Although there is strong evidence for an excitotoxic component to myelin injury in multiple sclerosis, functional protection against demyelination by glutamate receptor antagonists is controversial.
To deploy a novel medium-throughput screen to generate dose-response curves for myelin protection by NMDA- and AMPA-type glutamate antagonists and probe for synergy between these drugs at low concentrations.
An in vitro super-acute myelin protection assay based upon isolated brain slice and optic nerve exposure to cuprizone was used to test the protective properties of several experimental and clinically approved AMPA and NMDA receptor antagonists. A standard EAE model of multiple sclerosis was used to examine one paradigm.
Both AMPA and NMDA receptor antagonists protected central myelin from acute cuprizone-mediated injury in a concentration-dependant manner. When these two drug types were combined at concentrations 1-2 order lower than the minimally effective concentrations required when applied alone, significant protection was achieved. In the case of clinically approved drugs, an effective combined concentration was ~2 orders of magnitude below the normal treatment doses (200 nM perampamel + 500 nM memantine). One combined low-dose regiment (1 mg/Kg CP465022 + 2 mg/Kg QNZ-46) was tested in a standard EAE model of disease and produced significant levels of functional and clinical protection.
Super-low combinations of AMPA and NMDA antagonists were identified as a potential therapy using a novel myelin protection assay. The approach was confirmed in an in vivo model of disease. These very low doses of clinically approved medicines will have a low barrier to translation as they work at much lower doses to those used in current clinical practice in the treatment of non-demyelinating disorders.