Statins are valuable drugs in the treatment of atherosclerotic cardiovascular disease. This family of drugs reduces mortality from these diseases in the form of primary (Patients who have no clinical evidence of coronary heart disease) and secondary prevention (Patients with specific coronary heart disease), even if serum cholesterol levels are normal. Independent studies in patients with heart failure that have been associated with LDL-C levels have reported beneficial effects of statin administration [21, 22]. Statins have an impact on serum cholesterol concentration [23]. Controlled trials have shown that drug treatments with statins reduce LDL-C levels and reduce the risk of cardiovascular disease as well [24–27].
All statins competitively bind to the catalytic domain of HMG-COA reductase. This family of drugs prevents HMG-CoA from reaching the active site of the LDL-C receptor. As a result, it enhances the reabsorption of LDL-C and LDL-C precursors from the systemic circulation. Proteins that bind to the sterol regulatory unit (SREBP) sense changes in cholesterol levels and subsequently increase the expression of LDL-C receptors to reabsorb LDL-C from serum, to compensate for the decrease in cellular cholesterol As a result, a significant proportion of cholesterol-lowering statins, indirectly clear LDL-C from plasma [28]. Simvastatin treatment reduced serum cholesterol levels [29].
Simvastatin is inactive as a prodrug and is converted to active beta-hydroxy derivatives in the gastrointestinal tract. The greatest effect of this drug is on the liver. This preferential effect can be attributed to differences in different tissues in removing the drug from the blood. Plasma triglycerides decrease and HDL-C levels increase during treatment with this drug. The HMG-COA inhibitor is effective in patients with elevated plasma LDL levels [30–34]. The results of the present study, which was performed on male rats for 28 days, showed a significant decrease in serum LDL-C levels in the SimH group and the SimH + VD group and a significant decrease in serum TC levels in the SimH group and the SimH group + VD in male rats (Diagrams 1 and 2). These results indicate the positive effect of simvastatin on cholesterol reduction [35]. However, other groups did not show any significant effect on these two factors compared to the healthy control group, and this lack of effect is due to the low dose of Sim 1 mg / kg, which is a low dose.
Cholesterol is an important biological molecule in all cells and cell membranes as well as in the blood that includes many functions including myelin sheath formation, expression of neurotransmitter receptors, neuronal synapses, production of steroid hormones (eg testosterone, estrogen, etc.). Cortisol and vitamin D) are involved in signaling the central and peripheral nervous systems, as well as in healthy cell function and the transport of antioxidants such as vitamin E, carotenoids, and coenzyme Q 10 Important for energy production, cellular function, and defense of the body against free radicals [36]. Lipophilic statins such as simvastatin are able to cross the blood-brain barrier and as a result, can affect most high-cholesterol organs such as the brain [6]. Studies have shown that high doses of simvastatin (100 mg / kg) affect brain cholesterol synthesis, most likely due to the drug passing directly through the blood-brain barrier, being lipophilic, and locally inhibiting cholesterol synthesis in the brain. It seems that the ability of different statins to inhibit cholesterol synthesis in the CNS depends on their lipophilicity and distribution in the brain. It is possible that the use of lipophilic statins such as simvastatin in high doses may affect the cholesterol synthesis of the brain in humans [14].
The results of the study of Ajaib S. Paintlia and Manjeet K. Paintlia et al. showed no side effects of different statins on the expression of proteins that are directly involved in cholesterol synthesis. However, cholesterol levels in the cerebral cortex decreased slightly during the experiment [37]. Given the important role of cholesterol in the CNS, altering its metabolism can have devastating consequences in humans [38]. In addition, research has shown that HMGR activity is low in the brainstem, while higher activity is observed in the hippocampus, cortex, and cerebellum [39]. In the present study, the effects of simvastatin at doses of 1 mg / kg and 10 mg / kg orally over a period of 28 years on healthy adult male rats were evaluated for the effect of simvastatin on hippocampal tissue. Although in the present study, the level of cerebral cholesterol was not specifically studied, the results of the study of serum profiles showed that simvastatin at a dose of 10 mg / kg causes a significant reduction in LDL-C and total serum cholesterol (Diagrams 1 and 2). In this regard, in the present study, the results of the examination of hippocampal tissue in male rats that received the drugs for 28 days showed that the pyramidal cells of CA1 regions in the SimH group (Fig. 4- B) and SimH + VD group (Fig. 6-B) have degenerated and the staining of these cells during passage Tissue enhanced (Diagram 3).
Interestingly, the presence of vitamin D supplementation in the CA1 group in the SimH + VD group reduces the percentage of degenerate cells compared to the SimH group, which indicates the positive effect of vitamin D supplementation in reducing the negative effect of simvastatin, although This significant positive effect was not observed in CA2 and CA3 regions (Fig. 4, 6-C, D). The statistical results of the study of pyramidal cells in the CA2 region showed a significant percentage of degenerate cells in the SimH (Fig. 4-C) and SimH + VD groups (Fig. 6-C) compared to the control group and other groups (Diagrams 4). However, in the groups receiving SimL, SimL + VD, and VD, no significant effect was observed on the degenerate of cells in the CA2 region compared to the control group. The statistical results of the study of pyramidal cells in the CA3 region show a significant percentage of degenerate cells in the groups receiving SimH (Fig. 4-D), SimH + VD (Fig. 6-D), SimL (Fig. 3-D) and, SimL + VD (Fig. 5-D) compared to the control group (Diagrams 5).
The results of degenerative pyramid cell studies in CA1, CA2, and CA3 regions may seem very strange. Perhaps the reason for this difference in results in these hippocampal regions is due to the physiological and biochemical differences of cells in different regions of the hippocampus. Despite the significant effect of simvastatin on cell destruction in all three hippocampal regions at a dose of 10 mg / kg, simvastatin at a dose of 1 mg / kg showed only a significant negative effect on cells in the CA3 region. Measures that directly study cerebral structure, cerebral blood flow, cholesterol circulation, and neuronal activity can be used to understand how statins affect the CNS, but there are few studies in this area and their results are different. Decreased hippocampal volume along with memory impairment has been studied in some age-related studies, however, there are few studies on the effect of statins on the hippocampus and there are many differences in their results .[40, 41] Previous and current research on the effect of statin drugs has shown a significant effect of simvastatin on the hippocampus [39].
Simvastatin-induced toxicity has been reported on different cell types .[11] Simvastatin interferes with myelin repair in myelinated mice .[42] The results of research by Kamminskey et al. Showed that treatment of astrocytes with simvastatin induced apoptosis in cells depending on dose and time [11]. Statins lower cholesterol [43], and because cholesterol is an integral part of animal cell membranes, any drug that affects cholesterol levels can affect animal cell membrane cholesterol. Because statins are cholesterol-lowering drugs, they can affect cell membranes. Cholesterol does not cross the blood-brain barrier, and brain cholesterol is produced by its production in this organ [44]. Any interference with the concentration of cholesterol in the brain can affect the cell wall. As a result of the effect of statins on cholesterol and increase in cell membrane permeability, the cholesterol balance of the cell wall is disturbed and in the process of preparing tissue sections for microscopic studies, dye can enter the cell and affect the results of the studies. Cells in different areas of the hippocampus are no exception. Each region of the hippocampus has cells with different functions from other regions of the hippocampus, and the cells in each region have different cellular characteristics and even different afferents and efferents from other regions [45] [46] [47].
Some studies of the negative effects of statins include cessation of DNA synthesis [48] and proliferation cell death in primary neuronal cell culture [12, 49], death of neuroblasts [50], loss of synapses [51], and negative impact on cognitive function in clinical trials .[52] The results of Beitan et al.'s study to evaluate the effect of statins on memory showed contradictory results so that the use of simvastatin for four weeks at a dose of 10 mg / kg per day caused memory impairment in the Barnes maze test, this effect was not observed in rats that took simvastatin at a dose of 30 mg/kg/day[19]. The results of the present study, which was performed to evaluate the effect of oral administration of simvastatin for four weeks on healthy mice, show a significant negative effect of simvastatin on pyramidal cells of CA1, CA2 and CA3 regions of the hippocampus at a dose of 10 mg / kg simvastatin. This result obtained in the present study confirms the negative effect of 10 mg / kg simvastatin in the research of Beitan et al [19]. It should be noted that the hippocampus is one of the main components in the memory process [13]. In this regard, the results of Zongmin and Steven (Zhongmin Xiang, Steven A. Reeves) research to investigate the effect of simvastatin on the progression of myelination in a mouse cerebellum cell culture model, indicating inhibition of cholesterol synthesis by simvastatin during the progression of primary cells to neurons And showed oligodendrocytes and harmful effects of simvastatin on myelination [53]. Simvastatin may affect oligodendrocyte cell survival signaling by blocking isoprenylation [50]. Simvastatin interferes with myelin repair by inhibiting lipid-associated signaling and cholesterol-dependent processes [54].
The findings of Sierra et al. In order to evaluate statins as neuroprotectants showed the preventive properties of statins as an effective strategy in protecting the brain against stroke.
After careful study of parameters such as potential access to the brain, the ability to lower cholesterol in neurons with appropriate immune profiles, and the ability to prevent nerve cell death from related mechanisms, the researchers said that simvastatin was the best statin for Used in the prevention of neurogenic diseases [55]. The results of some studies suggest that simvastatin was effective in inhibiting hippocampal cell apoptosis and inflammation in mice with Alzheimer's disease, and that simvastatin had protective effects on the nervous system [9, 56].
Research shows that treatment with simvastatin has potentially inhibitory effects on hippocampal nerve apoptosis, thus helping to improve memory [57, 58]. Sun, J .;, Et al., In a study to investigate simvastatin in the hippocampus, reported that treatment with simvastatin significantly reduced nerve damage and reduced apoptosis in the hippocampus [59]. However, the results of the present study showed that the effect of simvastatin on the hippocampal tissue of healthy male rats was inconsistent with the positive effects of simvastatin on the hippocampal tissue mentioned above.