Thrombin mutant W215A/E217A treatment improves neurological outcome and attenuates central nervous system damage in
Norah G Verbout1, Xiaolin Yu, Laura D Healy
1Department of Biomedical Engineering, School of Medicine, Oregon Health & Science University, Portland, OR, 97239, USA, verboutn@ohsu.edu.
Abstract:
Multiple sclerosis (MS) is a neuroinflammatory disease characterized by demyelination and axonal damage of the central nervous system. The pathogenesis of MS has also been linked to vascular inflammation and local activation of the coagulation system, resulting in perivascular fibrin deposition. Treatment of experimental autoimmune encephalomyelitis (EAE), a model of human MS, with antithrombotic and antiinflammatory activated protein C (APC) reduces disease severity. Since recombinant APC (Drotecogin alfa), originally approved for the treatment of severe sepsis, is not available for human MS studies, we tested the hypothesis that pharmacologic activation of endogenous protein C could likewise improve the outcome of EAE. Mice were immunized with murine myelin oligodendrocyte glycoprotein (MOG) peptides and at the onset of EAE symptoms, were treated every other day with either WE thrombin (25 μg/kg; i.v.), a selective recombinant protein C activator thrombin analog, or saline control. Mice were monitored for changes in disease score until euthanized for ex vivo analysis of inflammation. Administration of WE thrombin significantly ameliorated clinical severity of EAE, reduced inflammatory cell infiltration and demyelination, suppressed the activation of macrophages comprising the CD11b + population and reduced accumulation of fibrin (ogen) in the spinal cord. These data suggest that symptomatic MS may respond to a treatment strategy that involves temporal pharmacological enhancement of endogenous APC generation.
Insights
Pharmacological activation of endogenous protein C, using WE thrombin, significantly reduced multiple sclerosis (MS) symptoms and inflammation in a mouse model. This approach offers a potential new treatment strategy for MS patients.
Area of Science:
- Neuroimmunology
- Hematology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a central nervous system neuroinflammatory disease involving demyelination and axonal damage.
- Vascular inflammation and coagulation system activation, leading to fibrin deposition, are implicated in MS pathogenesis.
- Activated protein C (APC) shows therapeutic potential, but recombinant APC is unavailable for human MS studies.
Purpose of the Study:
- To investigate if pharmacologic activation of endogenous protein C can improve outcomes in experimental autoimmune encephalomyelitis (EAE), a model for human MS.
- To test the efficacy of WE thrombin, a selective protein C activator, in ameliorating EAE.
- To explore a novel therapeutic strategy for symptomatic MS by enhancing endogenous APC generation.
Main Methods:
- EAE was induced in mice using myelin oligodendrocyte glycoprotein (MOG) peptides.
- Mice exhibiting EAE symptoms were treated with WE thrombin or saline control every other day.
- Disease severity was monitored, and spinal cords were analyzed ex vivo for inflammation, demyelination, macrophage activation, and fibrin deposition.
Main Results:
- WE thrombin treatment significantly reduced the clinical severity of EAE.
- Histological analysis revealed decreased inflammatory cell infiltration and demyelination in WE thrombin-treated mice.
- WE thrombin suppressed CD11b+ macrophage activation and reduced fibrin accumulation in the spinal cord.
Conclusions:
- Pharmacological enhancement of endogenous protein C generation via WE thrombin ameliorated EAE.
- Targeting the coagulation system and inflammation through endogenous APC activation presents a promising therapeutic avenue for MS.
- This study supports the potential of temporal pharmacological enhancement of endogenous APC for treating symptomatic MS.
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