The roles of inflammation and degeneration as well as of grey matter abnormalities in multiple sclerosis (MS) and its animal model experimental autoimmune encephalomyelitis (EAE) are controversial. We analyzed the pathological manifestations in two EAE models, the chronic oligodendrocyte glycoprotein (MOG)-induced versus the relapsing-remitting proteolipid protein (PLP)-induced, along the disease progression, using advanced magnetic resonance imaging (MRI) parameters. The emphasis of this study was the overall assessment of the whole brain by histogram analysis, as well as the detection of specific affected regions by voxel based analysis (VBA) using quantitative T2, magnetization transfer ratio (MTR) and diffusion tensor imaging (DTI). Brains of EAE-mice from both models revealed multiple white and grey matter areas with significant changes from naïve mice for all MRI parameters. Ventricle swelling was more characteristic to the PLP-induced model. Decreased MTR values and increased apparent diffusion coefficient (ADC) were observed mainly in MOG-induced EAE, indicative of macromolecular loss and structural CNS damage involvement in the chronic disease. The MS drug glatiramer acetate (GA), applied either as prevention or therapeutic treatment, affected all the MRI pathological manifestations, resulting in reduced T2 values and ventricle volume, elevated MTR and decreased ADC, in comparison to untreated EAE-inflicted mice. In accord, immunohistochemical analysis indicated less histological damage and higher amount of proliferating oligodendrocyte progenitor cells after GA treatment. The higher brain tissue integrity reflected by the MRI parameters on the level of the whole brain and in specific regions supports the in situ anti-inflammatory and neuroprotevtive consequences of GA treatment.
Imaging the brain of mice with EAE can show some changes in MRI outcomes and some of them that they show brain damage in mice. Treating with Copaxone/Glaterimer acetate can inhibit these changes. However, Clinical Profiling tells us that EAE in the C57BL/6 is degenerative because they do not recover from their attacks, SJL mice recover from their first attack and this can relapse Therefore we already know that disease is neurodegenerative in this strain. This is because they do not tolerate the attack very well and lose nerves as a consequence. This can be seen histologically. It can also be seen histologically that the clinical disease is associated mainly with spinal cord involvement. Therefore imaging the brain is going to miss alot and is not well correlated with the clinical disease. However imaging the spinal cord is difficult because it is small and moves because of breathing unlike a still head which is easier to image. Same problem happens in humans. Adapting the way that Glaterimer acetate is delivered such that it is immunosuppressive, will inhibit the immune response such that it does not arrive in the brain in the first place, so it is not in the brain to cause nerve damage. Then it is not surprising there is neuroprotection. This is like saying "Not hitting yourself over the head with a hammer is neuroprotective". It is obvious every single immunosuppressive drug will do this. However, this does not stop neurodegeneration in progressive MS. Therefore we need a different approach in animals to show this. It is amazing how many EAE studies churn out the neuroprotection angle when it is nothing more than peripheral immunosuppression.
The senior author of this paper was one of the inventors of glaterimer acetate in the 1970s. This drug has been used in humans for many years and its patent expires in a few. We do not need to see how glaterimer acetate works or does not work in animal models any longer, in humans maybe.......its mechanism of action has changed with every major dogma that has appeared in immunology over the years. We know it is of low efficacy compared to more recent MS drugs, if it is really neuroprotective as is claimed, there are papers showing neuroprotection in non-immunological model systems too, then it is more incumbant on the company to really show this in MSers. Therefore rather than funding scientists to do work that keeps glaterimer acetate in the literature they should use their money to show it is neuroprotective and slows progression in humans.
Oh but they have done a very large trial
in progressive MSers.....it was stopped because they said the placebo trial was not progressing fast enough (to show a difference)? There was no significant drug effect. There has been plenty of time to re-do the studies but nothing besides numerous animal studies and so this argument is not compelling.
Labels: EAE, Glaterimer Acetate