Warne J, Pryce G, Hill J, Shi X, Lennerås F, Puentes F, Kip M, Hilditch L, Walker P, Simone MI, Chan AW, Towers GJ, Coker A, Duchen MR, Szabadkai G, Baker D, Selwood DL.Selective inhibition of the mitochondrial permeability transition pore protects against neuro-degeneration in experimental multiple sclerosis.
J Biol Chem. 2015. pii: jbc.M115.700385. [Epub ahead of print]
The mitochondrial permeability transition pore (PT pore) is a recognised drug target for neurodegenerative conditions such as multiple sclerosis (MS) and for ischaemia-reperfusion injury in the brain and heart. The peptidylprolyl isomerase, cyclophilin D (CypD, ppif) is a positive regulator of the pore and genetic downregulation or knockout improves outcomes in disease models. Current inhibitors of peptidylprolyl isomerases show no selectivity between the tightly conserved cyclophilin paralogs and exhibit significant off target effects, immune-suppression and toxicity. We therefore designed and synthesised a new mitochondrially-targeted CypD inhibitor, JW47, using a quinolinium cation tethered to cyclosporine (CsA). X-ray analysis was used to validate the design concept and biological evaluation revealed selective cellular inhibition of CypD and the PT pore with reduced cellular toxicity compared to CsA. In an experimental autoimmune encephalomyelitis disease model of neurodegeneration in multiple sclerosis (MS), JW47 demonstrated significant protection of axons and improved motor assessments with minimal immunosuppression. These findings suggest that selective CypD inhibition may represent a viable therapeutic strategy for MS and identify quinolinium as a mitochondrial targeting group for in vivo use.
The mitochondria are organelles within a cell and they are the power houses that makes energy, which allows the cells to function. The brain consumes about 20% of the bodies energy and so any problem with the mitochondria is going be bad for the brain and spinal cord. Demyelinated nerves have to work much harder to keep nerves signalling during MS and so consume more energy, but there is increasing evidence that mitochondrial problems occur in MS and this may be damaging, indeed it is thought that this may cause the slow burning damage in progressive MS.
The Mitochondrial Permeability Transition pore causes an increase in the permeability of the mitochndrial membrane and is formed under pathological conditions and can lead to mitochondrial swelling and shut down leading to cell death. MPT is one of the major causes of cell death in a variety of conditions. For example, it is key in neuronal cell death in excitotoxicity, in which overactivation of glutamate receptors causes excessive calcium entry into the cell.[ MPT also appears to play a key role in damage caused by ischemia, as occurs in a heart attack and stroke.
The only MPTP components identified so far are the TSPO (previously known as the peripheral benzodiazepine receptor) located in the mitochondrial outer membrane and cyclophilin D in the mitochondrial matrix. we know that loss of cyclophilin D is associated with damage because if it is knockouted out mice with EAE do much better in terms of accumulating less nerve loss in response to the damaging inflammatory attack
Forte M, Gold BG, Marracci G, Chaudhary P, Basso E, Johnsen D, Yu X, Fowlkes J, Rahder M, Stem K, Bernardi P, Bourdette D. Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Proc Natl Acad Sci U S A. 2007;104:7558-63.
So you would like a blocker of cyclophilin D to block the MPT pore. This is what was done in this paper and it was shown that indeed there was neuroprotection, despite inflmmatory response so it should have the potential to slow progressive MS.
There has been a cyclophilin D molecule used in MS, and it did actually signficantly block the worsening of EDSS in progressive MS, despite it being eliminated from the brain by drug pumps in the blood vessels. However, it was being used to stop relapsing MS to target autoimmunity and not progressive MS and it had a small effect on gadolinium lesions due to immunosuppression but at the dose used it caused kidney problems.
However, these problems was because the molecule targeted cyclophilin A and calcineurin in addition to cyclophilin D. Calcineurin activates nuclear factor of activated T cells (NFATc), a transcription factor, by dephosphorylating it. The activated NFATc is then translocated into the nucleus, where it upregulates the expression of interleukin 2 (IL-2), which, in turn, stimulates the growth and differentiation of T cell response and so can block T cell activation. However it can also cause the kidney disease and this also occurs with a a dru called a tacrolemus and another called cyclosporin A, which was the drug used in MS that had an effect on progression, which is used a s a transplant rejection drug.
In this paper ProfDave did a bit of chemistry magic and designed a series of compounds that target and inhibit cyclophilinD and the MTP pore, by targeting the drug based on cyclopsorinA into the mitochondria using quinolium chemical group, but have a limited ability to block cyclophilin A/Calcineurin so they will be neuroprotective without the immunosuppressive and kidney problems
So here we report on one of them called Jw47 (after Justin Warne who made it). It blocks the mitochondrial pore and gets in the brain but it does not have a strong potential to inhibit immune responses, as seen using T cell proliferation assays in test tubes and in animals. We can find doses that do not affect the peripheral immune responses and do not stop EAE from developing, however it saves nerves as a consequence of these attacks and blocks nerve loss. So this is a type of drug that needs to be added to immunosuppressive drugs currently used in relapsing MS.
Can we develop these drugs to cause neroprotection in MS, just as we have moved our anti-spasticity drugs all the way to studies aiming to treat spasticity. This is a step in the right direction and we have compounds that are more potent than Jw47, but’s that’s for another day.
CoI. TeamG are authors of this paper and have filed patents