R-(+)-[2,3-Dihydro-5-methyl-3-(4-morpholinylmethyl)-pyrrolo-[1,2,3-de]-1,4-benzoxazin-6-yl]-1-naphtalenylmethanone (WIN-2) ameliorates experimental autoimmune encephalomyelitis and induces encephalitogenic T cell apoptosis: partial involvement of the CB(2) receptor.
Many reports have shown that cannabinoids might be beneficial in the symptomatic treatment of multiple sclerosis (MS). We have investigated the therapeutic properties of the non-selective cannabinoid receptor agonist WIN-2 as a suppressive drug in the experimental autoimmune encephalomyelitis (EAE) model of MS. In the passive variety of EAE, induced in Lewis rats by adoptive transfer of myelin-reactive T cells, WIN-2 ameliorates the clinical signs and diminishes the cell infiltration of the spinal cord. Due to the involvement of cannabinoids in the regulation of cell death and survival, we investigated the effects of WIN-2 on the encephalitogenic T cell population. WIN-2 induced a profound increase of apoptosis in a dose- and time-dependent manner. The potential involvement of cannabinoid receptors (CB) was investigated by encephalitogenic T cell stimulation in the presence of the CB(1) (SR141716A) and CB(2) (SR144528) antagonists, pertussis toxin (PTX) and the inactive enantiomer WIN-3. WIN-2-induced apoptosis was partially blocked by SR144528 and PTX, whereas, WIN-3 only exerted a mild effect on cell viability. These results point to the partial involvement of CB(2) receptor together with other receptor-independent mechanism or by yet unknown cannabinoid receptors. Moreover, WIN-2 induced the extrinsic pathway of apoptosis, as shown by caspase-10 and -3 activation. These results suggest that cannabinoid-induced apoptosis of encephalitogenic T cells may cooperate in their anti-inflammatory action in EAE models. The partial involvement of CB(2) receptors in WIN-2 action may open new therapeutic doors in the management of MS by non-psychoactive selective cannabinoid agonists.
Sánchez
Antonio J
AJ
Neuroimmunology Unit, Hospital Universitario Puerta de Hierro, Universidad Autónoma de Madrid, San Martin de Porres 4, 28035 Madrid, Spain.
González-Pérez
Paz
P
Galve-Roperh
Ismael
I
García-Merino
Antonio
A
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D048588:Benzoxazines; D002186:Cannabinoids / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004679:Encephalomyelitis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D007274:Injections, Intraperitoneal; D009025:Morpholines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D009281:Naphthalenes / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D020721:Nervous System Autoimmune Disease, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D043885:Receptor, Cannabinoid, CB2 / Q000819:agonists / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology
D048588:Benzoxazines; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D009025:Morpholines; D009281:Naphthalenes; D043885:Receptor, Cannabinoid, CB2; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone; D020169:Caspases