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Measuring Progressive Neurological Disability in a Mouse Model of Multiple Sclerosis
Published on: November 14, 2016
Tonabersat Significantly Reduces Disease Progression in an Experimental Mouse Model of Multiple Sclerosis
Andrea Kwakowsky1,2, Bhavya Chawdhary1,3, Antonio de Souza1,3
1Department of Anatomy and Medical Imaging, Centre for Brain Research, Faculty of Medical and Health Science, University of Auckland, Auckland 1023, New Zealand.
Abstract:
Multiple sclerosis (MS) is a neurodegenerative disease marked by chronic neuroinflammation thought to be mediated by the inflammasome pathway. Connexin 43 (Cx43) hemichannels contribute to the activation of the inflammasome through the release of adenosine triphosphate (ATP) inflammasome activation signals. The objective of the study was to evaluate if the Cx43 hemichannel blocker, tonabersat, is effective in modulating the inflammatory response and reducing disability in the myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis (MOG35-55 EAE) model of MS. Here, we show that the Cx43 hemichannel blocking drug, tonabersat, significantly reduced expression of neuroinflammatory markers for microglial activation (ionized calcium-binding adapter molecule 1 (Iba1)) and astrogliosis (glial fibrillary acidic protein (GFAP)) while preserving myelin basic protein (MBP) expression levels in the corpus callosum, motor cortex, and striatum regions of the brain in MOG35-55 EAE mice. Reduced NOD-like receptor protein 3 (NLRP3) inflammasome complex assembly and Caspase-1 activation confirmed the drug's mode of action. MOG35-55 EAE mice showed clinical signs of MS, but MOG35-55 EAE mice treated with tonabersat retained behavior closer to normal. These data suggest that clinical trial phase IIb-ready tonabersat may merit further investigation as a promising candidate for MS treatment.
Insights
Tonabersat, a connexin 43 (Cx43) hemichannel blocker, reduced neuroinflammation and preserved myelin in a multiple sclerosis (MS) mouse model. This suggests tonabersat may be a promising therapeutic candidate for MS treatment.
Area of Science:
- Neuroscience
- Immunology
- Pharmacology
Background:
- Multiple sclerosis (MS) is a neurodegenerative disease characterized by chronic neuroinflammation.
- The inflammasome pathway and connexin 43 (Cx43) hemichannels, releasing adenosine triphosphate (ATP), are implicated in MS pathogenesis.
- Cx43 hemichannels are key mediators in inflammasome activation, contributing to neuroinflammation in MS.
Purpose of the Study:
- To investigate the efficacy of tonabersat, a Cx43 hemichannel blocker, in modulating neuroinflammation.
- To assess the therapeutic potential of tonabersat in reducing disability in a mouse model of MS.
- To evaluate tonabersat's effect on inflammasome pathway activation and key inflammatory markers.
Main Methods:
- Utilized the myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis (MOG35-55 EAE) mouse model to simulate MS.
- Administered tonabersat to MOG35-55 EAE mice and assessed neuroinflammatory markers (Iba1, GFAP, MBP).
- Analyzed inflammasome complex assembly (NLRP3) and Caspase-1 activation to confirm the drug's mechanism of action.
Main Results:
- Tonabersat significantly reduced microglial activation (Iba1) and astrogliosis (GFAP) markers.
- Myelin basic protein (MBP) expression was preserved in key brain regions following tonabersat treatment.
- Tonabersat treatment led to reduced NLRP3 inflammasome assembly and Caspase-1 activation.
- Mice treated with tonabersat exhibited improved clinical outcomes and behaviors compared to untreated MOG35-55 EAE mice.
Conclusions:
- Tonabersat effectively reduces neuroinflammation and preserves myelin integrity in an MS mouse model.
- The drug's mechanism involves inhibiting the NLRP3 inflammasome pathway and Cx43 hemichannel activity.
- Tonabersat demonstrates potential as a therapeutic agent for MS and warrants further clinical investigation (Phase IIb).
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