Are statin medications safe in patients with ALS?

Statin medications for elevated cholesterol are one of the most commonly prescribed medications worldwide. The aim of this study was to determine if statin medications affect the rate of disease progression, the severity and frequency of muscle cramping, and serum CK levels in patients with ALS. We conducted a prospective cohort study in patients diagnosed with ALS with statin medication as the predetermined exposure variable and the rate of decline of the ALS Functional Rating Scale-Revised (ALSFRS-R) as the primary outcome. One hundred and sixty-four consecutive patients with laboratory supported probable, clinically probable, or clinically definite ALS were evaluated from January 2006 to September 2007. Thirty-two patients (20%) were taking statin medications and 132 were in the control group. After adjusting for covariates, we found a highly significant increase in the rate of decline in the ALSFRS-R for the statin group (1.71 units/month) compared to the control group (1.05 units/month, pB0.0001) representing a 63% increase in the rate of functional decline. Patients on statin therapy also reported a significant increase in muscle cramp frequency and severity (pB0.0001). This study has demonstrated a strong association between statin medications and an increased rate of functional decline and muscle cramping in patients with ALS. Although this association does not prove a causal relationship, it is prudent to exercise caution and discuss discontinuation or replacement of statin medications in patients with ALS.

Liver X receptor activator downregulates angiotensin II type 1 receptor expression through dephosphorylation of Sp1.

Atherosclerosis is considered to be a combined disorder of lipid metabolism and chronic inflammation. Recent studies have reported that liver X receptors (LXRs) are involved in lipid metabolism and inflammation and that LXR agonists inhibit atherogenesis. In contrast, angiotensin II is well known to accelerate atherogenesis through activation of the angiotensin II type 1 receptor (AT1R). To better understand the mechanism of LXR on the prevention of atherogenesis, we examined whether activation of LXR affects AT1R expression in vascular smooth muscle cells. T0901317, a synthetic LXR ligand, decreased AT1R mRNA and protein expression with a peak reduction at 6 hours and 12 hours of incubation, respectively. A well-established ligand of LXR, 22-(R)-hydroxycholesterol, also suppressed AT1R expression. The downregulation of AT1R by T0901317 required de novo protein synthesis. AT1R gene promoter activity measured by luciferase assay revealed that the DNA segment between -61 bp and +25 bp was sufficient for downregulation. Luciferase construct with a mutation in Sp1 binding site located in this segment lost its response to T0901317. T0901317 decreased Sp1 serine phosphorylation. Although preincubation of vascular smooth muscle cells with T0901317 for 30 minutes had no effect on angiotensin II-induced extracellular signal-regulated kinase phosphorylation, phosphorylation of extracellular signal-regulated kinase by angiotensin II was markedly suppressed after 6 hours of preincubation. These results indicate that the suppression of AT1R may be one of the important mechanisms by which LXR ligands exert antiatherogenic effects.