Hill 2015 Abstract MiPschool London 2015

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A novel inhibitor of the mitochondrial permeability transition pore is beneficial in an experimental model of multiple sclerosis.

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Hill JH, Pryce G, Baker D, Duchen M, Szabadkai G, Selwood D (2015)

Event: MiPschool London 2015

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system, characterized by demyelinated lesions, which lead to neurodegeneration and severely impaired motor skills. It was recently discovered that these lesions disrupt the blood brain barrier, providing an opportunity for lesion specific drug targeting by compounds that will not otherwise cross the blood brain barrier [1]. There is evidence for a role of the mitochondrial permeability transition pore (mPTP) in the pathology [2]. mPTP is a large conductance pore that opens in the mitochondrial inner membrane, causing loss of mitochondrial membrane potential and depletion of ATP, leading to a cellular energetic crisis and cell death.

Four novel compounds targeting the mPTP were developed and screened in vitro using mitochondria isolated from mouse liver. Compounds were screened in isolated mitochondrial preparations using the calcium retention capacity assay to determine whether they inhibited mPTP opening. Compounds were compared to cyclosporin A – the canonical inhibitor of pore opening. Two of the compounds inhibited pore opening with significantly greater potency than CsA. The effects of the most potent compound on mitochondrial function were investigated by respirometry and by measurements of the mitochondrial membrane potential in cortical neurons. At low concentrations, the compound did not alter respiration of isolated liver mitochondria or neuronal mitochondrial membrane potential, although at high concentrations it reduced state 3 and maximal uncoupled respiration, and neuronal membrane potential. Importantly, in an in vivo autoimmune encephalomyelitis mouse, a model of demyelinating disease, the compound significantly improved clinical score and prevented deterioration of motor skills, suggesting significant neuroprotective potential.

Keywords: Multiple sclerosis, mPTP


Labels: MiParea: mt-Membrane  Pathology: Other 

Organism: Mouse  Tissue;cell: Liver  Preparation: Isolated mitochondria 


Coupling state: OXPHOS, ET 

HRR: Oxygraph-2k 


Affiliations

1-Dept Cell Developm Biol, Univ College London, UK. - julia.hill.12@ucl.ac.uk

2-Centre Neurosc Trauma, Blizard Inst

3-Dept Biomed Sc, Univ Padova

4-Med Chem, Wolfson Inst Biomed Research

References

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  2. Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu X, Fowlkes J, Rahder M, Stem K, Bernardi P, Bourdette D (2007) Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc Natl Acad Sci USA 104:7558-63