Prophylactic Effect of BIO-1211 Small-Molecule Antagonist of VLA-4 in the EAE Mouse Model of Multiple Sclerosis.

Abstract

BACKGROUND AND PURPOSE:

Some functional limitations and economic burden of therapeutic antibodies indicated that introducing of alternative therapeutic compounds with same or different mechanism of action could be worthwhile. In this regard small-molecule antagonists can have a wide range of impacts, so in this research, we examine the prophylactic effects of BIO-1211 [Very Late Antigen-4 (VLA4) blocker], in experimental autoimmune encephalomyelitis (EAE) mouse model of multiple sclerosis in comparison with commercial available medicine, Natalizumab (NTZ)].

METHODS:

EAE was induced by subcutaneous immunization of myelin oligodendrocyte glycoprotein (MOG35-55) in 8-week-old C57BL/6 mice. During EAE induction, mice were separated to distinct groups and provided either BIO-1211 (5 and 10 mg/kg) or NTZ (5 mg/kg) and co-administration of these two compounds. After 21 days, neuro-inflammatory responses were analyzed using qRT-PCR, western blot, and ELISA methods. Pervade of immune cells to brain was examined by Evans blue staining and immunohistochemistry (IHC) analysis of specific markers of microglia/monocytes (CD11b) and leukocytes (CD45).

RESULTS:

Targeted disruption of VLA4/VCAM1 interactions, by BIO-1211 agonist in mice, results in reduced cytokines expression, leukocyte trafficking, and inhibition of inflammatory responses in EAE (p < 0.01) in a dose-independent manner (data not shown). Mice treated with both BIO-1211 and NTZ exhibited a considerable depletion in the EAE clinical score, which correlated with decreased expression of TNF-α, IL-17, IFN-γ and pervade of CD11b(+) and CD45(+) cells into the cerebral cortex.

CONCLUSION:

Our results indicated that BIO12-11 compound would be an useful tool to further understand the biological roles of VLA4/VCAM1 interactions, and could also be considered as EAE-suppressing agent.

• Authors: Nourollah Ramroodi, Masood Khani, Zohre Ganjali, Mohammad Reza Javan, Nima Sanadgol, Roghayeh Khalseh, Hadi Ravan, Ehsan Sanadgol, Mohammad Abdollahi
• Journal: Immunological investigations (Immunol Invest) Vol. 44 Issue 7 Pg. 694-712 ( 2015) ISSN: 1532-4311 [Electronic] England
• PMID: 26436854 (Publication Type: Journal Article)

Chemical References

• CD11b Antigen
• Cytokines
• Inflammation Mediators
• Integrin alpha4beta1
• Nitro Compounds
• Oligopeptides
• RNA, Messenger
• Thiazoles
• BIO 1211
• Leukocyte Common Antigens
• nitazoxanide

Topics

• Animals
• Blood-Brain Barrier (drug effects, metabolism)
• CD11b Antigen (metabolism)
• Cell Movement (immunology)
• Cerebral Cortex (immunology, metabolism, pathology)
• Cytokines (genetics, metabolism)
• Disease Models, Animal
• Disease Progression
• Encephalomyelitis, Autoimmune, Experimental (drug therapy, genetics, immunology, metabolism, pathology)
• Gene Expression Regulation (drug effects)
• Inflammation Mediators (metabolism)
• Integrin alpha4beta1 (antagonists & inhibitors)
• Leukocyte Common Antigens (metabolism)
• Leukocytes (immunology, metabolism)
• Male
• Mice
• Monocytes (immunology, metabolism)
• Multiple Sclerosis (drug therapy, genetics, immunology, metabolism, pathology)
• Nitro Compounds
• Oligopeptides (administration & dosage, chemistry, pharmacology)
• Permeability (drug effects)
• RNA, Messenger (genetics, metabolism)
• Thiazoles (administration & dosage, pharmacology)