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Visualizing Impairment of the Endothelial and Glial Barriers of the Neurovascular Unit during Experimental Autoimmune Encephalomyelitis In Vivo
Published on: March 26, 2019
Pixantrone (BBR2778) reduces the severity of experimental allergic encephalomyelitis
G Cavaletti1, E Cavalletti, L Crippa
1Department of Neuroscience and Biomedical Technologies, University of Milan Bicocca, and Department of Neurology, S. Gerardo Hospital, Monza, Italy. guido.cavaletti@unimib.it
Abstract:
Pixantrone is less cardiotoxic and is similarly effective to mitoxantrone (MTX) as an antineoplastic drug. In our study, pixantrone reduced the severity of acute and decreased the relapse rate of chronic relapsing experimental allergic encephalomyelitis (EAE) in rats. A marked and long-lasting decrease in CD3+, CD4+, CD8+ and CD45RA+ blood cells and reduced anti-MBP titers were observed with both pixantrone and MTX. In vitro mitogen- and antigen-induced T-cell proliferation tests of human and rodents cells evidenced that pixantrone was effective at concentrations which can be effectively obtained after i.v. administration in humans. Cardiotoxicity was present only in MTX-treated rats. The effectiveness and the favorable safety profile makes pixantrone a most promising immunosuppressant agent for clinical use in multiple sclerosis (MS).
Insights
Pixantrone demonstrates efficacy in treating experimental allergic encephalomyelitis (EAE) in rats, showing reduced disease severity and relapse rates. This immunosuppressant agent exhibits a favorable safety profile compared to mitoxantrone, suggesting potential for multiple sclerosis treatment.
Area of Science:
- Immunology
- Pharmacology
- Neuroscience
Background:
- Mitoxantrone (MTX) is an effective antineoplastic drug but carries cardiotoxicity risks.
- Experimental Allergic Encephalomyelitis (EAE) serves as a model for studying autoimmune demyelinating diseases like Multiple Sclerosis (MS).
- Pixantrone, a related compound, is being investigated for its therapeutic potential and safety profile.
Purpose of the Study:
- To evaluate the efficacy and safety of pixantrone in a rat model of EAE.
- To compare the immunosuppressive effects and cardiotoxicity of pixantrone with mitoxantrone.
- To assess the in vitro activity of pixantrone on T-cell proliferation.
Main Methods:
- Rats with chronic relapsing EAE were treated with pixantrone or mitoxantrone.
- Blood cell counts (CD3+, CD4+, CD8+, CD45RA+) and anti-myelin basic protein (MBP) titers were measured.
- In vitro assays assessed T-cell proliferation in response to mitogens and antigens using human and rodent cells.
- Cardiotoxicity was monitored in treated rats.
Main Results:
- Pixantrone significantly reduced acute EAE severity and chronic relapse rates.
- Both pixantrone and MTX caused a marked decrease in CD3+, CD4+, CD8+, and CD45RA+ blood cells and anti-MBP titers.
- Pixantrone demonstrated efficacy in vitro at achievable human therapeutic concentrations.
- Cardiotoxicity was observed only in MTX-treated rats, not in pixantrone-treated rats.
Conclusions:
- Pixantrone is an effective immunosuppressant in the EAE model.
- Pixantrone exhibits a more favorable safety profile, specifically reduced cardiotoxicity, compared to mitoxantrone.
- These findings highlight pixantrone as a promising candidate for clinical application in treating Multiple Sclerosis.
