Lipid Statins for Neurodegenerative Disease

    We too are intrigued by the recent reports of the use of lipid statins in controlling the immune defect seen in the experimental model of multiple sclerosis (MS). This work in mice showed that there was reduction of exacerbation in the exacerbating remitting form of experimental allergic encephalitis (EAE) and that the onset of signs for the development of EAE could be suppressed or delayed. Most importantly, the researchers found that existing EAE signs could be reduced by starting lipid statins after EAE was established. Moreover, the lipid statins could reduce signs in chronic EAE (where the signs have been present for more than a week). This latter finding is the most significant for MS and for the disease we treat in dogs, German Shepherd degenerative myelopathy (GSDM). For this work, Lipitor®, was the lipid statin used at doses 10 times higher than used for controlling blood lipids in human patients.
    Additional work of interest that is recent is that various other lipid statins also correct the immunologic defect of blood cells taken from human patients with exacerbating-remitting MS. Thus, the lipid statins appear to regulate the TH-1 (T Helper cells which are part of the lymphocyte population that regulate auto-immune reactions) responses by altering the cytokine production of these blood cells. It is, therefore, postulated that lipid statins might have the same responses in reducing signs of MS as were seen in EAE. Similar changes in cytokine production were seen in the mouse studies. This study with human blood cells also showed that some statins were better than others at producing this effect. On the other hand, this effect of the statins is also independent of the effect of statins on blood lipids, so we are just beginning to understand what mechanisms are involved.
    Certainly, our work with CSF of dogs afflicted with GSDM suggests that similar mechanisms are involved in GSDM and MS. I have found that medications which help in EAE often help in MS and in GSDM. That was the original rationale for using aminocaproic acid in GSDM over 2 decades ago. On the other hand, I have seen many promising directions turn out to be dead ends and have the opposite effect than the one desired. I understand why people with dogs affected with GSDM will grasp at any new potential treatment, but I want to express caution until we know whether lipid statins are going to be helpful or harmful. GSDM is not exacerbating-remitting MS, at least by the time a diagnosis is made. It seems to me that GSDM is either primary progressive MS or secondary progressive MS whish is left after the exacerbating-remitting form becomes advanced. Since most of the products used to treat MS in human beings are directed at reducing the likelihood of developing an acute attack or reducing the inflammation during an acute attack, they are directed at the form of MS which is least like GSDM. This is also true of EAE which represents an acute disease. Even chronic EAE is more acute than primary or secondary progressive MS or GSDM. As such, treatments for GSDM must be different. Moreover, the life-span of dogs is much short than the life expectancy of human beings, which means that treatment frequency must be altered to account for the compressed disease course. Something that can be used every other day in human beings may need to be used every 8 hours in dogs to get the same results.
    The reason that we have treatments for dogs with GSDM today and have an established protocol for diagnosis of GSDM is because of a few courageous people who have allowed me to look very carefully at those treatments and diagnostic measures in their pets. We cannot preform basic research on a clinical disease. We can perform clinical research which takes the patient into account first and foremost, only doing what will not harm them. This bring us to the question of using lipid statins for treatment of GSDM.
    I am reluctant to tell people to use something that we have not tried on patients who we know have the disease based upon our protocol. Since I may be the only one who uses this protocol, that limits these studies to our own patients. Why do I say this. For one thing, we see lots of patients diagnosed with GSDM who, in fact, have other problems. In Dr. Coates’ study of methionine and treatment of GSDM, she found through necropsy at the end of the study that only 3 of the 12 patients she selected had DM. She did not follow our protocol. While it is true that the only way to absolutely confirm GSDM is with histopathology (only possible at the end of life), I have been able to confirm GSDM in many of our patients at the end of their lives. Enough where I am comfortable, that we do not miss simple things like intervertebral disc disease, infection, neoplasia and lumbosacral stenosis, those diseases which were confused for GSDM in Dr. Coates’ study. Many GSD owners flocked to the use of methionine which was found to be non-effective by Dr. Coates, even though her numbers of true GSDM patients was low. That suggests the we must be cautious.
    I have 2 patients who we are trying with lipid statins. One of these is severely affected and near the end of life the other is still mobile and has not responded as well as we would like with the current treatment protocol. We added Lipitor® to their treatment. The more severe patient developed acute renal failure. While the renal failure may not be due to the Lipitor®, I can not prove that it is not. Renal failure has been seen in human patients taking lipid statins, but usually this is thought to be secondary to rhabdomyolysis from muscle damage that can be caused by lipid statins. In fact, the muscle damage is thought to be due to the fact that the lipid statins also block the formation of CoQ-10 which is necessary for normal muscle health. When CoQ-10 levels fall, muscle damage results. This can be overcome, in theory, by supplemental oral CoQ-10 (around 100 mg twice a day). However, the patient who developed renal failure does not appear to have developed renal failure through this mechanism. Until we know, I think it is better to use the existing medications and keep informed of our progress.
    The use of lipid statins in controlling immune-related neurodegenerative is certainly interesting and I hope it does turn out to add significantly to our overall treatment program. It is too early to suggest its wide-spread use, particularly if the diagnosis is not certain. Early treatment with our current medications is effective in most patients who have GSDM, even if it only delays progression. That remains the best starting point for treatment.

Best wishes for health and long life,

RM Clemmons, DVM, PhD
Associate Professor of Neurology & Neurosurgery

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