The anticholesterol drugs known as statins act primarily by inhibiting the rate-limiting step in cholesterol biosynthesis. However, these compounds also have effects mediated by other mechanisms: for example, we recently learned that the antioxidant activity of one such drug, rosuvastatin, helps limit age-related increases in reactive oxygen species.
Now, Andras et al. report that another statin, simvastatin, can protect against the inflammatory effects of expression the Alzheimer’s-related protein Aß:
SIMVASTATIN PROTECTS AGAINST AMYLOID BETA AND HIV-1 TAT-INDUCED PROMOTER ACTIVITIES OF INFLAMMATORY GENES IN BRAIN ENDOTHELIAL CELLS
Increased deposition of amyloid beta (Aß) is characteristic for normal aging and HIV-1-associated alterations of the central nervous system. In addition, both Aß and HIV-1 are known to induce cellular oxidative stress and disruption of the blood-brain barrier (BBB). Therefore, we hypothesize that Aß and HIV-1 protein Tat can potentiate their proinflammatory effects at the brain endothelium level. To address this hypothesis, we studied promoter activity of three proinflammatory genes in an in vitro BBB model of human brain microvascular endothelial cells (HBMEC) co-cultured with a human astrocyte cell line producing Tat (SVGA-Tat cells) and exposed to Aß. Treatment of HBMEC with Aß(1-40) in the presence of SVGA-Tat cells resulted in a significant upregulation of E-selectin, CCL-2, and IL-6 promoter activities and protein levels as compared to the individual effects of Aß or Tat. In addition, A markedly amplified E-selectin promoter activity in HBMEC co-cultured with HIV-1-infected Jurkat T cells. Simvastatin, the HMG-CoA reductase inhibitor, effectively blocked proinflammatory reactions induced by Aß in co-cultures with SVGA-Tat cells or with HIV-1-infected Jurkat cells. The present study indicates that a combined exposure to A and Tat or HIV-1 can synergistically potentiate expression of inflammatory genes in brain endothelial cells. In addition, simvastatin may provide a beneficial influence by reducing these effects at the BBB level.
The compound also prevents inflammation resulting from HIV infection, suggesting that the mechanism of simvastatin action is not peculiar to the effects of one specific protein. It remains to be seen whether the compound is directly altering transcription of inflammatory genes, or whether the effect on inflammation is somehow mediated by the drug’s effect on cholesterol.
Reports like this always make me marvel: Is there anything statins can’t do? (I remember attending a conference where one speaker half-jokingly suggested we put statins in the drinking water; my only objection at the time was that I don’t think they’re particularly soluble.) When I have thoughts like that, I always take care to remind myself that we have yet to invent a drug with no side effects. In the case of statins, the problem is myalgia (muscle weakness), and it can be severe enough to be debilitating. Definitely not for recreational use.