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Annals of Advanced Biomedical Sciences Research Article 21 min read

Lovastatin as a Treatment of Cardiovascular and Neurological Disorders

Mussina K, Akhmetova A and Tokay T*
* Corresponding author
ISSN: 2641-9459  10.23880/aabsc-16000138  Received: June 20, 2019  Published: August 09, 2019
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Keywords
Lovastatin Cardiovascular Diseases Multiple Sclerosis Combination Treatment of Lovastatin
Abstract

There is evidence that statins which are mainly used in treatments of dyslipidemia can be used for attenuating symptoms of cardiovascular and neurodegenerative diseases. Lovastatin and other statins are known to function through inhibition of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase which is involved in the majority processes such as cell differentiation, proliferation and migration. Recently it was revealed that lovastatin is effective in the reducing total and low-density-lipoprotein cholesterol, lowering the risks of post-surgical complications and mitigation of anticancer drugs’ side effects. Moreover, there are other combinations with other drugs to treat cardiovascular diseases. In addition, antiinflammatory and immunomodulatory effects of lovastatin diminish neurological disorders such as multiple sclerosis (MS). Especially, combination treatment of lovastatin and rolipram in suboptimal doses is considered to be the most promising approach for protecting neuronal axons from demyelination and promoting neuro repair in MS. Although lovastatin demonstrates promising option for treatment of cardiovascular and neurological diseases, more clinical trials and studies in vivo and in vitro are required.

Introduction

3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors or statins can be used in treatments of different diseases. The main purpose of using statins is considered to be lowering the elevated different types of cholesterol levels. Starting from the ninetieth several studies discovered lovastatin as a promising tool for the treatment of various disorders such as dyslipidemia, neurodegenerative and cardiovascular diseases [1, 2, 3, 4, 5, 6].

The ability of lovastatin to promote the treatments is justified on its pleiotropic effects. Inhibition of HMG-CoA reductase takes significant role in mevalonic acid pathway. Mevalonate acts as a precursor for both steroidal and non-steroidal isoprenoid intermediates. Cholesterol being the steroid has been already verified to be modulated by lovastatin in previous studies. On the other hand, non-steroidal isoprenoids affect proteins such as heterotrimeric G-proteins, HM-A, small GTP-bound protein Ras, and Ras-like proteins contributing to the intracellular signalling pathways of cell proliferation, myelination, cytoskeleton arrangement and endocytotic- exocytotic transport [7]. Therefore, since lovastatin has an impact on the mevalonate pathway it can indirectly change cell survival. The focus of this review paper is investigation of novel applications and effects of lovastatin in cardiovascular and neurological diseases. The administration of lovastatin alone and in combination with other drugs will be also presented with explanation of lovastatin activity mechanisms.

Effects of Lovastatin on Cardiovascular Diseases

The statin is widely used in the treatment of different cardiovascular diseases (CVDs) mostly by lowering increased total cholesterol (TC), low-density-lipoprotein (LDL) cholesterol and triglycerides (TG) levels in blood. According to several meta-analyzes, statins are able to reduce the risks of major vascular events with approximately the same effectivity in both of the lowest risk categories and the higher risk categories [8, 9, 10, 11]. The occurrence of major coronary events during 5 year period, coronary revascularisations, and ischaemic strokes was observed to be diminished after statin treatment affecting mainly LDL cholesterol levels [8, 9, 10, 11]. Additionally, statins are administered for other purposes except the diminishing the cholesterol levels. In this section we attempted to analyze most novel mechanisms and purposes of lovastatin administration in treatments of common CVDs.

Mechanisms of Actions of Lovastatin in the Treatment of Cardiovascular Diseases

Targeting High Levels of Low-density- lipoprotein Cholesterol

There are several mechanisms proposed how lovastatin can contribute to treatment of heart-related diseases. One of such mechanisms has been suggested by recent study investigated how exposure to three statins (i.e. lovastatin, atorvastatin and pravastatin) affected the complex formation between proprotein convertase subtilisin-kexin 9 (PCSK9) and the low density lipoprotein receptor (LDLR), which is known to be important in degradation of LDLR in lysosomes. The expression of PCSK9 indirectly downregulates the LDL cholesterol levels in the blood through the receptor-mediated endocytosis mechanism [12, 13, 14]. As soon as LDL cholesterol molecule is bound to LDLR expressed on the surface of cells, the PCSK9 associates to this complex and assists with intake of the cholesterol molecule by endosomal pathway [15]. Endosomes further fuse with lysosomes where degradation of both proteins occurs. It was established that lovastatin and atorvastatin induced expression of PCSK9 and consequently resulted in lowering the LDL cholesterol concentrations, whereas pravastatin effect was opposite [15]. So, high LDL cholesterol levels in CVDs can be counteracted by lovastatin treatment.

Prevention of Post-surgical Complications

There is evidence of effective usage of statins after cardiovascular interventions in order to reduce postsurgical complications related to CVDs [16, 17, 18]. Although lovastatin is known to augment CVD treatments by mitigation of LDL cholesterol levels, the activity of lovastatin could be also explained by cholesterol- independent cardioprotective mechanism. Graft failure after the bypass surgery or angioplasty are one of those cases that frequently result in intimal hyperplasia and atherosclerosis which arise from vascular smooth muscle cells’ (SMCs) dedifferentiation [19, 20, 21]. Since vascular SMCs preserve plasticity even after acquiring differentiated state expressing specific repertory of contractile proteins, ion channels and signaling molecules, dedifferentiation of SMCs’ phenotype occurs as a response to vascular injuries after bypass surgery [22, 23]. It was demonstrated that the complications after surgical intervention such as intimal hyperplasia and atherosclerosis are treatable with lovastatin use [24].

Wagner and colleagues [2010] established that lovastatin inhibits farnesylation of Ras homologue enriched in brain (Rheb) by blocking the activity of farnesyltransferase. Farnesylation is one type of prenylation where the farnesyl group (15-carbon isoprenoid) is covalently attached to cysteine residues near or at C-terminus of protein [25]. That in turn inhibits the activity of the mammalian target of rapamycin complex 1 (mTORC1) which is essential in vascular SMC transcription initiation under the additional action of growth factors, particular amino acids and energy stages [26, 27, 28]. By inhibiting the mTORC1 the modulation of vascular SMCs in intimal hyperplasia is held by differentiating SMCs to normal state of contraction. Thus, mTORC1 signaling pathway is suggested to be one of the mechanisms of lovastatin effects, allowing novel ways in cardiovascular treatments to emerge.

Attenuation of Anthracycline Cardiotoxicity Side-Effects

Another efficacious application of lovastatin has been shown in the alleviation of side-effects of anticancer treatments such as anthracyclines. The doxorubicin, an anthracycline derivative, is widely used in antineoplastic therapy [29]. However, doxorubicin besides its positive effects in anticancer treatment, also, leads to congestive heart diseases due to cardiomyopathy and liver damage [30, 31, 32, 33, 34, 35, 36]. The acute (within 1-3 days), subacute (within weeks) and delayed cardiotoxicity is observed during dose-dependent doxorubicin application [34, 35, 36, 37]. Congestive heart diseases results due to increased prolonged cardiotoxicity which was acquired through upregulation of interleukin 6 (IL-6), connective tissue growth factor (CTGF), brain natriuretic peptide (BNP) and heat shock protein A1B (Hspa1b) RNA in doxorubicin treatment (29). In addition, because of inhibition of topoisomerase II activity by doxorubicin, there was production of reactive oxygen species (ROS) and nitric oxide synthases (NOS) that contribute to doxorubicin cardiotoxicity [31, 38, 39, 40]. Weinstein, et al. [41], Cole, et al. [42] and Chaiswing, et al. [43] proposed alternative solution being co-treatment for doxorubicin with antioxidant called dexrazoxane. However, the dexrazoxane demonstrated opposite effects to expected ones exaggerating the side-effect cardiotoxicity of doxorubicin. On the other hand, LDL cholesterol lowering lovastatin treatment illustrated the results of significant mitigation of cardiotoxicity when used as co-treatment with doxorubicin [34, 44, 45]. Lovastatin is believed to operate on reducing IL-6, CTGF, BNP and Hspa1b RNA expression by repressing Rac1 signaling pathway [33, 34, 46, 47]. Doxorubicin upregulates expression of Rac1 which was observed to adduce to cardiomyocytes’ apoptotic death and result in myocardial dysfunction by its NADPH oxidase activity and consequent ROS generation [48]. Therefore, inhibition of Rac1 by lovastatin is one of the promising approaches to ease the cardiotoxic side-effects of doxorubicin.

Concomitant Adverse Effects of Lovastatin

Upon the treatment of CVDs based on targeting reduction of total cholesterol (TL) and LDL cholesterol by statin application, there might be concerns about its own side-effects. Diabetes mellitus type 2, renal injury and myopathy rarely presented in form of rhabdomyolysis are the most recognized adverse effects of statin treatment [49, 50, 51]. Although, there are various side effects of statin treatment, it is believed that its significant effects on CVDs therapy outweigh presented side-effects. Moreover, it was established that statins do not elevate risks of cognitive disease and progression of cancer [50].

Combinatorial Treatments of Lovastatin with other Drugs in CVDs Treatment

Lovastatin is seen to be also used in combinations with other drugs to improve CVDs treatments. Lovastatin with cholestyramine and lovastatin with colestipol are ones of effective combinations used in order to reduce lesions after coronary bypass surgery [52, 53, 54, 55]. In addition, Alsheikh-Ali and Karas et al. [16] observed that the combination of lovastatin and niacin brought the same liver damage and rhabdomyolysis progression as in the lovastatin and niacin treatments used separately and demonstrated that these adverse effects are more manifested in simvastatin treatment. Nevertheless, there are combinations that can result in ameliorated CVDs treatment methods, physicians are still concerned with adverse outcomes that these combinations can cause; thus, more studies are required to clarify the efficacy of complementary administration of lovastatin with other drugs.

From all mentioned above it can be concluded that the lovastatin treatment gives perspective opportunities for treating various CVDs by the help of its pleiotropic activities. It was noted that there were eight most cited studies [1, 2, 3, 4, 5, 6, 56, 57] all of them indicating that lovastatin is one of the effective statins that positively influence the treatment of coronary atherosclerosis and cardiovascular events. However, the validity of those studies’ results can be put under questioning, since all of them were performed between 1991 and 1999 and concomitant therapies such as blood pressure lowering, diuretics, anticoagulants were used in different way compared to care standard to date back [10]. Therefore, there is a necessity of new clinical trials with higher sample sizes to investigate the effect of lovastatin use in CVDs therapy methods.

Effect of Lovastatin to Neurodegenerative Diseases

Multiple Sclerosis

Early studies have revealed that lovastatin in addition to lipid-lowering effects, have anti-inflammatory and immunomodulatory characteristics [58]. These characteristics of statins are suggested to have valuable effects for immune mediated neurological abnormalities. In this section we will focus on the mechanisms and effects of two drug combination treatments with lovastatin on the multiple sclerosis neurological disease. Multiple sclerosis (MS) is a demyelinating disease of central nervous system (CNS) that leads to motor, sensory and cognitive impairment. There are variety of studies that indicated both genetic and environmental factors to have impacts on the process of demyelination of CNS. Moreover, the viral infections are considered to be the main cause for the disease, while it was noted that several patients had genetically promoted MS [59].

Demyelination of axons results in the deficiency and complete absence of nerve impulse transmission due to the infiltration of leukocytes from vasculature to the neural tissue [59, 60]. The migration of transendothelial lymphocyte in the CNS is contingent on activation of lymphocytes and capability of leukocytes to induce signaling responses in endothelial cells. These CNS endothelia are connected by tight junctions who form blood-brain barrier (BBB) [60]. The BBB plays a crucial role in the restriction transmigration of cells from peripheral blood to the CNS; hence, provides an immune system and homeostasis to the CNS. During the immune mediated multiple sclerosis the transmigration of antigen, the infiltration of inflammatory cells through the BBB and the neuronal damage are known to take place.

Experimental Autoimmune Encephalomyelitis (EAE)

In order to obtain a disease mechanism, several models have been established. Much comprehensive research on MS disease has been accomplished predominantly in animal model which is called experimental autoimmune encephalomyelitis (EAE). Since it is one of the best studied models for human immune mediated disease, EAE animal models used as a potential treatment of MS. Disease in the EAE are induced by T cells. It starts from brain inflammation by crossing the leukocytes through endothelial cells, consequently migrating through blood-brain barrier (BBB) to the CNS. Within CNS, antigen-presenting cells (APCs) introduce MHC class II associated peptides which causes myelin- specific T-cell reactivation. It initiates signaling cascade of secretion of chemokines that induces macrophages to the sites of T-cell activation. As a result, chemokines and cytokines are released that produce inflammation. This neuroinflammatory response leads to infiltration of leukocytes and demyelination of axons in CNS which is analogous to the pathology identified in MS. Due to this correlation, EAE is accepted as a model of MS [60].

Nowadays several therapeutics are useable, however, even though they are very effective treatment of MS, they have serious side effects. Therefore, in order to overcome these complications lovastatins are introduced which are considered to be the most promising approach. Statins have multiple effects such as anti-inflammatory effects, antioxidant effects, immunomodulatory effects, plague stability, thrombus formation. These numerous lipid- independent effects are known as “pleiotropic effects” of lovastatin. Lovastatins develop the immune function in EAE, as a result, immune response from Th1 to the protective Th2 is induced in EAE [59, 7].

Anti-Inflammatory Effects of Lovastatin

The anti-inflammatory effect of lovastatin specifically targets mitigation of leukocyte migration across BBB. There are two studies demonstrating that lovastatins reduce migration of intercellular adhesion molecule-1 (ICAM-1; CD54) on CNS endothelium which does not allow interacting with T cell integrin αLβ2 (lymphocyte function-associated antigen) (LFA-1) [60, 61]. Recent studies identified that ICAM-1 does not only act as adhesion molecule, but also promotes lymphocyte transendothelial migration. The efficient ICAM-1 signal transmission depends on functional Rho GTPase. Statins reduce Rho prenylation, hence antagonize leukocyte migration across endothelial cells [60, 61].

Immunomodulatory effect of Lovastatin

Combination Treatment of Lovastatin and Rolipram

The immunomodulatory effects of lovastatin treatment are observed in co-administration therapies of lovastatin with other drugs. Several studies support that the combination of lovastatin with rolipram (RLP) can prevent the progression of MS by different mechanisms. The RLP is a phosphodiesterase-4 inhibitor which prevents the degradation of cyclic AMP (cAMP) and induces immunomodulation of myelin-reactive Th1 to Th2. Therefore, combination therapy promotes neurorepair of demyelinated axons in MS model [62, 63, 64]. Moreover, reduced doses of drugs in combination are more efficient in lowering CNS demyelination and promoting neurorepair. However, the explanation of such observations have not yet established. Early studies demonstrated that optimal dose of lovastatin and RLP was ≥2mg/kg for repression of inflammation in EAE [64]. However, recent researches determined that suboptimal doses (≥1mg/kg) of lovastatin and RLP are more efficient in reducing disease conditions [62]. Treatment with these drugs is conducted after demyelination symptoms appeared. As a result, leukocyte infiltration and some pathological changes were dramatically declined by drug combination therapy. Since CNS demyelination is associated with an increase of cellular infiltration, drug combination treatment reduces the loss of neuronal axons and degeneration of oligodendrocytes in EAE animal models.

The mechanism of drug combination therapy of lovastatin and RLP is as follows. As it was mentioned before RLP prevents the degradation of cAMP which is very crucial step in therapy [65]. Activation starts from specific pathways including nuclear-cytoplasmic CREB- protein (cAMP responsive element binding protein) which initiates gene transcription with cAMP in the promoter region. cAMP induces the phosphorylation and activates CREB protein. Consequently, it promotes the activation of protein kinase cascade in neurons, PKA [66]. As a result, elevated level of cAMP regulates by decreasing the demyelination of axons in CNS. This can be achieved by combination of lovastatin and RLP therapy. In addition, it was verified that PKA activity was relatively lower when lovastatin or RPL was applied separately rather than in combination [67].

Another effect of combination therapy of lovastatin and RLP is neurorepair in CNS. Induction of platelet derived growth factor-α receptor (PDGF-αR) and marker of myelin-forming oligodendrocyte (MBP) initiates myelin repair in the drug combination treatment. Moreover, oligodendrocytes transcription factors also increased due to the combination therapy which led to myelin repair. Transcripts for neurotrophins such as ciliary neurotrophic factor (CNTF) and NT-3 which are essential in myelin repair also were increased by drug combination therapy [68, 69]. To sum up, combinatorial therapy of lovastatin and RLP seems to protect neuronal axons from demyelination and induce a spontaneous myelin repair by increasing the development of oligodendrocytes.

Since the combination therapy of lovastatin and RLP has synergistic effects, acts with different mechanisms, has no additional toxicities and severe side effects, it is more promising tool for preventing MS development. In addition, lovastatin and RLP both are able to cross the BBB and induce neurorepair of CNS. On the basis of these findings, the combination of lovastatin and RLP is likely to be an excellent approach for MS prevention, by using suboptimal doses of drugs.

Combination Treatment of Lovastatin and AICAR

Another promising approach is a combination therapy of lovastatin and 5- aminoimidazole-4-carboxamide-1- beta-D-ribofuranoside (AICAR), an immunomodulating agent that activates AMP-activated protein kinase. It affects with the same mechanism as the combination of lovastatin and RLP but with difference in their doses, RLP (≥1 mg/kg) whereas AICAR (≥50 mg/kg) [62]. Suboptimal doses of drugs in combination of lovastatin and AICAR decline leukocyte infiltration and proinflammatory immune response but it induces the anti-inflammatory immune response. Treatment with AICAR promotes the immune response from myelin-reactive T-cells to Th2 differentiation and develops immunomodulatory effect in APC by activating secretion of anti-inflammatory cytokines. As a result, it increases the survival of neurons and develops neuroprotective ability against CNS demyelination. Since the combination of lovastatin and AICAR results in progress of protective Th2 immune response, it is concluded that this combination could be one of the approaches for the treatment of CNS inflammation and neurodegeneration in MS. By summarizing all arguments which were mentioned above, it can be concluded that lovastatin in combination with RLP and AICAR are known to be promising and efficient approaches for the treatment of MS introducing minimal adverse and toxic effects. Moreover, other studies suggest that lovastatin can be used as a therapy for other neurological disorders such as Alzheimer’s disease, Early Stage Parkinson's Disease and other peripheral nerve injuries that works with the same mechanism which was discussed above [69, 70, 71, 72, 73, 74]. Therefore, for the future perspectives it is necessary to conduct clinical trials to investigate the effects of these combination therapies in other neurodegenerative abnormalities.

Conclusion

After analyzing the most recent research papers, it was concluded that lovastatin is one of the most perspective treatments of both CVDs and MS. Additionally, more studies in vitro and in vivo are required to fully evaluate the effectiveness of lovastatin in different diseases.

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@article{mussina2019,
  title   = {Lovastatin as a Treatment of Cardiovascular and Neurological Disorders},
  author  = {Mussina K, Akhmetova A and Tokay T},
  journal = {Annals of Advanced Biomedical Sciences},
  year    = {2019},
  volume  = {2},
  number  = {2},
  doi     = {10.23880/aabsc-16000138}
}
Mussina K, Akhmetova A and Tokay T (2019). Lovastatin as a Treatment of Cardiovascular and Neurological Disorders. Annals of Advanced Biomedical Sciences, 2(2). https://doi.org/10.23880/aabsc-16000138
TY  - JOUR
TI  - Lovastatin as a Treatment of Cardiovascular and Neurological Disorders
AU  - Mussina K, Akhmetova A and Tokay T
JO  - Annals of Advanced Biomedical Sciences
PY  - 2019
VL  - 2
IS  - 2
DO  - 10.23880/aabsc-16000138
ER  -