Epub: Schattling et al. TRPM4 cation channel mediates axonal and neuronal degeneration in experimental autoimmune encephalomyelitis and multiple sclerosis Published online: 18 November 2012 | doi:10.1038/nm.3015
In multiple sclerosis, an inflammatory disease of the central nervous system (CNS), axonal and neuronal loss are major causes for irreversible neurological disability. However, which molecules contribute to axonal and neuronal injury under inflammatory conditions remains largely unknown. Here we show that the transient receptor potential melastatin 4 (TRPM4) cation channel is crucial in this process. TRPM4 is expressed in mouse and human neuronal somata, but it is also expressed in axons in inflammatory CNS lesions in experimental autoimmune encephalomyelitis (EAE) in mice and in human multiple sclerosis tissue. Deficiency or pharmacological inhibition of TRPM4 using the anti-diabetic drug glibenclamide resulted in reduced axonal and neuronal degeneration and attenuated clinical disease scores in EAE, but this occurred without altering EAE-relevant immune function. Furthermore, Trpm4−/− mouse neurons were protected against inflammatory effector mechanisms such as excitotoxic stress and energy deficiency in vitro. Electrophysiological recordings revealed TRPM4-dependent neuronal ion influx and oncotic cell swelling upon excitotoxic stimulation. Therefore, interference with TRPM4 could translate into a new neuroprotective treatment strategy.
The Transient Receptor Potential Melastatin 4 (TRPM4) is an ion channel
that controls Calcium signals in excitable and non-excitable cells including nerves. This study indicates that if you block this channel that nerve damage is blocked. This may be achieved with an anti-diabetic drug. We also have data on the value of calcium channel (not TRPM4) blockage as neuroprotectant using differnt drugs, again already used in human conditions other than MS.
The question is how we get existing drugs re-purposed for use as neuroprotectants in MS, if the drug is out of patent. Sure we (academics) have expertise to do the clinical trials, but that is not the problem. It is how we then get them accepted by the regulators and who will pay for this if there is not a drug company behind it. Do academics have to do two phase III trials as appears to be a requirement for pharma. Pharma have teams/companies doing this and they mess up so if academics do this, some infrastructure is needed. If we cannot get an active drug approved is it worth spending millions doing the studies.
Is this relevant...yes it is. Phase II simvastatin looked interesting in progressive MS. What about more trials and regulatory submission
Labels: Calcium channels, neuroprotection