Neuroprotection without immunomodulation is not sufficient to reduce first relapse severity in experimental autoimmune encephalomyelitis.
OBJECTIVE
Multiple sclerosis can be characterized by a strong neuroinflammatory and progressive neurodegenerative component leading to prolonged disability. The synthetic compound R(+)WIN55,212-2 is reported to be neuroprotective at moderate doses and both neuroprotective and immunomodulatory at high doses, most likely due to differences in receptor affinities. In order to investigate the effects of neuroprotection and immunomodulation in an animal model of multiple sclerosis, we examined the impact of increasing concentrations of R(+)WIN55,212-2 on the inflammatory profile in CNS during first relapse and related this to demyelination, axonal degeneration and relapse severity.


METHODS
Experimental autoimmune encephalomyelitis was induced in Dark Agouti rats and treatment with R(+)WIN55,212-2 was initiated at symptom debut. The animals were scored clinically throughout the experiment, and axonal degeneration, demyelination, T cells, microglia/macrophages, TNF-alpha, IL-12, IFN-gamma, IL-10 and the T(H)17 response were estimated at the peak of the first relapse.


RESULTS
Treatment with high-dose R(+)WIN55,212-2 (10 and 20 mg/kg) significantly improved the clinical performance of the animals during relapse. Interestingly, treatment at any dosage did not affect the brain levels of TNF-alpha, IL-12 and IFN-gamma (T(H)1 response), whereas high-dose cannabinoid treatment reduced the number of T cells and microglia/macrophages in addition to the T(H)17 response. At the same time, we observed a significant reduction in axonal degeneration in all treatment groups whereas only high-dose treatment resulted in reduced demyelination.


CONCLUSIONS
High-dose R(+)WIN55,212-2 treatment reduces demyelination and axonal degeneration and has immunomodulatory effects which significantly improve clinical performance, whereas a reduction in axonal degeneration on its own, induced by 5 mg/kg R(+)WIN55,212-2, has no impact on first relapse severity.
Hasseldam
Henrik
H
Department of Biomedical Sciences, Biotech Research and Innovation Center, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark. henrik.hasseldam @ bric.dk
Johansen
Flemming Fryd
FF
D000818:Animals; D048588:Benzoxazines / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000187:drug effects / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects / Q000276:immunology; D003711:Demyelinating Diseases / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000503:physiopathology; D005260:Female; D056747:Immunomodulation / Q000187:drug effects / Q000276:immunology; D017628:Microglia / Q000187:drug effects / Q000276:immunology; D009025:Morpholines / Q000494:pharmacology* / Q000627:therapeutic use; D009103:Multiple Sclerosis / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology; D009281:Naphthalenes / Q000494:pharmacology* / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D018377:Neurotransmitter Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D016896:Treatment Outcome; D014855:Wallerian Degeneration / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology
D048588:Benzoxazines; D016207:Cytokines; D009025:Morpholines; D009281:Naphthalenes; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; C070417:(3R)-((2,3-dihydro-5-methyl-3-((4-morpholinyl)methyl)pyrrolo-(1,2,3-de)-1,4-benzoxazin-6-yl)(1-naphthalenyl))methanone