Statins: multiple mechanisms of action in the ischemic brain.
Although substantial epidemiological studies have failed to find a correlation between cholesterol levels and stroke, clinical trials have shown that HMG-CoA reductase inhibitors (or statins, the most potent hypocholesterolemic drugs available) greatly reduce the incidence of stroke. These clinical observations have opened the way to a number of studies of the non-cholesterol-dependent (or pleiotropic) effects in animal models of stroke, indicating that the neuroprotection is attributable to multiple activities. One of the main protective mechanisms elicited by statin administration is the increase in nitric oxide bioavailability that regulates cerebral perfusion and improves endothelial function, but others include antioxidant properties, the inhibition of inflammatory responses, immunomodulatory actions, the regulation of progenitor cells, and the stabilization of atherosclerotic plaques. Many of these effects are due to the inhibited synthesis of isoprenoid intermediates, which serve as lipid attachments for a variety of intracellular signaling molecules. This article describes the mechanisms involved in the neuroprotective effects of statins.
Cimino
Mauro
M
Institute of Pharmacology and Pharmacognosy, University of Urbino Carlo Bo, Urbino, Italy.
Gelosa
Paolo
P
Gianella
Anita
A
Nobili
Elena
E
Tremoli
Elena
E
Sironi
Luigi
L
D000818:Animals; D002545:Brain Ischemia / Q000517:prevention & control*; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D007249:Inflammation / Q000188:drug therapy; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D018696:Neuroprotective Agents; D052250:Nitric Oxide Synthase Type III