Monday November 12 2007
MS-like disease in mice will not be exactly like MS in humans
Multiple sclerosis sufferers could benefit from a drug that has been used for decades to treat blood pressure the BBC reported today.
The report is based on a study in mice which found that the drug, amiloride “a drug used for many years to treat high blood pressure and heart failure”, protects mouse cells from damage caused to the nerves by an MS-like disease.
The BBC said that, should the drug be effective, the process of the getting the treatment to patients would be speeded up, as the drug was already licensed.
The study is a complex laboratory study using mice as subjects. The mice have a disease which mimics MS in humans. As with all animal studies there is an issue of extrapolation of the findings to health in humans. The findings will be of interest to the scientific community and may prompt more research into the effects of the drug in human sufferers of MS. Human studies will have more direct relevance to us and we look forward to their findings.
Where did the story come from?
Dr Manual Friese and colleagues from the University of Oxford, the University of Iowa and Aarhus University Hospital in Denmark conducted this research. The study is funded by several financial bodies including the Danish and UK Medical Research Councils, the Danish Multiple Sclerosis Society and the European Union. The authors declare competing interests in that the Medical Research Council UK has filed a patent for treatments for MS based on the research in this paper.
The study was published as a letter in the peer-reviewed medical journal: Nature Medicine.
What kind of scientific study was this?
The study investigated a theory that the functional problems associated with MS are caused by too much calcium and sodium being channelled into the nerve cells of the MS sufferer. The researchers were particularly interested in the role of one type of sodium and calcium channel, the ASIC1 channel, that is only active in acidic conditions. They were also interested in whether amiloride (a drug used to manage hypertension and known to block the ASIC1 channels in cells) could reduce disease severity.
The researchers compared genetically mutated mice whose ASIC1 channels had been stopped from working to normal mice whose ASIC1 channels were functioning normally. An MS-like disease was induced in both groups of mice and the impact of the disease on functioning (walking and paralysis) was then compared.
ASIC1 channels require a more acidic environment in order to open, therefore the researchers investigated whether there were pH changes in the mice’s nervous system in response to the MS-like disease, to see if the disease created conditions that would favour ASIC1 opening.
Parts of the optic nerve and retina from both types of mice were extracted and the cells were incubated with substances that are known to block the ASIC1 channels. These substances included amiloride. They repeated their assessment of the effects of amiloride in live mice by seeing whether the drug protected normal mice against the MS-like disease. They also compared the effects of the drug on normal mice and knock-out mice to confirm whether it was directly acting on the ASIC1 channelling mechanism.
What were the results of the study?
The researchers found that when they tried to induce the MS-like disease in the knockout-mice which lacked ASIC1, the disease was less severe than it was in normal mice.
They also confirmed that the MS-like disease results in a more acidic environment (i.e. lower pH) in the central nervous system. As low pH is known to cause the ASIC1 channels to open, this was a significant finding for their study.
When they extracted the optic nerves from the mice and experimented with them in the laboratory (i.e. not in the live mice), the researchers found that amiloride protected the optic nerves from the MS-like damage. They postulated that this was because it blocked the ASIC1 channels.
The findings from the laboratory were successfully repeated in an experiment in live mice where the drug was found to reduce the clinical severity of the MS-like disease (in terms of how the mice walked or whether the disease paralysed them).
The researchers were able to show that amiloride was acting by blocking the ASIC1 channels because they found no protective effect in the mice who did not have ASIC1 channels (the knock out mice) but found that normal mice were protected.
What interpretations did the researchers draw from these results?
The researchers conclude that excessive sodium and calcium channelling through ASIC1 channels, induced by the acidic environment which occurs in an MS-like disease in mice, is responsible for nerve damage, and that amiloride blocks these channels and protects the nerves.
They say that amiloride, “which is already licensed for treatment of hypertension and heart failure” may be valuable for treatment of MS either on its own or in combination with existing treatments.
What does the NHS Knowledge Service make of this study?
This is a well-conducted laboratory study which used complex methods. Importantly, as it has been conducted in mice, it is difficult to say exactly how the findings will apply to health in humans. Obviously the pathology of disease is hugely different between mice and humans, and the MS-like disease induced in the mice in this experiment will not be exactly like MS in humans.
Human studies, which sometimes follow on from animal studies which show promise, will be more useful for us and the results from these are needed before we can appreciate whether amiloride has a place in the treatment for multiple sclerosis in humans.