Increasing evidence suggests that the benefits of statins may extend beyond their hypolipidemic activity. In this study, the authors review the main mechanisms potentially related to statins neuroprotective properties like antioxidant effects, regulation of nitric oxide production and modulation of eNOS and matrix metalloproteases (MMPs) that play an important role in the immune-modulatory effects of statins in cerebral ischemic stroke and the action of statins in main neurological disorders.
Major cardiovascular risk factors such as hypercholesterolaemia, diabetes mellitus, chronic smoking, metabolic syndrome, and hypertension are associated with overproduction of reactive oxygen species (ROS) as well as neuronal tissue damage. Abnormal ROS production and the subsequent decrease in vascular bioavailability of nitric oxide (NO) have been proposed as the common pathogenetic mechanism involved in endothelial dysfunction. Recent studies indicate that nicotinamide dinucleotide phosphate (NADPH) oxidase is a predominant source of superoxide generation in the vasculature as well as in the central nervous system (CNS). The inhibition of NADPH oxidase is indicated by multiple studies as one of the major mechanisms of the pleiotropic effects of statins. In most situations in which endothelial dysfunction due to increased oxidative stress is encountered, the expression of NOS has been shown to be paradoxically increased. Neuroprotective effects of statins are potentially due to the up-regulation of eNOS.
Findings showed that statins enhance eNOS expression and activity, improve its enzymatic coupling, thus leading to increase NO bioavailability and improve endothelial function. Twenty-three members comprise the family of MMP in humans and their functions are important in the CNS during development, in normal adulthood and after injury. Several MMP members’ levels are enhanced in diseases such as: multiple sclerosis (MS), ischemic stroke, spinal cord injury and neurodegenerative diseases. Statins are considered MMP inhibitors since inhibit MMP production and activity. Statins work in several neurological diseases such as CNS malignancies (anti-proliferative, anti-tumor and apoptotic effects), depression (by lowering cholesterol that plays same important role in the serotonin system), post-stroke-depression, Alzheimer disease (cholesterol promotes the production of Aβ). Furthermore, recent studies in animal models have shown that statins have immune-modulatory properties that might be of benefit in the treatment of neuro-inflammatory disorders such as MS.
The scientific rationale for advocating statins as immune-modulators is their capability to inhibit the expression of the major histocompatibility complex (MHC) class II gene and transcription of the MHC class II transactivator CIITA, a transcription factor essential for the expression of MHC II gene. Moreover, some other immune-modulatory effects of statins have been proved such as inhibition of human natural killer cell activity, reduction of leukocyte endothelial adhesion, inhibition of CD40 and adhesion molecule expression and blockage of lymphocyte function-associated antigen-mediated co-stimulation, indeed, simvastatin inhibits secretion of Th17 polarizing cytokines and antigen presentation by DCs. Statins have also been shown to inhibit the release of pro-inflammatory cytokines in astrocytes, microglia, and macrophages in vitro.
Simvastatin was tested in a small open-label trial in relapsing–remitting MS with an active disease course. Patients with at least one gadolinium (Gd)-enhancing lesion in the three-month pre-treatment period were treated with the highest FDA-approved dose of 80 mg simvastatin daily over six months. Brain MRIs were performed at months 4, 5 and 6 of simvastatin treatment.
Analysis of pre-treatment and post-treatment MRI data indicated a decrease of around 45 per cent in the mean number of Gd-enhancing lesions and in the mean volume of Gd-enhancing lesions in treated subjects.
Larger placebo-controlled trials need to be conducted. Because they are well tolerated and orally administered, statins might be useful in combination with existing disease-modifying medications. Ideally, medications chosen for combination therapy should have different mode of action without overlapping toxicities, and should provide an additive or synergic effect when given in combination. New clinical trials are currently testing the combination of IFN-1a and statins. Despite the catalogue of experimental data showing beneficial effects of the statins, inhibition of cholesterol synthesis by statins has been shown to induce apoptosis in several models, including neuronal and glial cells in culture. Systemic adverse effects of statins are uncommon but are well known, including myopathy and liver toxicity.
Authors: Malfitano AM, Marasco G
Source: Pharmacol Res. 2014 Jun 19. pii: S1043-6618(14)00099-1. doi: 10.1016/j.phrs.2014.06.007. [Epub ahead of print]
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