arvanil and Disease-Models--Animal

Recent evidence reveals therapeutic potential for cannabinoids to reduce seizure frequency, severity and duration. Animal models are useful tools to determine the potential antiseizure or antiepileptic effects of cannabinoids. The objective of this study was evaluation of the effect of arvanil, olvanil, AM 1172 and LY 2183240, the compounds interacted with endocannabinoid and/or endovanilloid systems, on convulsions in the commonly used model of convulsions in mice.. Arvanil and olvanil were injected intraperitoneally (ip) 30min and AM 1172 and LY 2183240 were administered ip 60min before the maximal electroshock seizure threshold (MEST) test. The criterion for convulsant activity was tonic hindlimb extension.. Arvanil, olvanil, AM 1172 and LY 2183240 dose-dependently increased the electroconvulsive threshold in mice. The TID. This study identified anticonvulsant effects of arvanil, olvanil, AM 1172 and LY 2183240. The order of the magnitude of the anticonvulsant effects of the examined compounds was following: arvanil>olvanil>AM 1172>LY 2183240.

Topics: Animals; Arachidonic Acids; Benzamides; Brain; Brain Waves; Cannabinoid Receptor Agonists; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Electroshock; Heterocyclic Compounds, 1-Ring; Male; Mice; Receptor, Cannabinoid, CB1; Seizures; Signal Transduction; Urea

Cardio-respiratory effects of an intravenous injection of arvanil, a structural "hybrid" between capsaicin and anandamide, were investigated in 40 urethane-chloralose anaesthetized and spontaneously breathing rats. In the group of rats the response to arvanil was checked to establish the appropriate dose of the drug. To analyze the pattern of the cardio-respiratory effects rats were challenged with bolus injection of arvanil (0.8 mg kg(-1)) into the femoral vein. Administration of the drug evoked, in all tested rats, a significant increase of tidal volume (V(T)) and diaphragm activity, hypertension coupled with a fall in respiratory rate (f). To test the contribution of vanilloid (VR1) and cannabinoid (CB1) receptors to post-arvanil response, administrations of the drug were preceded by nonselective VR1 antagonist ruthenium red, selective VR1 antagonist SB366791 or selective CB1 antagonist AM281. All antagonists eliminated an increase in V(T) but failed to block the hypertension evoked by arvanil. Ruthenium red as well as SB366791 abolished post-arvanil fall in respiratory rate. The rise of diaphragm activity was totally eliminated by ruthenium red and markedly reduced by SB366791. AM281 blockade of post-arvanil changes in f and diaphragm activity was ineffective. These findings indicated that the post-arvanil rise of V(T) was mediated by both VR1 and CB1 receptors. Only vanilloid receptors were involved in the increase of diaphragm activity and decrease of respiratory frequency. Hypertensive response to arvanil might depend on different types of receptors.

Topics: Anilides; Animals; Blood Pressure; Cannabinoid Receptor Modulators; Capsaicin; Cinnamates; Disease Models, Animal; Endocannabinoids; Hypertension; Injections, Intravenous; Male; Morpholines; Pyrazoles; Rats; Rats, Wistar; Receptor, Cannabinoid, CB1; Respiration; Respiration Disorders; Ruthenium Red; Tidal Volume; TRPV Cation Channels

This study examined the immunomodulatory effect of arvanil, a synthetic capsaicin-anandamide hybrid. Arvanil inhibits lymphocyte proliferation and IFN-gamma production. The phenotype of activated CD4+T cells treated with arvanil shows a down-regulation of T cell activation markers such as CD25, HLA-DR and CD134/OX40. Arvanil and anandamide do not induce apoptosis on CD4+T cells. Arvanil blocks the G1/S phase transition of the cell cycle in stimulated peripheral blood mononuclear cells, inducing activation of p21waf-1/cip-1 and phosphorylation of Akt/PKB. In vivo, arvanil ameliorates experimental autoimmune encephalomyelitis in the SJL/J mouse. Our findings have relevance for the use of arvanil and related compounds as a novel immunotherapeutic approach in the treatment of multiple sclerosis.

Topics: Animals; Arachidonic Acids; Blotting, Western; Body Weight; Cannabinoid Receptor Modulators; Capsaicin; CD4-Positive T-Lymphocytes; Cell Line; Cell Proliferation; Cytokines; Disease Models, Animal; Dose-Response Relationship, Drug; Dose-Response Relationship, Immunologic; Drug Interactions; Encephalomyelitis, Autoimmune, Experimental; Endocannabinoids; Enzyme Activation; Female; Flow Cytometry; Humans; Leukocytes, Mononuclear; Lymphocyte Activation; Mice; Myelin Proteolipid Protein; Peptide Fragments; Polyunsaturated Alkamides; Proto-Oncogene Proteins c-akt; Statistics, Nonparametric; Time Factors

The present study was designed to examine whether arvanil (N-arachidonoyl-vanillyl-amide), an endocannabinoid/vanilloid structural "hybrid", might provide symptom relief in the rat model of Huntington's disease (HD) generated by bilateral intrastriatal application of 3-nitropropionic acid (3-NP), where previous evidence suggests that hybrid cannabinoid/vanilloid compounds might be effective. As expected, arvanil did reduce ambulation, stereotypic activity, and number of hole entries, and increased the inactivity, in control rats. It was also active in 3-NP-lesioned rats, where, despite its lowering effects on stereotypic activity and number of hole entries, arvanil reduced the hyperkinesia (increased ambulation) typical of these rats, and also increased the inactivity, these two effects being more moderate than those found in control rats. Arvanil caused its antihyperkinetic effects in 3-NP-lesioned rats presumably by enhancing excitatory transmission at the globus pallidus, since it increased glutamate content in this region. This contrasts with its effects in control rats where arvanil enhanced GABA transmission at the globus pallidus. In summary, arvanil does alleviate hyperkinesia typical of HD, although it also affects locomotion in normal rats. Nevertheless, considering the lack of efficacious pharmacological treatments in this basal ganglia disorder, our findings might provide the basis for the development of more specific drugs against HD.

Topics: Animals; Brain Chemistry; Capsaicin; Convulsants; Disease Models, Animal; Dopamine; gamma-Aminobutyric Acid; Glutamic Acid; Huntington Disease; Hyperkinesis; Male; Motor Activity; Nitro Compounds; Propionates; Rats; Rats, Sprague-Dawley

Recent studies have addressed the changes in endocannabinoid ligands and receptors that occur in multiple sclerosis, as a way to explain the efficacy of cannabinoid compounds to alleviate spasticity, pain, tremor, and other signs of this autoimmune disease. Using Lewis rats with experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, we recently found a decrease in cannabinoid CB1 receptors mainly circumscribed to the basal ganglia, which could be related to the motor disturbances characteristic of these rats. In the present study, using the same model, we explored the potential changes in several neurotransmitters in the basal ganglia that might be associated with the motor disturbances described in these rats, but we only found a small increase in glutamate contents in the globus pallidus. We also examined whether the motor disturbances and the changes of CB1 receptors found in the basal ganglia of EAE rats disappear after the treatment with rolipram, an inhibitor of type IV phosphodiesterase able to supress EAE in different species. Rolipram attenuated clinical decline, reduced motor inhibition, and normalized CB1 receptor gene expression in the basal ganglia. As a third objective, we examined whether EAE rats also exhibited changes in endocannabinoid levels as shown for CB1 receptors. Anandamide and 2-arachidonoylglycerol levels decreased in motor related regions (striatum, midbrain) but also in other brain regions, although the pattern of changes for each endocannabinoid was different. Finally, we hypothesized that the elevation of the endocannabinoid activity, following inhibition of endocannabinoid uptake, might be beneficial in EAE rats. AM404, arvanil, and OMDM2 were effective to reduce the magnitude of the neurological impairment in EAE rats, whereas VDM11 did not produce any effect. The beneficial effects of AM404 were reversed by blocking TRPV1 receptors with capsazepine, but not by blocking CB1 receptors with SR141716, thus indicating the involvement of endovanilloid mechanisms in these effects. However, a role for CB1 receptors is supported by additional data showing that CP55,940 delayed EAE progression. In summary, our data suggest that reduction of endocannabinoid signaling is associated with the development of EAE in rats. We have also proved that the reduction of CB1 receptors observed in these rats is corrected following treatment with a compound used in EAE such as rolipram. In addition, the direct or i

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Animals; Arachidonic Acids; Basal Ganglia; Brain; Cannabinoid Receptor Modulators; Capsaicin; Cyclic Nucleotide Phosphodiesterases, Type 4; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Endocannabinoids; Gene Expression; Glycerides; Male; Multiple Sclerosis; Phosphodiesterase Inhibitors; Polyunsaturated Alkamides; Rats; Rats, Inbred Lew; Receptor, Cannabinoid, CB1; Receptors, Cannabinoid; Rolipram; TRPV Cation Channels

Activation of cannabinoid receptors causes inhibition of spasticity, in a mouse model of multiple sclerosis, and of persistent pain, in the rat formalin test. The endocannabinoid anandamide inhibits spasticity and persistent pain. It not only binds to cannabinoid receptors but is also a full agonist at vanilloid receptors of type 1 (VR1). We found here that vanilloid VR1 receptor agonists (capsaicin and N-N'-(3-methoxy-4-aminoethoxy-benzyl)-(4-tert-butyl-benzyl)-urea [SDZ-249-665]) exhibit a small, albeit significant, inhibition of spasticity that can be attenuated by the vanilloid VR1 receptor antagonist, capsazepine. Arvanil, a structural "hybrid" between capsaicin and anandamide, was a potent inhibitor of spasticity at doses (e.g. 0.01 mg/kg i.v.) where capsaicin and cannabinoid CB(1) receptor agonists were ineffective. The anti-spastic effect of arvanil was unchanged in cannabinoid CB(1) receptor gene-deficient mice or in wildtype mice in the presence of both cannabinoid and vanilloid receptor antagonists. Likewise, arvanil (0.1-0.25 mg/kg) exhibited a potent analgesic effect in the formalin test, which was not reversed by cannabinoid and vanilloid receptor antagonists. These findings suggest that activation by arvanil of sites of action different from cannabinoid CB(1)/CB(2) receptors and vanilloid VR1 receptors leads to anti-spastic/analgesic effects that might be exploited therapeutically.

Topics: Animals; Arachidonic Acids; Benzoxazines; Camphanes; Cannabinoid Receptor Modulators; Capsaicin; Disease Models, Animal; Dose-Response Relationship, Drug; Genotype; Mice; Mice, Inbred Strains; Mice, Knockout; Morpholines; Multiple Sclerosis; Muscle Spasticity; Naphthalenes; Pain; Pain Measurement; Piperidines; Pyrazoles; Receptors, Cannabinoid; Receptors, Drug; Rimonabant