Use of statins bad for myelination – possible long-term consequences

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The progressive loss of myelin as we age is now thought to be an important component of brain aging (see here) – so the last thing you want is to take a drug that might interfere with the turnover and remyelination that occurs naturally (though at a reduced level as we age). The new paper I discuss below indicates the widely prescribed drug statin may inhibit myelination – which could have serious consequences for the aging brain.

Statins are prescribed for a large group of patients at risk for cardiovascular disease (CVD) to improve blood lipid profiles – and hopefully lower their chance of CVD. In 2004 it was estimated that more than 25 million people worldwide are taking statins (probably far higher numbers now).

Previously, I wrote a piece  (is long-term statin use bad for your long-term health) suggesting that there could be long term negative consequences of statin use. The post basically described a paper that indicated statins pushed glial progenitor cells into differentiating into oligodendrocytes. The concern is that the faster rate of differentiation of progenitors cells into mature cells may lead to the ‘running out’ of progenitors when we get older.

The new paper by Klopfleisch et. al., 2008 wanted to more directly examine the effect of statins on myelin formation. Interestingly, statins, due to its anti-inflammatory function, has been tested clinically for multiple sclerosis – a progressive demyelinating disease (Volmer et. al., 2004). However, the results presented below raises concern for the use of statins to treat a demeylination disease.

Results:

First the group looked in vitro and found that statins reduced activated p21Ras and its downstream target Erk1/2 by 60-65% in oligodendrocytes. Additionally, Rho-A and ROCK activity was increased by 150-170% (interestingly, these two molecules are also important to axonal regeneration/growth). Previous work had indicated that inhibition of ROCK activity resulted in increased oligodendroglial process formation (indicating a move toward remyelination). Therefore, the increased ROCK activity observed with statin application suggested the possibility of decreased myelination (which the authors were not suspecting).

Now, with their surprising in vitro findings the researchers moved to an in vivo model to test how statins might effect myelination. Mice were fed cuprizone which results in demyelination of the corpus callosum. When you stop feeding the animals cuprizone there is spontaneous remyelination of this same brain region.

Long story made short is the animals that additionally received statins had significantly worse remyelination (both percentage of axons remyelinated and degree of myelination as measured by g-ratio, and measurements of the key components of mature myelin: e.g. myelin basic protein) compared to the control group.

Implications:

While statins improves outcome of animal models of MS called EAE and also has been tested clincally in humans (though not sure on the current clinical use of statins for MS) this paper raises some concerns for the long term use of statins. The author addresses these issue in their discussion suggesting that the anti-inflammatory action of statins may help MS at one level and produce favourable results – but their work still raises a concern of statins negative effect on remyelination.

However, what I am more interested in is that there is growing awareness that the loss of white matter (myelin) which is composed of oligodendrocytes wrapping of axons is an important component of brain aging (review article). If as described in the above paper taking the statin drug result in reduced spontaneous remyelination what would this mean to the aging brain. Throughout life there is spontaneous remyelination as part of a normal turnover and repair process. As we age there is probably more myelin loss and a reduced ability to spontaneously remyelinate. What would be the result of long-term use of the statin drugs you are taking to reduce your cardiovascular risk? Would it be a reduced rate of spontaneous remyelination and hence an overall increase of demyelination – and would this then increase the rate of cognitive decline which is observed with age induced loss of white matter?

It appears we need to take a closer examination of statins effect in brain aging studies (first in animals – though we could investigate deceased human brain samples and compare chronic statin users versus non-users) to get a more complete picture.

Another obvious answer is to make sure you are doing all the things possible that you have control over, such as exercise and healthy eating so you do not fall into the group with serious CVD risk factors and therefore have no need to take statins (or other similiar drugs).

Update: I recently posted about a paper which suggest that statin use reduces the risk of dying (from all causes of death).

Update II: maybe statins do not decrease mortality

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