction from ethanol extract showed presence of anti-asthmatic compound, 2-methyl, 1-hexadecanol. CONCLUSION: The ethyl acetate fraction from ethanol extract of seeds of the plant C. bonducella can inhibit parameters linked to asthma disease.
Subject(s)
Anti-Allergic Agents/pharmacology , Anti-Asthmatic Agents/pharmacology , Caesalpinia , Histamine Antagonists/pharmacology , Plant Extracts/pharmacology , Seeds , Acetates/chemistry , Animals , Anti-Allergic Agents/isolation & purification , Anti-Allergic Agents/toxicity , Anti-Asthmatic Agents/isolation & purification , Anti-Asthmatic Agents/toxicity , Caesalpinia/chemistry , Caesalpinia/toxicity , Catalepsy/chemically induced , Catalepsy/prevention & control , Cell Degranulation/drug effects , Clonidine , Disease Models, Animal , Dose-Response Relationship, Drug , Eosinophilia/chemically induced , Eosinophilia/prevention & control , Female , Guinea Pigs , Haloperidol , Histamine Antagonists/isolation & purification , Histamine Antagonists/toxicity , Ileum/drug effects , Ileum/metabolism , Lethal Dose 50 , Leukocytosis/chemically induced , Leukocytosis/prevention & control , Male , Mast Cells/drug effects , Mast Cells/metabolism , Mice , Milk , Muscle Relaxation/drug effects , Muscle, Smooth/drug effects , Muscle, Smooth/metabolism , Phytotherapy , Plant Extracts/isolation & purification , Plant Extracts/toxicity , Plants, Medicinal , Receptors, Adrenergic, beta-2/drug effects , Receptors, Adrenergic, beta-2/metabolism , Seeds/chemistry , Seeds/toxicity , Solvents/chemistry , Time FactorsABSTRACT
BACKGROUND: Desmodium adscendens extract (DAE) is used traditionally in Ghana for the management of psychosis. The present study aimed at providing pharmacological evidence for its ethnomedical use by testing the hypothesis that an ethanolic extract of Desmodium adscendens may possess antipsychotic properties. METHODS: The primary behavioral effects of DAE on the central nervous system of mice were investigated using Irwin's test paradigm. Novelty-induced and apomorphine-induced locomotor and rearing behaviors in mice were explored in an open-field observational test system. Apomorphine-induced cage climbing test in mice was used as the antipsychotic animal model. The ability of DAE to induce catalepsy and enhance haloperidol-induced catalepsy was also investigated in mice. RESULTS: The DAE produced sedation, cholinergic-, and serotonergic-like effects in mice when evaluated using the Irwin's test. No lethality was observed after 24 h post-treatment. The LD50 in mice was estimated to be greater than 3000 mg/kg. The DAE significantly decreased the frequency of novelty- and apomorphine-induced rearing and locomotor activities in mice. It also significantly lowered the frequency and duration of apomorphine-induced climbing activities in mice. It did not induce any cataleptic event in naïve mice but only significantly enhanced haloperidol-induced catalepsy at a dose of 1000 mg/kg. CONCLUSIONS: The ethanolic extract of Desmodium adscendens exhibited antipsychotic-like activities in mice. Motor side effects are only likely to develop at higher doses of the extract.
Subject(s)
Antipsychotic Agents/pharmacology , Ethanol/chemistry , Fabaceae/chemistry , Animals , Apomorphine/pharmacology , Catalepsy/chemically induced , Catalepsy/drug therapy , Disease Models, Animal , Female , Haloperidol/pharmacology , Mice , Mice, Inbred ICR , Motor Activity/drug effects , Phytotherapy/methods , Plant Extracts/pharmacologyABSTRACT
Among non-dopaminergic strategies for combating Parkinson's disease (PD), antagonism of the A2A adenosine receptor (AR) has emerged to show great potential. In this study, on the basis of two crystal structures of the A2A AR with the best capability to distinguish known antagonists from decoys, docking-based virtual screening (VS) was conducted to identify novel A2A AR antagonists. A total of 63 structurally diverse compounds identified by VS were submitted to experimental testing, and 11 of them exhibited substantial activity against the A2A AR (Ki < 10 µM), including two compounds with Ki below 1 µM (compound 43, 0.42 µM; compound 51, 0.27 µM) and good A2A/A1 selectivity (fold < 0.1). Compounds 43 and 51 demonstrated antagonistic activity according to the results of cAMP measurements (cAMP IC50 = 1.67 and 1.80 µM, respectively) and showed good efficacy in the haloperidol-induced catalepsy (HIC) rat model for PD at doses of up to 30 mg/kg. Further lead optimization based on a substructure searching strategy led to the discovery of compound 84 as an excellent A2A AR antagonist (A2A Ki = 54 nM, A2A/A1 fold < 0.1, cAMP IC50 = 0.3 µM) that exhibited significant improvement in anti-PD efficacy in the HIC rat model.
Subject(s)
Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Drug Evaluation, Preclinical/methods , Parkinson Disease/drug therapy , Receptor, Adenosine A2A/metabolism , Adenosine A2 Receptor Antagonists/therapeutic use , Animals , Catalepsy/chemically induced , Catalepsy/drug therapy , Haloperidol/pharmacology , Male , Models, Molecular , Molecular Conformation , Rats , Rats, Wistar , User-Computer InterfaceABSTRACT
AIMS AND BACKGROUND: Psychosis is a neurological disorder, which is usually defined as the "loss of contact with reality." As medicine 'Hemidesmusindicus' holds a reputed place in all systems of medicine in India. It is given in the form of infusion, fine particles, or syrup. It is also a component of several medicinal preparations. The present research work is pertaining to find out an anti-psychotic activity of an aqueous root extract of Hemidesmusindicus- a time bound study in rats. METHODS: In the present study, the dried roots of Hemidesmusindicus were crushed to a coarse powder and extracted with water under reflux for 36 hours to obtain the aqueous extract of roots of Hemidesmusindicus (AERHI). The extract was reconstituted in 2% aqueous tragacanth just before use and administered orally at a dose 0f 100 mg/kg, 300 mg/kg and 500 mg/kg. In a single dose study, the parameters were assessed after oral administration of the single dose of the AERHI, whereas in a multiple dose study, the animals daily received the suitable oral dose of the AERHI for a period of 30 days. The parameters were assessed on the 15th and 30th day. The antipsychotic activity was screened using Apomorphine induced Stereotyped behavior in rats and Haloperidol induced catalepsy models were used. In Apomorphine induced Stereotyped behavior inhibition of the Stereotyped behavior was considered to be anti-psychotic activity and in Haloperidol induced catalepsy, we observed whether the AERHI potentate or attenuate the catalepsy in rats. RESULTS: In this study, the extract of Hemidesmusindicus significantly inhibited the stereotyped behavior induced by apomorphine in rats and also potentiate the catalepsy induced by haloperidol, thereby showing its anti-psychotic activity. CONCLUSION: All these observations imply that Hemidesmusindicus extract possesses anti-psychotic activity in experimental animals.
Subject(s)
Antipsychotic Agents/pharmacology , Catalepsy/drug therapy , Hemidesmus/chemistry , Plant Extracts/pharmacology , Animals , Catalepsy/chemically induced , Drug Delivery Systems , Haloperidol , Patents as Topic , Plant Roots/chemistry , RatsABSTRACT
Chronic use of typical antipsychotic haloperidolis related to movement disturbances such as parkinsonism, akathisia and tardive dyskinesia which have been related to excitotoxicity in extrapyramidal brain areas, requiring their prevention and treatment. In the current study we evaluated the influence of the magnesium on prevention (for 28days before-), reversion (for 12days after-) and concomitant supplementation on haloperidol-induced movement disorders in rats. Sub-chronic haloperidol was related to orofacial dyskinesia (OD) and catalepsy development, increased generation of reactive species (RS) and levels of protein carbonyl (PC) in cortex, striatum and substantia nigra (SN) in all experimental protocols. When provided preventatively, Mg reduced the increase of OD and catalepsy time 14 and 7days after haloperidol administration, respectively. When supplemented after haloperidol-induced OD establishment, Mg reversed this behavior after 12days, while catalepsy was reversed after 6days of Mg supplementation.When Mg was concomitantly supplemented with haloperidol administration, OD and catalepsy were prevented. Moreover, Mg supplementation was able to prevent the RS generation in both cortex and SN, reducing PC levels in all brain areas evaluated. When supplemented after haloperidol, Mg reversed RS generation in cortex and striatum, decreasing PC levels in SN and striatum.The co-administration of haloperidol and Mg supplementation prevented RS generation in cortex, striatum and SN, and PC levels in the SN.These outcomes indicate that Mg supplementation may be a useful alternative to prevent movement disturbances resulting of classic antipsychotic pharmacotherapy as haloperidol.
Subject(s)
Antipsychotic Agents/pharmacology , Catalepsy/chemically induced , Catalepsy/drug therapy , Dyskinesias/drug therapy , Haloperidol/pharmacology , Magnesium/pharmacology , Analysis of Variance , Animals , Brain/drug effects , Brain/metabolism , Chick Embryo , Disease Models, Animal , Dose-Response Relationship, Drug , Dyskinesias/etiology , Haloperidol/administration & dosage , Male , Protein Carbonylation/drug effects , Rats , Rats, Wistar , Time FactorsABSTRACT
A series of novel compounds with two halogen substituents have been designed and synthesized to further optimize the 2-phenylcyclopropylmethylamine scaffold in the quest for drug-like 5-HT2C agonists. Compound (+)-22a was identified as a potent 5-HT2C receptor agonist, with good selectivity against the 5-HT2B and the 5-HT2A receptors. ADMET assays showed that compound (+)-22a possessed desirable properties in terms of its microsomal stability, and CYP and hERG inhibition, along with an excellent brain penetration profile. Evaluation of (+)-22a in animal models of schizophrenia-related behaviors revealed that it had a desirable activity profile, as it reduced d-amphetamine-stimulated hyperlocomotion in the open field test, it restored d-amphetamine-disrupted prepulse inhibition, it induced cognitive improvements in the novel object recognition memory test in NR1-KD animals, and it produced very little catalepsy relative to haloperidol. These data support the further development of (+)-22a as a drug candidate for the treatment of schizophrenia.
Subject(s)
Cognition/drug effects , Hyperkinesis/psychology , Prepulse Inhibition/drug effects , Receptor, Serotonin, 5-HT2C/drug effects , Serotonin 5-HT2 Receptor Agonists/chemical synthesis , Serotonin 5-HT2 Receptor Agonists/pharmacology , Animals , Brain/metabolism , Catalepsy/chemically induced , Central Nervous System Stimulants , Dextroamphetamine , Drug Design , Drug Evaluation, Preclinical , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Female , Humans , Hyperkinesis/chemically induced , Hyperkinesis/drug therapy , Male , Mice , Mice, Inbred C57BL , Microsomes, Liver/metabolism , Recognition, Psychology/drug effects , Schizophrenia/drug therapy , Schizophrenic Psychology , Structure-Activity Relationship , Substrate SpecificityABSTRACT
Adamantane-containing glutamate blocker IEM-1913 (1-amino-4-(1-adamantane-amino)-butane dihydrochloride) equals to memantine in antiparkinsonian potency, but surpasses it in anticonvulsive, antidepressant, and analgesic activities. Moreover, its use is less toxic and safer. IEM-1913 produces significant pharmacological effects at a wide concentration diapason (0.03-1.00 mg/kg), while memantine is effective within a narrow range only (15-20 mg/kg). High pharmacological efficacy and low toxicity of IEM-1913 can be explained by the fact that in contrast to monocationic selective NMDA antagonist memantine, the dicationic glutamate blocker IEM-1913 produces a combined block of cerebral NMDA and AMPA receptors.
Subject(s)
Bridged-Ring Compounds/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Memantine/pharmacology , Putrescine/analogs & derivatives , Analgesics/pharmacology , Analgesics/therapeutic use , Animals , Anticonvulsants/pharmacology , Anticonvulsants/toxicity , Antidepressive Agents/pharmacology , Antidepressive Agents/toxicity , Antiparkinson Agents/pharmacology , Antiparkinson Agents/toxicity , Bridged-Ring Compounds/toxicity , Catalepsy/chemically induced , Catalepsy/drug therapy , Drug Evaluation, Preclinical , Excitatory Amino Acid Antagonists/toxicity , Haloperidol/toxicity , Hot Temperature/adverse effects , Lethal Dose 50 , Memantine/toxicity , Mice , Pentylenetetrazole/toxicity , Physical Endurance/drug effects , Putrescine/pharmacology , Putrescine/toxicity , Rats , Rats, Wistar , Receptors, AMPA/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Reflex/drug effects , Seizures/chemically induced , Seizures/drug therapyABSTRACT
Phosphodiesterase 10A (PDE10A) has garnered attention as a potential therapeutic target for schizophrenia due to its prominent striatal expression and ability to modulate striatal signaling. The present study used the selective PDE10A inhibitor MP-10 and the dopamine D2 antagonist haloperidol to compare effects of PDE10A inhibition and dopamine D2 blockade on striatopallidal (D2) and striatonigral (D1) pathway activation. Our studies confirmed that administration of MP-10 significantly elevates expression of the immediate early genes (IEG) c-fos, egr-1, and arc in rat striatum. Furthermore, we demonstrated that MP-10 induced egr-1 expression was distributed evenly between enkephalin-containing D2-neurons and substance P-containing D1-neurons. In contrast, haloperidol (3 mg/kg) selectively activated egr-1 expression in enkephalin neurons. Co-administration of MP-10 and haloperidol (0.5 mg/kg) increased IEG expression to a greater extent than either compound alone. Similarly, in a rat catalepsy assay, administration of haloperidol (0.5 mg/kg) or MP-10 (3-30 mg/kg) did not produce cataleptic behavior when dosed alone, but co-administration of haloperidol with MP-10 (3 and 10 mg/kg) induced cataleptic behaviors. Interestingly, co-administration of haloperidol with a high dose of MP-10 (30 mg/kg) failed to produce cataleptic behavior. These findings are important for understanding the neural circuits involved in catalepsy and suggest that the behavioral effects produced by PDE10A inhibitors may be influenced by concomitant medication and the level of PDE10A inhibition achieved by the dose of the inhibitor.
Subject(s)
Catalepsy/chemically induced , Corpus Striatum/drug effects , Dopamine Antagonists/pharmacology , Haloperidol/pharmacology , Phosphodiesterase Inhibitors/pharmacology , Pyrazoles/pharmacology , Quinolines/pharmacology , Animals , Catalepsy/metabolism , Corpus Striatum/metabolism , Cytoskeletal Proteins/metabolism , Dose-Response Relationship, Drug , Early Growth Response Protein 1/metabolism , Enkephalins/metabolism , Gene Expression/drug effects , Gene Expression Profiling , Male , Nerve Tissue Proteins/metabolism , Neurons/drug effects , Neurons/metabolism , Phosphoric Diester Hydrolases/metabolism , Proto-Oncogene Proteins c-fos/metabolism , Rats, Sprague-Dawley , Rats, Wistar , Receptors, Dopamine D2/metabolism , Substance P/metabolism , Substantia Nigra/drug effects , Substantia Nigra/metabolismABSTRACT
Tea is the most popular beverage worldwide. Caffeine, the psychoactive principle of tea, pharmacologically interacts with several drugs and bioactive molecules. Epigallocatechin gallate (EGCG) is a major component of tea and its known interactions with caffeine make it worthwhile to further study them by investigating the influence of EGCG on the anticataleptic and locomotor-sensitizing effects of caffeine. In the present investigation, we observed that (a) administration of caffeine or EGCG alone inhibited haloperidol-induced catalepsy, a widely used animal model to study parkinsonism, and (b) a combination of caffeine and EGCG produced greater inhibition of haloperidol-induced catalepsy. Furthermore, after repeated administration of caffeine and EGCG, either alone or in combination, we observed that (c) caffeine and EGCG contrasted the sensitization of catalepsy observed after repeated haloperidol administration by significantly reducing the duration of catalepsy. Furthermore, as haloperidol-induced catalepsy was also associated with increased lipid peroxidation, we observed that (d) EGCG administration reduced striatal lipid peroxide levels in a dose-dependent manner and that (e) the combination of caffeine with EGCG was most effective in reducing haloperidol-increased striatal lipid peroxide. Finally, we observed that (f) chronic caffeine and EGCG significantly elicited locomotor sensitization and that (g) their combination resulted in significantly greater effects. In conclusion, EGCG potentiated the effects of caffeine on haloperidol-induced catalepsy and of caffeine-elicited locomotor sensitization. Overall, these observations indicate critical interactions between caffeine and EGCG in an animal model of parkinsonism and locomotor activity and suggest that tea consumption might reduce antipsychotic-induced side effects.
Subject(s)
Caffeine/pharmacology , Catalepsy/drug therapy , Catechin/analogs & derivatives , Haloperidol/toxicity , Animals , Antipsychotic Agents/toxicity , Caffeine/administration & dosage , Catalepsy/chemically induced , Catechin/administration & dosage , Catechin/isolation & purification , Catechin/pharmacology , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Synergism , Lipid Peroxidation/drug effects , Male , Mice , Motor Activity/drug effects , Parkinsonian Disorders/drug therapy , Parkinsonian Disorders/physiopathology , Tea/chemistryABSTRACT
OBJECTIVE: To examine the effects of dehydroepiandrosterone (DHEA) on animal models of schizophrenia. METHODS: Seventy Swiss albino female mice (25-35 g) were divided into 4 groups: amphetamine-free (control), amphetamine, 50, and 100 mg/kg DHEA. The DHEA was administered intraperitoneally (ip) for 5 days. Amphetamine (3 mg/kg ip) induced hyper locomotion, apomorphine (1.5 mg/kg subcutaneously [sc]) induced climbing, and haloperidol (1.5 mg/kg sc) induced catalepsy tests were used as animal models of schizophrenia. The study was conducted at the Animal Experiment Laboratories, Department of Pharmacology, Medical School, Eskisehir Osmangazi University, Eskisehir, Turkey between March and May 2012. Statistical analysis was carried out using Kruskal-Wallis test for hyper locomotion, and one-way ANOVA for climbing and catalepsy tests. RESULTS: In the amphetamine-induced locomotion test, there were significant increases in all movements compared with the amphetamine-free group. Both DHEA 50 mg/kg (p<0.05), and 100 mg/kg (p<0.01) significantly decreased all movements compared with the amphetamine-induced locomotion group. There was a significant difference between groups in the haloperidol-induced catalepsy test (p<0.05). There was no significant difference between groups in terms of total climbing time in the apomorphine-induced climbing test (p>0.05). CONCLUSION: We observed that DHEA reduced locomotor activity and increased catalepsy at both doses, while it had no effect on climbing behavior. We suggest that DHEA displays typical neuroleptic-like effects, and may be used in the treatment of schizophrenia.
Subject(s)
Adjuvants, Immunologic/therapeutic use , Amphetamine/toxicity , Central Nervous System Stimulants/toxicity , Dehydroepiandrosterone/therapeutic use , Schizophrenia/chemically induced , Schizophrenia/drug therapy , Animals , Apomorphine , Catalepsy/chemically induced , Catalepsy/physiopathology , Disease Models, Animal , Dose-Response Relationship, Drug , Locomotion/drug effects , Mice , Schizophrenia/physiopathology , Statistics, Nonparametric , Time FactorsABSTRACT
Lectin-functionalized, polyethylene glycol-block-poly-(D,L)-lactic-co-glycolic acid nanoparticles loaded with haloperidol were prepared with narrow size distributions and sizes <135nm. The nanoparticles exhibited high Solanum tuberosum lectin (STL) conjugation efficiencies, encapsulation efficiencies, and drug loading capacities. The in vitro release of haloperidol was 6-8% of the loaded amount in endo-lysosomal conditions over 96h, demonstrating minimal drug leakage and the potential for the efficient drug transport to the targeted brain tissue. The haloperidol released upon erosion was successful in displacing [(3)H] N-propylnorapomorphine and binding to bovine striatal dopamine D2 receptors. Both haloperidol-loaded nanoparticle formulations were found to be highly effective at inducing catalepsy. Intranasal administration of STL-functionalized nanoparticles increased the brain tissue haloperidol concentrations by 1.5-3-fold compared to non-STL-functionalized particles and other routes of administration. This formulation demonstrates promise in the reduction of the drug dose necessary to produce a therapeutic effect with antipsychotic drugs for the treatment of schizophrenia.