title: Decreased endocannabinoid levels in the brain and beneficial effects of agents activating cannabinoid and/or vanilloid receptors in a rat model of multiple sclerosis.
abstract: 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 indirect activation of vanilloid or cannabinoid receptors may reduce the neurological impairment experienced by EAE rats, although the efficacy of the different compounds examined seems to be determined by their particular pharmacodynamic and pharmacokinetic characteristics.
authors.affiliation: Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad Complutense, 28040-Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Cabranes
authors.forename: Katerina
authors.initials: K
authors.lastname: Venderova
authors.forename: Eva
authors.initials: E
authors.lastname: de Lago
authors.forename: Filomena
authors.initials: F
authors.lastname: Fezza
authors.forename: Antonio
authors.initials: A
authors.lastname: Sánchez
authors.forename: Leyre
authors.initials: L
authors.lastname: Mestre
authors.forename: Marta
authors.initials: M
authors.lastname: Valenti
authors.forename: Antonio
authors.initials: A
authors.lastname: García-Merino
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Ramos
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Di Marzo
authors.forename: Javier
authors.initials: J
authors.lastname: Fernández-Ruiz
mesh_terms: D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D001095:Arachidonic Acids / Q000378:metabolism / Q000494:pharmacology; D001479:Basal Ganglia / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D002211:Capsaicin / Q000031:analogs & derivatives / Q000494:pharmacology; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D063388:Endocannabinoids; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D005989:Glycerides / Q000378:metabolism; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D053284:Polyunsaturated Alkamides; D051381:Rats; D011917:Rats, Inbred Lew; D043884:Receptor, Cannabinoid, CB1 / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D043882:Receptors, Cannabinoid / Q000187:drug effects / Q000378:metabolism*; D020889:Rolipram / Q000494:pharmacology; D050916:TRPV Cation Channels / Q000187:drug effects / Q000378:metabolism*
chemical_list: D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D005989:Glycerides; D010726:Phosphodiesterase Inhibitors; D053284:Polyunsaturated Alkamides; D043884:Receptor, Cannabinoid, CB1; D043882:Receptors, Cannabinoid; D050916:TRPV Cation Channels; C494484:TRPV1 receptor; C121153:arvanil; C094503:glyceryl 2-arachidonate; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D020889:Rolipram; D002211:Capsaicin; C078814:anandamide; C107594:N-(4-hydroxyphenyl)arachidonylamide