Neuroprotection without immunomodulation is not sufficient to reduce first relapse severity in experimental autoimmune encephalomyelitis

TY - JOUR

T1 - Neuroprotection without immunomodulation is not sufficient to reduce first relapse severity in experimental autoimmune encephalomyelitis

AU - Hasseldam, Henrik

AU - Johansen, Flemming Fryd

PY - 2010/3

Y1 - 2010/3

N2 - Objectives: 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-α, IL-12, IFN-γ, IL-10 and the TH17 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-α, IL-12 and IFN-γ (TH1 response), whereas high-dose cannabinoid treatment reduced the number of T cells and microglia/macrophages in addition to the TH17 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. Conclusion: 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.

AB - Objectives: 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-α, IL-12, IFN-γ, IL-10 and the TH17 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-α, IL-12 and IFN-γ (TH1 response), whereas high-dose cannabinoid treatment reduced the number of T cells and microglia/macrophages in addition to the TH17 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. Conclusion: 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.

KW - Animals

KW - Benzoxazines

KW - Cytokines

KW - Cytoprotection

KW - Demyelinating Diseases

KW - Disease Models, Animal

KW - Dose-Response Relationship, Drug

KW - Encephalomyelitis, Autoimmune, Experimental

KW - Female

KW - Immunomodulation

KW - Microglia

KW - Morpholines

KW - Multiple Sclerosis

KW - Naphthalenes

KW - Neuroprotective Agents

KW - Neurotransmitter Agents

KW - Rats

KW - T-Lymphocytes

KW - Treatment Outcome

KW - Wallerian Degeneration

U2 - 10.1159/000290041

DO - 10.1159/000290041

M3 - Journal article

C2 - 20203531

SN - 1021-7401

VL - 17

SP - 252

EP - 264

JO - NeuroImmunoModulation

JF - NeuroImmunoModulation

IS - 4

ER -