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Review
. 2023 Jun 22;16(7):914.
doi: 10.3390/ph16070914.

The Potential Therapeutic Application of Simvastatin for Brain Complications and Mechanisms of Action

Yen My Vuu  1 , Ashraf Kadar Shahib  1 , Mojgan Rastegar  1
Affiliations
Review

The Potential Therapeutic Application of Simvastatin for Brain Complications and Mechanisms of Action

Yen My Vuu et al. Pharmaceuticals (Basel). .

Abstract

Statins are common drugs that are clinically used to reduce elevated plasma cholesterol levels. Based on their solubility, statins are considered to be either hydrophilic or lipophilic. Amongst them, simvastatin has the highest lipophilicity to facilitate its ability to cross the blood-brain barrier. Recent studies have suggested that simvastatin could be a promising therapeutic option for different brain complications and diseases ranging from brain tumors (i.e., medulloblastoma and glioblastoma) to neurological disorders (i.e., Alzheimer's disease, Parkinson's disease, and Huntington's disease). Specific mechanisms of disease amelioration, however, are still unclear. Independent studies suggest that simvastatin may reduce the risk of developing certain neurodegenerative disorders. Meanwhile, other studies point towards inducing cell death in brain tumor cell lines. In this review, we outline the potential therapeutic effects of simvastatin on brain complications and review the clinically relevant molecular mechanisms in different cases.

Keywords: Alzheimer’s disease; ApoE; CYP46A1; Hh family; Huntington’s disease; LDLR; Parkinson’s disease; cholesterol; lipid rafts; medulloblastoma.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 2
Figure 2
The natural structure, along with the function and different statin categories. The natural structure of statins includes a hexahydronaphthalene ring system and a polyketide structure. R1 and R2 are replaced by specific functional groups, according to different statins. Statins inhibit HMG-CoA reductase, a rate-limiting enzyme in the mevalonate pathway, which is responsible for producing cholesterol in the liver. Statins also promote SREBP-2 expression, which functions as a transcription factor for many genes related to lipid homeostasis regulation, including LDLR. LDLR presence on the membranes increases cholesterol absorption into the hepatocytes and other cells, helping to reduce plasma cholesterol levels. Information obtained from [111,112,119,120,121,122]. This Figure is created with BioRender.com.
Figure 3
Figure 3
Pharmacodynamics and pharmacokinetics of simvastatin. Different doses of simvastatin (5 mg, 10 mg, 20 mg, 40 mg, and 80 mg) are available in the markets. To function in the body, simvastatin must be converted from the inactive lactone form into the active β-hydroxyacid form. Simvastatin metabolism mainly occurs in the liver through the main enzyme CYP3A4 to reach the proper concentration in the circulation. Simvastatin-derived metabolites are commonly excreted through the feces and in a minor amount in the urine. Information obtained from [125,138,139]. This Figure is created with BioRender.com.
Figure 4
Figure 4
Potential applications of simvastatin for brain complications. Simvastatin may reduce the risk of Alzheimer’s disease and Parkinson’s disease as well as delay the onset of movement disorders in Huntington’s disease. Moreover, simvastatin may inhibit the growth of medulloblastoma. Information obtained from [13,107,156,160,164,165,166,167,168,169,170]. This Figure is created with BioRender.com.
Figure 1
Figure 1
Cholesterol metabolism and homeostasis in the brain. Brain cholesterol is mainly synthesized in the astrocytes and transported into neurons through lipoprotein-ApoEs. Cholesterol is tightly regulated through many factors, such as ApoEs, LDLR, NPC1/2, and CYP46A1. The ApoE4 isoform is highly prevalent in Alzheimer’s disease (AD) pathology, while LRP1 may be a key factor in reducing the risk of AD. The abnormal level of NPC1/2, a factor involved in intracellular cholesterol transporters, is related to AD dementia. In addition, the accumulation of cholesterol in neurons caused by impaired CYP46A1 activity is associated with AD. Beyond its general roles, cholesterol also contributes to post-translational modification and an essential composition of lipid rafts. Disturbed Shh signaling can lead to medulloblastoma brain tumor; meanwhile, dampened lipid rafts may be linked to multiple diseases, such as AD, Parkinson’s disease (PD), and Huntington’s disease (HD). Yellow rectangles indicate upstream factors of brain cholesterol homeostasis. Pink rectangles show the downstream biological role of cholesterol, particularly in neurons. Information obtained from [8,14,15,16,17,18,19,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40]. This Figure is created with BioRender.com.
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