Dyslipidemia is a protective factor in amyotrophic lateral sclerosis

The intriguing paper by Dr. Dupuis et al. suggests that elevated low-density lipoprotein cholesterol levels are a positive prognostic factor for the survival of patients with amyotrophic lateral sclerosis (ALS). [1]

Their findings are particularly interesting since a recent report suggests that HMG-CoA reductase inhibitor (statin) therapy is associated with an increase in ALS or an ALS-like syndrome. [2] This begs the question: Is hyperlipidemia protective or are statins harmful in ALS?

A novel in vivo pleiotropic effect of statins is to induce the transcription factor forkhead box P3, resulting in a significant increase in the number of regulatory T cells (Tregs). [3] Tregs down-regulate central nervous system self-reactive T helper 1 (Th1) cells, which are needed to minimize glutamate induced neuronal damage that occurs in ALS. [4] Therefore, there is an impairment of the neuroprotective immune response, which may lead to a more rapid clinical decline in patients with ALS. Moreover, central nervous system cholesterol deprivation may result in an enhanced accumulation of extracellular glutamate. [5]

Perhaps the authors can provide additional data on whether the ALS patients in their large cohort were given statin therapy during the 24-month follow-up period. This may help answer the proposed question.

Regardless, statin therapy should be contraindicated in patients with ALS. Furthermore, other agents that lower cholesterol levels should also be avoided in these patients. Finally, raising the cholesterol levels of ALS patients by dietary means might be beneficial and should be investigated.

References

1. Dupuis L, Corcia P, Fergani A, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology 2008 Jan 16 [Epub ahead of print].

2.Edwards IR, Star K, Kiuru A. Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from Vigibase. Drug Saf 2007; 30: 515-525.

3. Mausner-Fainberg K, Luboshits G, Mor A, et al. The effect of HMG-CoA reductase inhibitors on naturally occurring CD4+CD25+ T cells. Atherosclerosis 2007 Sept 7 [Epub ahead of print].

4. Pacheco R, Gallart T, Lluis C, Franco R. Role of glutamate on T-cell mediated immunity. J Neuroimmunol 2007; 185: 9-19.

5. Tsai H-I, Tsai L-H, Chen M-Y, Chou Y-C. Cholesterol deficiency perturbs actin signaling and glutamate homeostasis in hippocampal astrocytes. Brain Res 2006; 1104: 27-38.

We read the article by Dupuis et al. with great interest. The authors caution clinicians treating ALS patients with dyslipidemia with lipid lowering drugs since dyslipidemia is a protective factor in ALS. [1]

We recently performed a study using wobbler mice treated with 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statin). The results showed that the statin group had significantly increased duration of normal functioning of the forelimbs yet the contraction of forelimbs was delayed.

The wobbler mouse carries a mutation in the Vps54 gene coding for a protein [2] involved in the retrograde transport of late endosomes from the periphery to the Golgi apparatus. [3] This type of mouse has long been used to test the efficacy of novel treatments for human motor neuron disease. [4]

Since statin has a pleiotropic effect including anti-inflammatory effect on Alzheimer disease and possible neuroprotective effect on Parkinson disease, we investigated the neuroprotective effect of statin on the wobbler mouse. Atrovastatin was mixed with feed at 0.01% (10mg/kg) and randomly given to symptomatic wobbler mice (3-4 weeks of age). Control group mice were given normal feed.

Motor function was evaluated with the degree of contraction (five stages: normal to severe contraction) of forelimbs and muscle strength using a dynamometer. Symptomatic evaluation was performed until bilateral forelimbs changed to moderate contracture. Atrovastatin group significantly increased the duration until the loss of function of forelimbs (average 4.7 weeks). Progression of muscle weakness was significantly delayed in the atrovastatin group.

Based on these data, we concluded that statin has a neuroprotective effect on the wobbler mouse. We also confirmed that atorvastatin has a neuroprotective effect against glutamate-induced sliced spinal cord cultures. Although an unfavorable relationship between ALS and statin has been reported [5], we contend that dyslipidemia brings a toxic effect to neurons and statin has a positive effect on ALS.

References

1. Dupuis L, Corcia P, Fergani A, et al. Dyslipidemia is a protective factor in amyotrophic lateral sclerosis. Neurology. 2008;70:1004-1009.

2. Schmitt-John T, Drepper C,Mussmann, et al. Mutation of Vps54 causes motor neuron disease and defective spermiogenesis in the wobbler mouse. Nat. Genet. 37:1213-1215.

3. Liewen H, Meinhold-Heerlein I, Oliveira, et al. Characterization of the human GARP (Golgi associated retrograde protein) complex. Exp. Cell Res. 306:24-34.

4. Duchen LW, Strich SJ. An hereditary motor neurone disease with progressive denervation of muscle in the mouse: the mutant 'wobbler'. J Neurol Neurosurg Psychiatry. 1968;31:535-542.

5. Edwards IR, Star K, Kiuru A. Statins, neuromuscular degenerative disease and an amyotrophic lateral sclerosis-like syndrome: an analysis of individual case safety reports from vigibase. Drug Saf. 2007;30:515-525.

Disclosure: The authors report no conflicts of interest.

We thank Goldstein et al. for their comments on our recent study. [1] They raise two important points that we would like to address.

First, we would like to point out that the observed protective effect of dyslipidemia observed in our study was not due to any pharmacological interference. For more than a decade, we have been considering a possible worsening effect of statins that has been recently confirmed and we systematically stop this family of drugs in our patients at first visit. [2] Thus, in the published study, all patients included were free of statin medication during the whole study. [1] This strongly suggests that the protective effect of dyslipidemia is not due to a higher frequency of statin therapy in the low LDL/HDL group of patients.

Second, we agree with Goldstein et al. that statin therapy has to be avoided in ALS patients, although the mechanism invoked by them might not be the only one. As stated, statins might enhance glutamate excitotoxicity through their immunomodulatory properties, [2-5] but these drugs might also trigger myotoxicity. [6-8]

Finally, by reducing LDL-cholesterol, statins are able to decrease nutrient availability to muscle which might contribute to neuromuscular junction damage and motor neuron death as previously shown in an animal model of ALS. [9-10] Multiple pathways activated by statins might be deleterious in ALS patients and the correspondence by Goldstein et al. strengthens our conclusions.

References

6. Sirvent P, Mercier J, Lacampagne A. New insights into mechanisms of statin-associated myotoxicity. Curr Opin Pharmacol. 2008 Jan 31.

7. Calabrò P, Yeh ET. The pleiotropic effects of statins. Curr Opin Cardiol. 2005;20:541-546.

8. Wierzbicki AS, Poston R, Ferro A. The lipid and non-lipid effects of statins. Pharmacol Ther. 2003;99:95-112.

9. Fergani A, Oudart H, Gonzalez De Aguilar JL, et al. Increased peripheral lipid clearance in an animal model of amyotrophic lateral sclerosis. J Lipid Res. 2007;48:1571-1580.

10. Dupuis L, Oudart H, René F, Gonzalez de Aguilar JL, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci U S A. 2004; 101: 11159-11164.

Disclosure: The authors report no conflicts of interest.

We thank Dr Yoshii et al. for providing their unpublished results suggesting a protective effect of atorvastatin in the wobbler mouse. However, we have several concerns about their findings and subsequent conclusions.

First, the relevance of the wobbler mouse as a model for human treatments strategies with regard to ALS is still unclear. To our knowledge, there is no known mutation of the vps54 gene in ALS cases and the symptoms developed by the wobbler mouse are closer to spinal muscular atrophy than ALS.

Second, Dr Yoshii and colleagues based the rationale of their studies on the neuroprotective effect of statins in other neurodegenerative diseases (AD and PD) and their results show that the wobbler mouse is similarly protected. We do not claim that statins are devoid of neuroprotective or anti-inflammatory properties that could make them useful in some neurodegenerative conditions. However, we and others have suggested that statins might be detrimental in ALS because of their systemic and widely documented hypolipemic effect that would obscure a potential neuroprotection. Our assumption is based on our own results showing the probable "protective" effect of hyperlipemia in ALS patients and also on results [5] suggesting that statin intake could accelerate the ALS disease process.

Dr Yoshii et al's commentary illustrates that, as suggested by numerous recent studies, there are a number of steps between preclinical studies in mice and clinical trials in ALS patients. Our studies have consistently shown profound differences between mSOD1 mice energy metabolism and ALS patients.

Murine metabolism is strikingly different between mice and men and we therefore think that the discrepancy between our results and those of Dr Yoshii et al. may be due to interspecies differences.

Disclosure: The authors report no disclosures.