Statins and the Brain: More than Lipid Lowering Agents?

Abstract

Background: Statins represent a class of medications widely prescribed to efficiently treat dyslipidemia. These drugs inhibit 3-βhydroxy 3β-methylglutaryl Coenzyme A reductase (HMGR), the rate-limiting enzyme of mevalonate (MVA) pathway. Besides cholesterol, MVA pathway leads to the production of several other compounds, which are essential in the regulation of a plethora of biological activities, including in the central nervous system. For these reasons, statins are able to induce pleiotropic actions, and acquire increased interest as potential and novel modulators in brain processes, especially during pathological conditions.

Objective: The purpose of this review is to summarize and examine the current knowledge about pharmacokinetic and pharmacodynamic properties of statins in the brain. In addition, effects of statin on brain diseases are discussed providing the most up-to-date information.

Methods: Relevant scientific information was identified from PubMed database using the following keywords: statins and brain, central nervous system, neurological diseases, neurodegeneration, brain tumors, mood, stroke.

Results: 315 scientific articles were selected and analyzed for the writing of this review article. Several papers highlighted that statin treatment is effective in preventing or ameliorating the symptomatology of a number of brain pathologies. However, other studies failed to demonstrate a neuroprotective effect.

Conclusion: Even though considerable research studies suggest pivotal functional outcomes induced by statin therapy, additional investigation is required to better determine the pharmacological effectiveness of statins in the brain, and support their clinical use in the management of different neuropathologies.

Keywords: Statins; brain; brain tumors; mood; neurodegeneration; neurological disorders..

Fig. (1)

The main steps of MVA pathway. MVA pathway, also known as cholesterol/isoprenoid biosynthetic pathway, is a pivotal metabolic pathway expressed in all mammalian cells. It leads to the production of several end-products, required for the proper functioning of cell physiology. HMGR represents the key and rate-limiting enzyme of the whole pathway, and is responsible for the conversion of HMG-CoA into MVA. HMGR is strongly inhibited by statins.

Fig. (2)

Statins exert neurotrophic actions and modulate synaptic plasticity. Statins are able to induce neurotrophism and synaptic plasticity through the activation of CREB. The molecular pathways by which statins activate CREB signaling are mediated by MVA pathway-dependent and independent mechanisms. For details see the main text.

Fig. (3)

Statins activate neurogenesis. Statins influence adult neurogenesis at multiple levels. Indeed, this class of drugs can induce both proliferation and differentiation of neuronal precursor cells by modulating RhoA, Akt and Wnt signaling pathways.

Fig. (4)

Statins reduce neuroinflammation and oxidative stress. Statins show strong anti-inflammatory and antioxidant properties in several physiopathological conditions. In particular, HMGR inhibition by statins determine the downregulation of protein prenylation, which in turn leads to the suppression of NOX activity and to the reduction of pro-inflammatory cytokines.

Fig. (5)

Statins interfere with brain tumor growth at multiple levels. Statins lead to the alteration of both pro-survival and pro-apoptotic intracellular pathways, causing the inhibition of proliferation and the induction of apoptosis in brain cancer cells. Dashed lines indicate indirect and/or unknown signal transduction mechanisms. For details see the main text.