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1.
Article in Chinese | WPRIM | ID: wpr-888005

ABSTRACT

Cannabinoid receptor type 2( CB2 R),a member of the G protein-coupled receptor( GPCR) superfamily,has a variety of biological activities,such as regulating pain response,resisting inflammation and fibrosis,and mediating bone metabolism. Some CB2 R regulators exhibit a good regulatory effect on bone metabolism. Cannabinoids in Cannabis sativa can cause psychoactive effects despite various pharmacological actions they exerted by targeting CB2 R. Therefore,it is of great significance to discover CB2 R regulators in non-Cannabis plants for finding new lead compounds without psychoactive effects and elucidating the action mechanism of plant drugs. The present study clarifies the discovery,structure,and physiological functions of CB2 R,especially its regulatory effects on bone metabolism,summarized CB2 R regulators extracted from non-Cannabis plants,and systematically analyzes the regulatory effects of CB2 R regulators on bone metabolism in animals,osteoblasts,and osteoclasts,to provide a scientific basis for the discovery of new CB2 R regulators and the development of anti-osteoporotic drugs.


Subject(s)
Animals , Cannabinoids/pharmacology , Cannabis , Osteoblasts , Osteoclasts , Receptors, Cannabinoid
2.
Chinese Journal of Biotechnology ; (12): 1968-1985, 2021.
Article in Chinese | WPRIM | ID: wpr-887775

ABSTRACT

Phytocannabinoids are bioactive terpenoids that are exclusive to Cannabis sativa L. The main pharmacologically active phytocannabinoids are Δ9-tetrahydrocannabinol and cannabidiol, both target endogenous cannabinoid receptors. Δ9-tetrahydrocannabinol and cannabidiol have extensive therapeutic potential due to their participation in many physiological and pathological processes in human body by activating the endocannabinoid system. At present, Δ9-tetrahydrocannabinol, cannabidiol and their analogues or combination preparations are used to treat epilepsy, vomiting in patients with cancer chemotherapy, spasticity in multiple sclerosis and relieve neuropathic pain and pain in patients with advanced cancer. With the further exploration of the application value of Δ9-tetrahydrocannabinol and cannabidiol as well as the increasing demand for standardization of pharmaceutical preparations, it is imminent to achieve large-scale production of Δ9-tetrahydrocannabinol and cannabidiol in the pharmaceutical industry. In this article, pharmacological research progress of phytocannabinoids in recent years, biosynthetic pathways of phytocannabinoids and the mechanism of key enzymes as well as various product development strategies of cannabinoids in pharmaceutical industry are reviewed. By exploring the potential of synthetic biology as an alternative strategy for the source of phytocannabinoids, it will provide a theoretical basis for the research and development of microbial engineering for cannabinoids synthesis, and promote the large-scale production of medicinal cannabinoids.


Subject(s)
Cannabidiol , Cannabinoids/biosynthesis , Cannabis , Humans , Receptors, Cannabinoid
3.
Mem. Inst. Oswaldo Cruz ; 114: e190062, 2019. tab, graf
Article in English | LILACS | ID: biblio-1012673

ABSTRACT

BACKGROUND Formation of schistosomal granulomata surrounding the ova can result in schistosomiasis-associated liver fibrosis (SSLF). The current standard of treatment is praziquantel (PZQ), which cannot effectively reverse SSLF. The role of the cannabinoid (CB) receptor family in liver fibrosis has recently been highlighted. OBJECTIVES This study aimed to assess the therapeutic effect of CB1 receptor antagonism in reversing SSLF in a murine model of Schistosoma mansoni infection. METHODS One hundred male Swiss albino mice were divided equally into five groups: healthy uninfected control (group I), infected control (group II), PZQ treated (group III), rimonabant (RIM) (SR141716, a CB1 receptor antagonist)-treated (group IV) and group V was treated with combined PZQ and RIM. Liver sections were obtained for histopathological examination, alpha-1 smooth muscle actin (α-SMA) immunostaining and assessment of CB1 receptor expression using real-time polymerase chain reaction (RT-PCR). FINDINGS The most effective reduction in fibrotic marker levels and granuloma load was achieved by combined treatment with PZQ+RIM (group V): CB1 receptor expression (H = 26.612, p < 0.001), number of α-SMA-positive cells (F = 57.086, p < 0.001), % hepatic portal fibrosis (F = 42.849, p < 0.001) and number of granulomata (F = 69.088, p < 0.001). MAIN CONCLUSIONS Combining PZQ with CB1 receptor antagonists yielded the best results in reversing SSLF. To our knowledge, this is the first study to test this regimen in S. mansoni infection.


Subject(s)
Humans , Fibrosis/diagnosis , Typhus, Endemic Flea-Borne/transmission , Liver/physiopathology , Receptors, Cannabinoid
4.
Article in English | WPRIM | ID: wpr-740755

ABSTRACT

BACKGROUND/AIMS: MicroRNAs (miRNAs) were reported to be responsible for intestinal permeability in diarrhea-predominant irritable bowel syndrome (IBS-D) rats in our previous study. However, whether and how miRNAs regulate visceral hypersensitivity in IBS-D remains largely unknown. METHODS: We established the IBS-D rat model and evaluated it using the nociceptive visceral hypersensitivity test, myeloperoxidase activity assay, restraint stress-induced defecation, and electromyographic (EMG) activity. The distal colon was subjected to miRNA microarray analysis followed by isolation and culture of colonic epithelial cells (CECs). Bioinformatic analysis and further experiments, including dual luciferase assays, quantitative real-time polymerase chain reaction, western blot, and enzyme-linked immunosorbent assay, were used to detect the expression of miRNAs and how it regulates visceral hypersensitivity in IBS-D rats. RESULTS: The IBS-D rat model was successfully established. A total of 24 miRNAs were differentially expressed in the distal colon of IBS-D rats; 9 were upregulated and 15 were downregulated. Among them, the most significant upregulation was miR-200a, accompanied by downregulation of cannabinoid receptor 1 (CNR1) and serotonin transporter (SERT). MiR-200a mimic markedly inhibited the expression of CNR1/SERT. Bioinformatic analysis and luciferase assay confirmed that CNR1/SERT are direct targets of miR-200a. Rescue experiments that overexpressed CNR1/SERT significantly abolished the inhibitory effect of miR-200a on the IBS-D rats CECs. CONCLUSIONS: This study suggests that miR-200a could induce visceral hyperalgesia by targeting the downregulation of CNR1 and SERT, aggravating or leading to the development and progression of IBS-D. MiR-200a may be a regulator of visceral hypersensitivity, which provides potential targets for the treatment of IBS-D.


Subject(s)
Animals , Blotting, Western , Colon , Computational Biology , Defecation , Diarrhea , Down-Regulation , Enzyme-Linked Immunosorbent Assay , Epithelial Cells , Hyperalgesia , Hypersensitivity , Irritable Bowel Syndrome , Luciferases , Microarray Analysis , MicroRNAs , Models, Animal , Permeability , Peroxidase , Rats , Real-Time Polymerase Chain Reaction , Receptors, Cannabinoid , Serotonin Plasma Membrane Transport Proteins , Serotonin , Up-Regulation
5.
Article in Korean | WPRIM | ID: wpr-725027

ABSTRACT

OBJECTIVES: According to previous studies, the cannabinoid receptor 1 (CNR1) gene could be an important candidate gene for schizophrenia. Some studies have linked the (AAT)n trinucleotide repeat polymorphism in CNR1 gene with the risk of schizophrenia. Meanwhile, smooth pursuit eye movement (SPEM) has been regarded as one of the most consistent endophenotypes of schizophrenia. In this study, we investigated the association between the (AAT)n trinucleotide repeats in CNR1 gene and SPEM abnormality in Korean patients with schizophrenia. METHODS: We measured SPEM function in 167 Korean patients with schizophrenia (84 male, 83 female) and they were divided according to SPEM function into two groups, good and poor SPEM function groups. We also investigated allele frequencies of (AAT)n repeat polymorphisms on CNR1 gene in each group. A logistic regression analysis was performed to find the association between SPEM abnormality and the number of (AAT)n trinucleotide repeats. RESULTS: The natural logarithm value of signal/noise ratio (Ln S/N ratio) of the good SPEM function group was 4.34 ± 0.29 and that of the poor SPEM function group was 3.21 ± 0.70. In total, 7 types of trinucleotide repeats were identified, each containing 7, 10, 11, 12, 13, 14, and 15 repeats, respectively. In the patients with (AAT)₇ allele, the distributions of the good and poor SPEM function groups were 18 (11.1%) and 19 (11.0%) respectively. In the patients with (AAT)₁₀ allele, (AAT)₁₁ allele, (AAT)₁₂ allele, (AAT)₁₃ allele, (AAT)₁₄ allele and (AAT)₁₅ allele, the distributions of good and poor SPEM function groups were 13 (8.0%) and 12 (7.0%), 4 (2.5%) and 6 (3.5%), 31 (19.8%) and 35 (20.3%), 51 (31.5%) and 51 (29.7%), 36 (22.2%) and 45 (26.2%), 9 (5.6%) and 4 (2.3%) respectively. As the number of (AAT) n repeat increased, there was no aggravation of abnormality of SPEM function. CONCLUSIONS: There was no significant aggravation of SPEM abnormality along with the increase of number of (AAT)n trinucleotide repeats in the CNR1 gene in Korean patients with schizophrenia.


Subject(s)
Alleles , Endophenotypes , Eye Movements , Gene Frequency , Humans , Logistic Models , Male , Pursuit, Smooth , Receptors, Cannabinoid , Schizophrenia , Trinucleotide Repeats
6.
Article in English | WPRIM | ID: wpr-147098

ABSTRACT

The cannabinoid (CB2) receptor type 2 has been proposed to prevent the degeneration of dopamine neurons in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. However, the mechanisms underlying CB2 receptor-mediated neuroprotection in MPTP mice have not been elucidated. The mechanisms underlying CB2 receptor-mediated neuroprotection of dopamine neurons in the substantia nigra (SN) were evaluated in the MPTP mouse model of Parkinson's disease (PD) by immunohistochemical staining (tyrosine hydroxylase, macrophage Ag complex-1, glial fibrillary acidic protein, myeloperoxidase (MPO), and CD3 and CD68), real-time PCR and a fluorescein isothiocyanate-labeled albumin assay. Treatment with the selective CB2 receptor agonist JWH-133 (10 μg kg⁻¹, intraperitoneal (i.p.)) prevented MPTP-induced degeneration of dopamine neurons in the SN and of their fibers in the striatum. This JWH-133-mediated neuroprotection was associated with the suppression of blood-brain barrier (BBB) damage, astroglial MPO expression, infiltration of peripheral immune cells and production of inducible nitric oxide synthase, proinflammatory cytokines and chemokines by activated microglia. The effects of JWH-133 were mimicked by the non-selective cannabinoid receptor WIN55,212 (10 μg kg⁻¹, i.p.). The observed neuroprotection and inhibition of glial-mediated neurotoxic events were reversed upon treatment with the selective CB2 receptor antagonist AM630, confirming the involvement of the CB2 receptor. Our results suggest that targeting the cannabinoid system may be beneficial for the treatment of neurodegenerative diseases, such as PD, that are associated with glial activation, BBB disruption and peripheral immune cell infiltration.


Subject(s)
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine , Animals , Blood-Brain Barrier , Chemokines , Cytokines , Dopamine , Dopaminergic Neurons , Fluorescein , Glial Fibrillary Acidic Protein , Macrophages , Mice , Microglia , Neurodegenerative Diseases , Neuroprotection , Nitric Oxide Synthase Type II , Parkinson Disease , Peroxidase , Real-Time Polymerase Chain Reaction , Receptor, Cannabinoid, CB2 , Receptors, Cannabinoid , Substantia Nigra
7.
Article in English | WPRIM | ID: wpr-109543

ABSTRACT

Irritable bowel syndrome (IBS) is the most common disorder referred to gastroenterologists and is characterized by altered bowel habits, abdominal pain, and bloating. Visceral hypersensitivity (VH) is a multifactorial process that may occur within the peripheral or central nervous systems and plays a principal role in the etiology of IBS symptoms. The pharmacological studies on selective drugs based on targeting specific ligands can provide novel therapies for modulation of persistent visceral hyperalgesia. The current paper reviews the cellular and molecular mechanisms underlying therapeutic targeting for providing future drugs to protect or treat visceroperception and pain sensitization in IBS patients. There are a wide range of mediators and receptors participating in visceral pain perception amongst which substances targeting afferent receptors are attractive sources of novel drugs. Novel therapeutic targets for the management of VH include compounds which alter gut-brain pathways and local neuroimmune pathways. Molecular mediators and receptors participating in pain perception and visceroperception include histamine-1 receptors, serotonin (5-hydrodytryptamine) receptors, transient receptor potential vanilloid type I, tachykinins ligands, opioid receptors, voltage-gated channels, tyrosine receptor kinase receptors, protease-activated receptors, adrenergic system ligands, cannabinoid receptors, sex hormones, and glutamate receptors which are discussed in the current review. Moreover, several plant-derived natural compounds with potential to alleviate VH in IBS have been highlighted. VH has an important role in the pathology and severity of complications in IBS. Therefore, managing VH can remarkably modulate the symptoms of IBS. More preclinical and clinical investigations are needed to provide efficacious and targeted medicines for the management of VH.


Subject(s)
Abdominal Pain , Central Nervous System , Gonadal Steroid Hormones , Humans , Hyperalgesia , Hypersensitivity , Irritable Bowel Syndrome , Ligands , Pain Perception , Pathology , Phosphotransferases , Receptors, Adrenergic , Receptors, Cannabinoid , Receptors, Glutamate , Receptors, Opioid , Receptors, Proteinase-Activated , Receptors, Serotonin , Tachykinins , Tyrosine , Visceral Pain
8.
IJRM-Iranian Journal of Reproductive Medicine. 2015; 13 (4): 221-226
in English | IMEMR | ID: emr-166770

ABSTRACT

Premenstrual dysphoric disorder [PMDD] is a mood disorder characterized with physical and affective symptoms during the luteal phase of susceptible women. The aim of this study was to investigate the association of Dopamine D3 receptor [DRD3] polymorphism, and Cannabinoid receptor Type 1 [CNR1] polymorphism with PMDD. Fifty one participants with documented PMDD according to the DSM IV criteria and 51 healthy controls were included in this cross sectional study. Symptom severity was measured with daily self-rating, monthly premenstrual assessment forms and psychiatric interviews. The genotyping of DRD3 receptor and Cannabinoid type 1 receptors were performed using Taqmanfluorogenic assay method. Distribution of DRD3 and CNR1 polymorphism was not different between patients and controls. These findings do not support a major role of DRD3, and CNR1 polymorphisms in contributing to susceptibility to premenstrual dysphoric disorder


Subject(s)
Humans , Female , Receptors, Dopamine D3 , Receptors, Cannabinoid , Polymorphism, Genetic , Cross-Sectional Studies , Receptor, Cannabinoid, CB1
9.
Article in English | WPRIM | ID: wpr-178042

ABSTRACT

Endocannabinoids can affect multiple cellular targets, such as cannabinoid (CB) receptors, transient receptor potential cation channel, subfamily V, member 1 (TRPV1) and peroxisome proliferator-activated receptor gamma (PPARgamma). The stimuli to induce adipocyte differentiation in hBM-MSCs increase the gene transcription of the CB1 receptor, TRPV1 and PPARgamma. In this study, the effects of three endocannabinoids, N-arachidonoyl ethanolamine (AEA), N-arachidonoyl dopamine (NADA) and 2-arachidonoyl glycerol (2-AG), on adipogenesis in hBM-MSCs were evaluated. The adipocyte differentiation was promoted by AEA whereas inhibited by NADA. No change was observed by the treatment of non-cytotoxic concentrations of 2-AG. The difference between AEA and NADA in the regulation of adipogenesis is associated with their effects on PPARgamma transactivation. AEA can directly activate PPARgamma. The effect of AEA on PPARgamma in hBM-MSCs may prevail over that on the CB1 receptor mediated signal transduction, giving rise to the AEA-induced promotion of adipogenesis. In contrast, NADA had no effect on the PPARgamma activity in the PPARgamma transactivation assay. The inhibitory effect of NADA on adipogenesis in hBM-MSCs was reversed not by capsazepine, a TRPV1 antagonist, but by rimonabant, a CB1 antagonist/inverse agonist. Rimonabant by itself promoted adipogenesis in hBM-MSCs, which may be interpreted as the result of the inverse agonism of the CB1 receptor. This result suggests that the constantly active CB1 receptor may contribute to suppress the adipocyte differentiation of hBM-MSCs. Therefore, the selective CB1 agonists that are unable to affect cellular PPARgamma activity inhibit adipogenesis in hBM-MSCs.


Subject(s)
Adipocytes , Adipogenesis , Dopamine , Endocannabinoids , Ethanolamine , Felodipine , Glycerol , Humans , Mesenchymal Stem Cells , PPAR gamma , Receptor, Cannabinoid, CB1 , Receptors, Cannabinoid , Signal Transduction , Transcriptional Activation
10.
Acta Physiologica Sinica ; (6): 332-340, 2014.
Article in Chinese | WPRIM | ID: wpr-297484

ABSTRACT

The aim of the present study was to explore the role of orphan G protein-coupled receptor 55 (GPR55) in diabetic gastroparesis (DG). Streptozotocin (STZ) was used to mimic the DG model, and the body weight and blood glucose concentration were tested 4 weeks after STZ injection (i.p.). Electrogastrogram and phenolsulfonphthalein test were used for detecting gastric emptying. Motilin (MTL), gastrin (GAS), vasoactive intestinal peptide (VIP), and somatostatin (SS) levels in plasma were determined using radioimmunology. Real-time PCR and Western blot were applied to identify the expression of GPR55 in gastric tissue, and immunohistochemistry was used to detect the distribution. The effect of lysophosphatidylinositol (LPI), an agonist of GPR55, was observed. STZ mice showed increased blood glucose concentration, lower body weight, decreased amplitude of slow wave, and delayed gastric emptying. LPI antagonized these effects of STZ. Compared to the control group, STZ caused significant decreases of MTL and GAS levels (P < 0.01), as well as increases of SS and VIP levels (P < 0.01). The changes of these hormones induced by STZ were counteracted when using LPI. GPR55 located in mice stomach, and it was up-regulated in DG. Although LPI showed no effects on the distribution and expression of GPR55 in normal mice, it could inhibit STZ-induced GPR55 up-regulation. These results suggest GPR55 is involved in the regulation of gastric movement of DG, and may serve as a new target of DG treatment. LPI, an agonist of GPR55, can protect against STZ-induced DG, and the mechanism may involve the change of GPR55 expression and modification of gastrointestinal movement regulating hormones.


Subject(s)
Animals , Diabetes Mellitus, Experimental , Metabolism , Pathology , Gastroparesis , Metabolism , Pathology , Lysophospholipids , Pharmacology , Mice , Receptors, Cannabinoid , Metabolism
11.
Rev. Fac. Odontol. (B.Aires) ; 28(65): 42-47, jul.-dic. 2013. ilus, graf, tab
Article in Spanish | LILACS | ID: lil-762480

ABSTRACT

El presente trabajo aporta evidencia de la presencia de receptores de cannabinoides en la glándula submaxilar de la rata, cuya expresión secircunscribe a componentes acinares y ductales. A su vez, los resultados expuestos confirman la participación de los receptores de cannabinoides en el control de la secreción salival, y por ende aportan una explicación empírica a la hiposialia observada luego del consumo de marihuana


The present study provides evidence for the presence of cannabinoid receptors in rat submandibular gland, whose expression is restricted to acinar and ductal components. In turn, the presented results confirm the involvement of cannabinoid receptors in the control of salivary secretion, and thus provide an empirical explanation to hyposialia observed after marijuana consumption.


Subject(s)
Animals , Rats , Submandibular Gland/physiopathology , Receptors, Cannabinoid , Xerostomia/etiology , Xerostomia/physiopathology , Cannabis/adverse effects , Salivation/physiology
12.
Rio de Janeiro; s.n; 2013. 125 p. ilus, tab, graf.
Thesis in Portuguese | LILACS | ID: lil-716025

ABSTRACT

Analisar a associação recíproca entre fatores de risco cardiometabólico, níveis de adipocitocinas (leptina e adiponectina de alto peso molecular), endocanabinoides (anandamida [AEA] e 2-araquidonoilglicerol [2-AG]), compostos canabimiméticos (N-oleoiletanolamina [OEA] e N-palmitoiletanolamina [PEA]) e polimorfismos em genes codificadores de componentes do sistema endocanabinoide (enzima de degradação de endocanabinoides FAAH [gene FAAH] e receptor endocanabinoide CB1 [gene CNR1]) e do receptor PPAR-α[genePPARA], em indivíduos com diferentes graus de adiposidade. Duzentos indivíduos, entre 18 e 60 anos, com diferentes graus de índice de massa corporal (IMC) compuseram a amostra, dividida em dois grupos: cem eutróficos (IMC < 25 kg/m2) e 100 obesos (IMC ≥30 kg/m2), com 50 homens e 50 mulheres em cada grupo. Os obesos ficaram assim distribuídos: grau 1, com IMC < 35 kg/m2(n=54), 27 homens e 27 mulheres; grau 2, com IMC < 40 kg/m2 (n=32), 16 homens e 16 mulheres e grau 3, com IMC ≥40 kg/m2(n=14), 7 homens e 7 mulheres. Todos os indivíduos foram recrutados entre funcionários, estudantes e residentes do Hospital Universitário Pedro Ernesto, bem como voluntários do quadro da Polícia Militar do Estado do Rio de Janeiro e selecionados com base em amostra de conveniência. Todos foram avaliados por parâmetros antropométricos, determinação da pressão arterial, análises laboratoriais e genotipagem, para determinar seu perfil metabólico, níveis de endocanabinoides e adipocitocinas e rastreamento dos polimorfismos FAAH385C>A, CNR13813A>G e PPARA484C>G. Foram excluídos do estudo aqueles com história de comorbidades crônicas, doenças inflamatórias agudas, dependência de drogas de qualquer natureza e em uso de medicação nos dez dias anteriores à entrada no estudo. A atividade inflamatória, avaliada pela proteína C reativa ultrassensível (PCRUS), acompanhou o grau de resistência insulínica...


To analyze the reciprocal association of cardiomet abolic risk factors, levels of adipocytokines (leptin and high molecular weight adiponectin), endocannabinoids (anandamide [AEA] and 2-arachidonoylglycerol [2-AG]), cannabimimetic compounds (N-oleoylethanolamine [OEA] and N-palmitoylethanolamine [PEA]) and polymorphisms in genes encoding components of the endocannabinoid system (endocannabinoid degradation enzyme FAAH [FAAHgene] and endocannabinoid receptor CB1 [CNR1gene]) and the PPAR-α receptor (PPARAgene) in subjects with varying degrees of adiposity. Two hundred individuals between 18 and 60 years with varying degrees of body mass index (BMI) comprised the sample, divided in two groups: one hundred eutrophic (BMI < 25 kg/m2) and 100 obese (BMI ≥30 kg/m2), 50 men and 50 women per group. The obese were distributed as follows: grade 1, with BMI < 35 kg/m2(n = 54), 27 men and 27 women; grade 2, with BMI between ≥35 and < 40 kg/m2 (n = 32), 16 men and 16 women and grade 3, with BMI ≥40 kg/m2(n = 14), 7 men and 7 women. All subjects were recruited from staff, students and residents of Pedro Ernesto University Hospital, as well as volunteers from Military Police of Rio de Janeiro State and selected based on a convenience sample. All were evaluated by anthropometric parameters, blood pressure determination, laboratory analysis and genotyping, to determine their metabolic profile, endocannabinoid and adipocytokine levels and investigate the polymorphisms FAAH385C>A, CNR1 3813G>A and PPARA484C>G. Those with a history of chronic comorbidities, acute inflammatory diseases, drug addiction of any kind and on medication in the ten days prior to study entry were withdrawn from the study.The inflammatory activity as assessed by high sensitive C reactive protein (hsCRP), accompanied the degree of insulin resistance...


Subject(s)
Humans , Male , Female , Adipokines/blood , Endocannabinoids/genetics , Polymorphism, Genetic , Adiposity , C-Reactive Protein , Cardiovascular Diseases/metabolism , Cardiovascular Diseases/blood , Endocannabinoids/blood , Insulin Resistance , Obesity/metabolism , Peroxisome Proliferator-Activated Receptors , PPAR alpha/genetics , Receptors, Cannabinoid/metabolism
13.
Article in English | WPRIM | ID: wpr-19500

ABSTRACT

Studies of epilepsy have mainly focused on the membrane proteins that control neuronal excitability. Recently, attention has been shifting to intracellular proteins and their interactions, signaling cascades and feedback regulation as they relate to epilepsy. The mTOR (mammalian target of rapamycin) signal transduction pathway, especially, has been suggested to play an important role in this regard. These pathways are involved in major physiological processes as well as in numerous pathological conditions. Here, involvement of the mTOR pathway in epilepsy will be reviewed by presenting; an overview of the pathway, a brief description of key signaling molecules, a summary of independent reports and possible implications of abnormalities of those molecules in epilepsy, a discussion of the lack of experimental data, and questions raised for the understanding its epileptogenic mechanism.


Subject(s)
Astrocytes/metabolism , Cell Death , Epilepsy/diet therapy , Humans , Diet, Ketogenic , Protein Binding/physiology , Protein Kinase Inhibitors/therapeutic use , Receptors, Cannabinoid/metabolism , Signal Transduction/physiology , Synapses/metabolism , TOR Serine-Threonine Kinases/antagonists & inhibitors , Temporal Lobe/metabolism
14.
Journal of Gorgan University of Medical Sciences. 2011; 13 (2): 9-15
in Persian | IMEMR | ID: emr-117382

ABSTRACT

Memory is an especial ability of brain in which saves the information and reuptake it. The memory is depended on hippocampus and amigdal. The neuronal density of hippocampus and amigdal have direct effect on their physiological functions. Cannabis sativa is belongs to Cannabinaceae family that Tetrahidrocanabinol is important component of this plant. The aim of this study was to assess the effect of alcoholic extract of Cannabis sativa on CA1, CA2 and CA3 subfields of hippocampus neuronal density in male Rats. This experimental study was performed on 18 male Rats with [250- 320gr] weight and 3 months old in faculty of science, Islamic Azad University of Mashhad, Iran [2010-2011]. At first the alcoholic extraction was provided by the soxhlet method of the seed of this plant with coded 2548. Eighteen male wistar Rats were allocated into 2 experimental groups [25,75mg/kg of alcoholic extract of Cannabis sativa] and one control group. Alcoholic extract of Cannabis sativa was injected intraperitonealy [I.P.] in experimental groups for two weeks [every week one injection]. After four weeks animal was decapitated and their brain dissected, fixed in 10% formalin, sectioned in 7?m thickness and stained by toluidin blue. By applying stereological techniques and systematic random sampling scheme the neuronal density of hippocampus were estimated. Neuronal density in control and treated with alcoholic extract [25,75mg/kg] CA1 was 17982, 26750 and 22801 respectively. Neuronal density in CA2 was 19171, 26750 and 22801 respectively and also in CA3 was 19391, 24043, 28571 respectively. Neuronal density in CA1, CA2 and CA3 of hippocampus in treated groups with alcoholic extract [25,75mg/kg] was significantly increased in comparison with controls [P<0.01]. This study determined that the alcoholic extract of Cannabis sativa can induce hippocampus neurogenesis which is not dose depended


Subject(s)
Animals, Laboratory , Male , Hippocampus/drug effects , Neurogenesis/drug effects , Neurons/drug effects , Models, Animal , Rats , Receptors, Cannabinoid
15.
Anatomy & Cell Biology ; : 135-142, 2011.
Article in English | WPRIM | ID: wpr-159927

ABSTRACT

Cannabinoids have been proposed to possess neuroprotective properties; though their mechanism of action remains contentious, they are posited to prevent neurodegenerative disorders, including Parkinson's disease, the pathogenesis of which has not been established. Recent studies have demonstrated that induction of proteasomal dysfunction in animal models results in a phenotype similar to Parkinson's disease. Here, we investigated the neuroprotective function of a synthetic cannabinoid-receptor agonist (WIN55.212.2) in dopaminergic neuronal death induced by a proteasomal synthase inhibitor (PSI), additionally testing the hypothesis that WIN55.212.2 modulates cytoplasmic accumulation of parkin and alpha-synuclein, a key feature of proteasomal dysfunction in Parkinson's. WIN55.212.2 protects PC12 cells from PSI-induced cytotoxicity, concomitantly inhibiting PSI-induced polyADP ribose polymerase expression and activation of caspase-3. While PSI induces cytoplasmic accumulation of alpha-synuclein and parkin, WIN55.212.2 counters these effects. Interestingly, however, while PSI induces the activation and nuclear translocalization of nuclear factor kappaB, WIN55.212.2 potentiates this effect. These data are suggestive that WIN55.212.2 might confer a neuroprotective benefit in PSI-induced proteasomal dysfunction, and could further protect against neuronal degeneration stemming from cytoplasmic accumulation of alpha-synuclein and parkin. These results indicate that WIN55.212.2 may be a candidate for treatment of neurodegenerative diseases, including Parkinson's disease.


Subject(s)
alpha-Synuclein , Animals , Cannabinoids , Caspase 3 , Cytoplasm , Dopaminergic Neurons , Models, Animal , Neurodegenerative Diseases , Neurons , NF-kappa B , Parkinson Disease , PC12 Cells , Phenotype , Receptors, Cannabinoid , Ribose
16.
Psychol. neurosci. (Impr.) ; 3(1): 39-42, Jan.-June 2010. ilus, tab
Article in English | LILACS | ID: lil-604499

ABSTRACT

The use of Cannabis sativa by humans dates back several thousand years, for both its psychotomimetic and potential medicinal properties. As scientific research methods developed, the cannabinoids present in this herb were characterized, as well as their complex interface with the human central nervous system, provided by the activation of specific receptors. The subsequent description of an endogenous cannabinoid system in the mammalian brain shifted the notion of cannabis as a recreational drug to a therapeutic alternative for psychiatric disorders. However, the neuroanatomical sites mediating its effects have remained uncertain. In the present paper, we review recent data suggesting that the midbrain periaqueductal gray may be a structure involved in the anxiolytic-like effects of cannabinoids.


Subject(s)
Anxiety , Endocannabinoids , Periaqueductal Gray , Receptors, Cannabinoid
17.
Rev. bras. psiquiatr ; 32(supl.1): 57-514, maio 2010. ilus, tab
Article in Portuguese | LILACS | ID: lil-547317

ABSTRACT

OBJETIVO: Este artigo revisa o sistema endocanabinoide e as respectivas estratégias de intervenções farmacológicas. MÉTODO: Realizou-se uma revisão da literatura sobre o sistema endocanabinoide e a sua farmacologia, considerando-se artigos originais ou de revisão escritos em inglês. DISCUSSÃO: Canabinoides são um grupo de compostos presentes na Cannabis Sativa (maconha), a exemplo do Δ9-tetraidrocanabinol e seus análogos sintéticos. Estudos sobre o seu perfil farmacológico levaram à descoberta do sistema endocanabinoide do cérebro de mamíferos. Este sistema é composto por pelo menos dois receptores acoplados a uma proteína G, CB1 e CB2, pelos seus ligantes endógenos (endocanabinoides; a exemplo da anandamida e do 2-araquidonoil glicerol) e pelas enzimas responsáveis por sintetizá-los e metabolizá-los. Os endocanabinoides representam uma classe de mensageiros neurais que são sintetizados sob demanda e liberados de neurônios pós-sinápticos para restringir a liberação de neurotransmissores clássicos de terminais pré-sinápticos. Esta sinalização retrógrada modula uma diversidade de funções cerebrais, incluindo ansiedade, medo e humor, em que a ativação de receptores CB1 pode exercer efeitos dos tipos ansiolítico e antidepressivo em estudos préclínicos. CONCLUSÃO: Experimentos com modelos animais sugerem que drogas que facilitam a ação dos endocanabinoides podem representar uma nova estratégia para o tratamento de transtornos de ansiedade e depressão.


OBJECTIVE: The present review provides a brief introduction into the endocannabinoid system and discusses main strategies of pharmacological interventions. METHOD: We have reviewed the literature relating to the endocannabinoid system and its pharmacology; both original and review articles written in English were considered. DISCUSSION: Cannabinoids are a group of compounds present in Cannabis Sativa (hemp), such as Δ9-tetrahydrocannabinol, and their synthetic analogues. Research on their pharmacological profile led to the discovery of the endocannabinoid system in the mammalian brain. This system comprises at least two G-protein coupled receptors, CB1 and CB2, their endogenous ligands (endocannabinoids; e.g. the fatty acid derivatives anandamide and 2-arachydonoyl glycerol), and the enzymes responsible for endocannabinoid synthesis and catabolism. Endocannabinoids represent a class of neuromessengers, which are synthesized on demand and released from post-synaptic neurons to restrain the release of classical neurotransmitters from pre-synaptic terminals.This retrograde signalling modulates a variety of brain functions, including anxiety, fear and mood, whereby activation of CB1 receptors was shown to exert anxiolytic-and antidepressant-like effects in preclinical studies. CONCLUSION: Animal experiments suggest that drugs promoting endocannabinoid action may represent a novel strategy for the treatment of depression and anxiety disorders.


Subject(s)
Animals , Humans , Anxiety Disorders/drug therapy , Cannabinoid Receptor Modulators/therapeutic use , Depression/drug therapy , Endocannabinoids , Anxiety Disorders/metabolism , Cannabinoid Receptor Agonists , Cannabinoid Receptor Antagonists , Cannabinoid Receptor Modulators/metabolism , Depression/metabolism , Receptors, Cannabinoid/metabolism , Signal Transduction/drug effects
18.
Braz. j. med. biol. res ; 43(4): 325-329, Apr. 2010. tab
Article in English | LILACS | ID: lil-543579

ABSTRACT

(-)-∆9-Tetrahydrocannabinol (∆9-THC), a psychoactive component of marijuana, has been reported to induce oxidative damage in vivo and in vitro. In this study, we administered (∆9-THC to healthy C57BL/6J mice aged 15 weeks in order to determine its effect on hepatic redox state. Mice were divided into 3 groups: (∆9-THC (N = 10), treated with 10 mg/kg body weight (∆9-THC daily; VCtrl (N = 10), treated with vehicle [1:1:18, cremophor EL® (polyoxyl 35 castor oil)/ethanol/saline]; Ctrl (N = 10), treated with saline. Animals were injected ip twice a day with 5 mg/kg body weight for 10 days. Lipid peroxidation, protein carbonylation and DNA oxidation were used as biomarkers of oxidative stress. The endogenous antioxidant defenses analyzed were glutathione (GSH) levels as well as enzyme activities of superoxide dismutase, catalase, glutathione S-transferase, glutathione reductase, and glutathione peroxidase (GPx) in liver homogenates. The levels of mRNA of the cannabinoid receptors CB1 and CB2 were also monitored. Treatment with ∆9-THC did not produce significant changes in oxidative stress markers or in mRNA levels of CB1 and CB2 receptors in the liver of mice, but attenuated the increase in the selenium-dependent GPx activity (∆9-THC: 8 percent; VCtrl: 23 percent increase) and the GSH/oxidized GSH ratio (∆9-THC: 61 percent; VCtrl: 96 percent increase), caused by treatment with the vehicle. ∆9-THC administration did not show any harmful effects on lipid peroxidation, protein carboxylation or DNA oxidation in the healthy liver of mice but attenuated unexpected effects produced by the vehicle containing ethanol/cremophor EL®.


Subject(s)
Animals , Mice , Lipid Peroxidation/drug effects , Liver/drug effects , Oxidative Stress/drug effects , Psychotropic Drugs/pharmacology , Dronabinol/pharmacology , Liver/enzymology , Oxidation-Reduction , Proteins/analysis , Proteins/drug effects , Reverse Transcriptase Polymerase Chain Reaction , RNA, Messenger/drug effects , Receptors, Cannabinoid/drug effects
19.
Journal of Zanjan University of Medical Sciences and Health Services. 2010; 18 (70): 10-21
in Persian | IMEMR | ID: emr-125610

ABSTRACT

Cannabinoids are a class of psychoactive compounds that produce a wide array of effects in a large number of species. In the present study, the effects of bilateral intra-CA1 injections of L-arginine on WIN55, 212-2 induced state-dependent memory of passive avoidance task was examined in mice. One-trial step-down paradigm was used for the assessment of memory retention in adult male NMRI mice. Post-training intraCA1 administration of cannabinoid receptor agonist, WIN55, 212-2 [0.5 and 1 micro g/mouse], decreased the memory retrieval. The memory impairment induced by post-training administration of WIN55, 212-2 [1micro g/mouse]was restored by pre-test administration of the same dose of the drug, showing the state-dependent memory of WIN55, 212-2. Single intra-CA1 administration of L-arginine [0.3, 1 and 3 micro g/mouse] 5min pre-test could not alter the memory retrieval. On the other hand, in the animals in which retrieval was impaired due to post-training administration of WIN55, 212-2 [1micro g/ mouse], pre-test intra-CA1 administration of L-arginine [1 and 3 micro g/ mouse], 24hr after training restored memory retrieval. Furthermore, in the animals under influence of post-training administration of WIN55, 212-2 [1 micro g/mouse], pre-test co-administration of non-effective doses of WIN55, 212-2 and L-arginine, increased the restoration of memory by the pre-test WIN55, 212-2. The findings of the present study suggest that NO system of dorsal hippocampus may play an important role in WIN55,212-2-induced amnesia and WIN55,212-2 state-dependent memory


Subject(s)
Animals, Laboratory , Male , Arginine/administration & dosage , CA1 Region, Hippocampal/drug effects , Morpholines , Receptors, Cannabinoid
20.
Article in English | WPRIM | ID: wpr-79065

ABSTRACT

BACKGROUND/AIMS: This study was designed to investigate the possibility that the enhanced nociceptive responsiveness associated with canabonoid type 1 receptors (CB1Rs) and identify its role in mediating visceral hypersensitivity induced by chronic restraint stress. METHODS: Rats were exposed to daily partial restraint stress or sham partial restraint stress with intraperitoneal injection of the vehicle, CB1R agonist or antagonist for 4 consecutive days. We tested the visceromotor reflex to colorectal distention at day 0 and 5. Reverse-transcription polymerase chain reaction and Western blot were used to assess the expression of CB1Rs. RESULTS: Intraperitoneal CB1 agonist (ACEA) injection significantly diminished (p < 0.05) the enhanced visceromotor reflex to colorectal distention at day 5 in stressed rats. Change in electromyogram response after ACEA over baseline, at pressure of 40 mmHg (+13.3 +/- 2.2), 60 mmHg (+15.3 +/- 2.8) and 80 mmHg (+17.0 +/- 4.0) were much lower than in the control animals, which were +35.9 +/- 5.1, +41.1 +/- 6.3 and +54.1 +/- 9.6, respectively. Whereas, CB1 antagonist (SR141716A) had an opposite effect. Compared with control group, the change in electromyogram response after SR141716A over baseline was significantly enhanced (p < 0.05) for the distending pressure of 40 mmHg (+56.0 +/- 10.3), 60 mmHg (+74.6 +/- 12.3) and 80 mmHg (+82.9 +/- 11.0), respectively. Reverse-transcription polymerase chain reaction and Western blotting demonstrated the stress-induced up-regulation of colon CB1Rs (p < 0.05). CONCLUSIONS: Our results suggest there is a key contribution of peripheral CB1Rs involved in the maintenance of visceral hyperalgesia after repeated restraint stress, providing a novel mechanism for development of peripheral visceral sensitization.


Subject(s)
Animals , Blotting, Western , Colon , Hyperalgesia , Hypersensitivity , Injections, Intraperitoneal , Irritable Bowel Syndrome , Negotiating , Piperidines , Polymerase Chain Reaction , Pyrazoles , Rats , Receptor, Cannabinoid, CB1 , Receptors, Cannabinoid , Reflex , Salicylamides , Up-Regulation
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