INTRODUCTION:

Cardiovascular diseases most often affect the myocardium as well as vascular bed and include coronary artery disease (CAD), also known as coronary heart disease (CHD). The term CAD used usually to refer the pathological processes influencing preferably the coronary arteries and include the diagnosis of AP, MI and silent heart attack¹_. These occur due to sudden and persistence deprivation of myocardial blood supply that leads to necrosis of myocardium.

Lipid peroxidation, oxidative stress, elevated level of cardiac marker and inflammation are mainly involved in pathogenesis of coronary artery diseases² . The most common risk factors of CAD are smoking, hypertension, diabetes, obesity including the history of coronary artery diseases^3,4. Several clinical as well as preclinical studies have been reported that certain sigma receptor ligands show protective action against coronary artery diseases. Sigma ligands significantly averted certain deviated biochemical parameters, for example, antioxidant parameters, enzyme markers and lipid profile near to usual level by acting at sigma receptors^5,6. Many conventional drugs reduce mortality rate, however their widespread use is restricted due to some complications like adverse events and costs⁷. Therefore, sigma receptors stimulation represent a new therapeutic strategy to prevent the cardiomyocytes from coronary artery diseases and hypertrophic dysfunction in case of heart failure^6,8.

Sigma receptors (σ- receptors)

σ- receptors are non- opioid intracellular receptors, mainly found in brain, cardiac cells, liver, lungs, gonads as well as in kidneys. The term “Sigma” of sigma receptors developed from the initial alphabet “S” of sigma antagonist, SKF 10,047 (±N-allylnormetazocine), which has been found to attach at a distinct binding site of sigma/opioid receptor ^9,10,11. Initially, these were identified as subtype of sigma/opioid receptor as their action were antagonized by the universal opioid antagonist, naloxone and therefore were suggested to contribute to the psychoses and delusions, but later on it is found as unique non- opioid receptor¹². For demonstration of sigma receptors many attempts performed by Su and he identified another binding site, although, it was the same that was labelled by prototypic sigma/opioid receptor ligand, (+) SKF 10,047. Nevertheless, this binding site was insensitive to effects of naloxone¹³. Mistakenly, this binding region was the same that was previously recognized as the sigma/opioid receptor, but, actually this was not a sigma/opioid receptor subtype, because it was insensitive to the effects of naloxone. Later on, similar SKF-10,047 experiments were performed by the same laboratory and investigated that the “psychotomimetic” actions were not antagonized by naltrexone, a potent analogue of naloxone¹⁴. Therefore, this term changed to sigma receptor, initially identified as sigma/opioid receptor^14,15. Moreover, when sigma receptor were isolated and cloned, these found to have no similarity with sigma/opioid receptors. At this point, sigma receptors were considered as a separate category of receptors ¹⁶.

σ-receptor (mainly σ₁-receptor) is predicted to have a single transmembrane domain with trimeric architecture and each protomer of trimer has amino acids 9-28, 81-101 and 176-203²⁴ as well as -COOH and-NH₂ groups, both present intracellulry on the same side of plasma membrane²⁵. Furthermore, transmembrane predictions revealed that amino acids 176–203 also consists of cholesterol/steroid- binding domain (CBD/SBD) motifs²⁶. The figure 1 depicts the presence of amino acid molecules required for the binding of σ-receptor ligands and the splice variant regions of non-drug binding splices^27,28,29.

Figure 1

Figure 2

SBDL1: Steroid Binding Domain Like 1

SBDL2: Steroid Binding Domain Like 2

Sigma subtypes:

Pharmacological and biochemical studies have categorized sigma receptors into two subtypes termed as σ₁ and σ₂ receptors. Although another subtype, σ₃ have also been suggested, however, these receptors have not been defined adequately^10,12. Moreover, only receptor subtype sigma-1 has been cloned in human and rodents, however, subtype sigma-2 has not been well examined or cloned^9,31,32.

Sigma1 receptors (σ₁-receptors)

The σ₁-receptor subtype is 29-kDa single chain polypeptide having 223 amino acid residues with three transmembrane domains (figure 1 and 2)^17,33. σ₁-receptor subtype mainly detected in frontal cortex, hippocampus and near to olfactory bulb region of brain. σ₁-receptors are also observed in peripheral tissues including liver, lungs, kidney and gonads^18,19,20. Further, both σ-1 receptor subtype was also documented on cardiac myocytes^22,23. Within cells, σ₁-receptors are located on the membrane of endoplasmic reticulum, mitochondria, plasma membrane and nuclear envelope, therefore, now-a-days this topic become an area of focus for recent research²⁷.

Sigma-2 receptors (σ₂-receptors)

σ₂-receptors, a slight shorter chain polypeptide than σ₁-receptors consists of 18-22 kDa proteins and has not been cloned yet, therefore σ₂-receptor amino acid sequence is unknown³⁵. Sigma-2 receptor are distributed in central nervous system, however, are limited as compared to subtype sigma, but, in periphery the σ₂-receptors are highly expressed in liver^10,34,36 as well as in heart³⁷. Sigma-2 receptors have been documented to be involved in myocardial survival and death related processes. Myocardial preparation of rat heart demonstrated specific binding activity for the prototypic ligand of sigma receptor, such as [³H]-1,3-di(2-tolyl) guanidine ([³H]-DTG)^13,39,40. Sigma-2 receptors still need to be cloned, although certain pharmacological agents with preferential affinity for these receptors have been identified, however, highly selective compounds are unavailable^30,35,38.

Sigma receptor ligands:

As, it was previously described that certain antipsychotics are potent sigma receptor ligands in central nervous system (CNS), however, these ligands have also been recognized to affect the electrical stability of the myocardium⁴². Therefore, the long-lasting interest in cardiac sigma receptors as well as sigma ligands in cardioprotection has been studied. A number of studies indicated the existence of sigma receptor binding sites on cardiomyocytes of both neonates as well as adult rats^22,45.

Since the discovery of the sub classification of sigma receptors, many selective ligands both endogenous and exogenous for either subtype have been described³⁵. Some ligands can bind to both sigma receptor subtypes. σ₁-receptor exhibits high affinity for (+)-isomer of SKF10,047, cyclazocine, pentazocine and (+)-3-(3-Hydroxyphenyl)-N-(1-propyl)-piperidine (3-PPP). However, sigma-2 receptor is reported as a low affinity receptor³³.

Endogenous ligands:

Only few endogenously released ligands of σ₁-receptors have been yet identified. Some neurosteroids such as dehydrroepiandrosterone (DHEA), their sulphate esters, pregnenolone, progesterone, allopregnenolone, 11β- hydroxyprogesterone and deoxycortisone are regarded the putative endogenous ligands of sigma receptors^{30, 42}. Currently, N, N- dimethyltryptamine (DMT), another endogenous ligand has been reported to have high affinity for σ₁-_-receptor ⁴⁴.

Exogenous ligands:

At present, with development of new drugs, the number of sigma receptor ligands is increasing rapidly³⁰. A wide variety of synthetic compounds have been identified that have the capability to bind with σ₁-receptors and produce agonistic or antagonistic response⁵⁴. Many clinically used drugs of various structural categories and having distinct therapeutic potential have affinity for σ₁-receptors such as typical antipsychotic drugs (haloperidol, perphenazine, risperidone), antidepressants (fluvoxamine, citalopram, sertaline), antiparkinson’s drugs (amantadine) or drugs used in Alzheimer’s disease (memantine, donepezil). Moreover, the certain addictive drugs (cocaine and methamphetamine) also interact with σ₁-receptor subtype. Therefore, in addition to their main targets, these drugs also bind to σ₁-receptors.

Considering the σ₂subtype, few pharmacological data are available. σ₂-receptors show high affinity for certain drugs including typical neuroleptics (haloperidol), DTG and few benzomorphanes⁴².

Mechanism of action in cardioprotection:

It is already reported that the myocardial σ₁-receptors and their modulation by sigma receptor ligands is cardioprotective ⁴¹. A wide range of σ-receptor ligands can modify the CV functions, myocardium is found to be the major site for their binding and therefore myocardial contraction both in vitro as well as vivo⁴³. In adult rat cultured myocardium, σ-receptors modulate contractility due to calcium influx⁴⁶, however, Ca²⁺ influx depends upon sarcoplasm reticulum Ca²⁺ concentration^47,48.

At cellular level, most of σ₁-receptors are localized upon myocardial endoplasmic reticulum (ER) membrane at the interface of mitochondria. At this point, after binding to immunoglobins, a Ca²⁺sensitive and ligand-operated chaperone complex formed, however this complex disintegrates due to ER stress, allowing σ₁-receptor to activate IP_3, thereby Ca²⁺ signalling from the ER to mitochondria enhances³⁵. Therefore, it is presumed that one of the major functions of σ₁-receptor is to safeguard mitochondrial Ca²⁺ concentrations for normal energy production under stressful cellular conditions²⁷. Furthermore, it is also speculated that in myocardium, the effects of sigma receptor ligands on myocardial contractility are executed via stimulation of phospholipase C (PLC) and elevation of IP₃ levels, similar in many ways to that of σ₁-receptor in brain¹⁰.

Cardioprotective Sigma Receptor Ligands:

Sigma receptors, initially considered as opioid receptors, are now recognized as sigma receptors and are expressed in neonatal rat cardiomyocyes and on the plasma membrane of adult rat cardiomyocytes. Furthermore, availabity of binding sites for sigma receptor ligands on the myocardium leads to altered myocardial contractility both in vivo an in vitro, therefore, a wide number of sigma ligands modulate the CV functions. A number of sigma ligands including haloperidol, fluvoxamine, sertraline, dextromethorphan, dimemorfan, memantine that behave as agonists or antagonists at σ₁ subtype have been described⁷⁰. Considering the σ₂-receptor subtype, few pharmacological data is available. However, σ₂-receptors show great affinity for some neuroleptics (typical) such as some benzomorphanes, haloperidol and DTG.

In this section, different sigma receptor ligands having the cardioprotective effects are reviewed and these include:

Afobazole:

Anxiolytic drug afobazole has shown ligand properties for σ₁-receptor and melatonin (MT₃₎receptors. Preclinical studies demonstrated that afobazole possess cytoprotective effect through interaction with both σ₁-receptor and MT₃-receptor⁴⁸. Afobazole has been reported to enhance myocardial fibrillation threshold significantly and therefore, it resembles with lidocaine, a class 1B antiarrythmisc drug in terms of this activity. It is assumed that afobazole produce this effect by acting as an agonist at cytosolic σ₁-receptors in myocardium⁴⁹. Furthermore, a seven-day study of afobazole treatment on rats with experimentally induced myocardial infarction leads to shrinkage of myocardial area with ischemic damage, enhancement of reparative process in cardiomyocyes as well as protection of left ventricle post-infarction remodelling. In this model, afobazole interaction with σ_1-receptors is presumed to produce anti- ischemic effect⁵⁰ .

Dehydroepiandrosterone (DHEA)

It has been demonstrated that the recurrent treatment of failing rat hearts with dehydroepiandrosterone, a steroidal hormone, not only significantly prevented left ventricular hypertrophy (LVH) with functional recovery induced by pressure overload (PO) in thoracic aorta but also enhances the expression of σ₁-receptor in thoracic aorta ⁴³. Furthermore, the potential role of σ₁-receptors expression was observed in cardiomyocytes to diminish pressure overload-induced hypertrophy in ovariectomized rats. DHEA therapy produce beneficial effect against PO-induced myocardial injury via sigma-1 receptor upregulation as well as by activation of σ₁-receptor mediated Akt- eNOS signalling^51,
69. In another study, DHEA also improved hypertrophy-induced impaired left ventricular, left ventricular developed pressure, end diastolic pressure and LV contractility (+/- dp/dt(max)). In addition, with DHEA treatment, a significant improvement of myocardial hypertrophy, pressure overload-induced impaired endothelial nitric oxide synthase (eNOS) and Akt activity was observed in left ventricle⁴³.

Fluvoxamine:

Fluvoxamine is an antidepressant drug, although act as a selective serotonin reuptake inhibitor (SSRI), in addition, it exhibit great affinity for σ₁-receptor. In several studies, selective serotonin inhibitors are known to attenuate morbidity and mortality due to post-myocardial infarction⁵².The effect of fluvoxamine on myocardial hypertrophy and functional recovery due to stimulation of σ₁-receptor was evaluated in mice. The results of this study suggested that myocardial dysfunction due to transverse aortic constriction (TAC) was prevented by fluvoxamine via upregulation of σ₁- receptors mediated by Akt- eNOS signalling⁶. Further, fluvoxamine has also been reported to produce beneficial effects in preventing IR- induced myocardial injury in guinea pig heart by reducing calcium overload and inhibiting mitochondrial permeability transition pore (MPTP) opening, thereby, reduce apoptotic death associated with endogenous deposition of serotonin⁵³. Moreover, pretreatment with fluvoxamine also improves the cardiac pump function in rat heart due to IR injury and documented to be cardioprotective⁴³.

Paroxetine:

Paroxetine as a SSRI has been indicated for attenuating the symptoms of depressive illness and anxiety disorders. However, the effect of paroxetin was also identified in vivo and in vitro including heart. Currently, few reports have recognized paroxetine as a G- protein coupled receptor kinase-2 (GRK-2) inhibitor, as it reported to reverse cardiac remodelling and dysfunction during acute IR model of myocardial injury^56,58. In failing heart, as cardiac output decreases, it enhances the activity of GRK-2 along with increase in mRNA and proteins level which promotes increased levels of circulatory catecholamine and result into uncoupling of beta- adrenergic receptors and attenuated inotropic reserve^{55, 56}. Therefore, it has been postulated that GRK-2 function inhibition would protect the delicate myocardium, so, beneficial during heart failure⁵⁷. Moreover, as a GRK-2 inhibitor, it has been reported to enhance β- receptors mediated myocardial contractility and reverse cardiac dysfunction in mouse failing heart⁵⁸.

In one study on paroxetine using mice hearts, those were over expressing GRK-2, this drug has been found to attenuate isoproterinol-induced cardiac dysfunction, calcium stimulation and reduced cyclic adenosine monophosphate (cAMP) levels⁵⁷. Further, paroxetine has also been reported to enhance isoproterenol- induced contraction and shortening amplitude in both in vitro model using isolated cardiomyocytes as well as in vivo model of mice. Further, left ventricular inotropic reserve is also enhanced in vivo model using paroxetine. Therefore, paroxetine application can enhance β- adrenergic (β- AR) receptor mediated contractility, consistent with direct GRK- 2 inhibition both in vivo and in culture myocytes⁵⁹. However, further investigations are required to explore the role of σ-receptors in relation to peroxetine effect on cardioprotection.

SA4503:

SA4503 is a potent sigma ligand and have high selectivity for σ₁-receptor subtype than σ₂-receptor⁶⁰. SA4503 has been reported to exhibit anti-hypertrophic effect and this effect is selectively evaluated at σ₁-receptors along with its mechanism of cardioprotection in hypertrophized culture myocytes. The outcomes of this invesigation revealed the protective effect of SA4503 in preventing myocardial hypertrophy and restoring ATP production in a mice model of transverse aortic constriction⁸. Further, the administration of this drug also produces beneficial effect in reducing the hypertrophy- induced dysfunction in left ventricular contractile function ⁵¹. Therefore, stimulation of σ₁-receptors by SA4503 represents a new therapeutic strategy to protect the myocardium from hypertrophic impairments due to cardiac failure.

BD737:

BD737 is highly selective and high affinity sigma receptor ligand. The effect of BD737 as positive inotropic agent was studied in adult rat isolated myocytes. Preclinical studies of BD737 in adult rat isolated hearts perfused on Langendorff’s apparatus were reported to possess the positive inotropic and chronotropic effects. The results suggest that these effects including contractility and heart rate were mediated by stimulation of sigma receptors via activation of PLC and elevation of IP₃ levels¹⁹. However, mechanism for electrical changes due to binding of sigma ligand to their receptor was not clear^18,49.

Berberine:

Berberine (BBR), a sigma receptor agonist, is an alkaloid belonging to isoquinolines and is isolated from Chinese herb Coptis chinensis (Huanglian). This herb consist of various pharmacological activities including antihypertensive, antidiabetic, antimicrobial, antidiarrhoeal, antiproliferative and anti-inflammatory effects. In addition, berberine also shows beneficial effect for cardiovascular disease both preclinically and clinically. Berberine was evaluated for its cardioprotectve properties against isoproterenol-induced myocardial infarction. It found to be lower the levels of lactate dehydrogenase (LDH), creatinine phasphokinase (CK-MB), tumor necrosis factor- α (TNF-α) and reduced ST- segment elevation induced by acute IR- injury. These results are attributed to anti-inflammatory and anti-oxidant properties⁶⁶. In another study, when rats were administered berberine in the absence and presence of silent information regulator- 1 (SIRT-1) inhibitor sirtinol (Stnl) followed by myocardial IR- injury, berberine conferred cardioprotection by diminishing infarct size, reducing lactate dehydrogenase (LDH), creatine kinase (CK-MB), apoptotic index, upregulationg Bcl-2 expressions, SIRT-1 and downregulating apoptopic proteins such as bax and caspases-3 expression⁶⁷. In addition, in this study, berberine was demonstrated to attenuate myocardial apoptosis and improved mitochondrial dysfunction⁶⁸. In another study, it has been reported that rats with MI after treatment with low dose (10 mg/kg) of berberine produced more myocardial shortening and therefore more left ventricular ejection pressure than the rats treated with high dose (50 mg/kg) of berberine. Furthermore, both doses were reported to prevent post myocardial IR- injury induced remodelling and interstitial fibrosis⁶¹. However, further investigations are required to investigate the importance of sigma receptor for the reduction of myocardial ischemia/reperfusion-induced injury after berberine administration.

Imipramine:

Imipramine is a tricyclic antidepressant (TCA), used in the treatment of major depression. Cardioprotective effects of imipramine in isolated dog atrium and on intact dogs were evaluated and observed that imipramine produced hypotension due to peripheral vasodilation as well as suppression of baroreceptive reflex mechanism⁶². In another study, imipramine when administerd intravenously, reduced arrhythmia after 15 minutes following coronary artery ligation^67,70. It is assumed that some non-specific effects of this drug accounts for antiarrhythmic action. However, involvement of sigma receptors still needs to be elucidated.

Haloperidol:

Haloperidol, a non-specific drug, has high affinity for a number of receptors such as D₂(dopamine) and 5-HT₂ (serotonin) receptors. Moreover, it also act as a prototypic ligand of sigma receptors acting as both σ₁-antagonist as well as σ₂- agonist^{64 ,65}. In one study, haloperidol reported to have a significant effect on heart rate as well as QT interval duration. Further, in another study, within atrium of haloperidol-exposed guinea pigs, a significant rise in sigma receptor’s expression was observed when compared with control. This effect might be produced partly through enhanced gene expression of sigma1 receptors and IP₃ receptors, partly via modulation of inward rectifying potassium (Kir) currents^23,70.

CONCLUSION:

A wide number of sigma receptor ligands including igmesine, memantine, dextrorphan, opipramole, ditolylguanidine and PRE 084 are available, whose cardioprotective effects are not yet elucidated. Although in human clinical studies, a significant improvement in cardioprotective parameters was observed with few sigma receptor ligands, however, additional efforts are required to understand the role σ ligands deeply which might offer new therapeutic perspectives in the cardiovascular sphere. In summary, to date very few conclusive results have been established. In this regard, continued efforts to identify novel sigma receptor drugs and their underlying mechanisms and subsequent development are crucial.

FUTURE DIRECTIONS:

During last few years, substantial advancement in the knowledge of the biology as well as pharmacology of sigma receptors has prompted the research on beneficial effects of sigma modulators in various pathological states. Indeed, few numbers of potent agonists or antagonists are a part of clinical trials for only some neurodegenerative or cardiovascular disorders. However, the identification of the new sigma receptor ligands responsible to produce protective effect on myocardial parameters would be a prime step to know the pathogenesis of heart related dysfunctions. Further research needs to focus to explore the role of σ-receptors in cardioprotection. Therefore, sigma ligands may act as a noval and important therapeutic intervention to protect the myocardium from hypertrophic dysfunction via σ-receptor stimulation.

ACKNOWLEDGEMENT:

The author expresses sincere gratitude to corresponding author Dr. Surya P Gautam.

CONFLICTS OF INTEREST:

The authors declare no conflict of interest.

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Received on 13.04.2020 Modified on 18.07.2020

Research J. Pharm. and Tech 2021; 14(12):6753-6760.

DOI: 10.52711/0974-360X.2021.01166

Sigma ligand	Subtype selectivity	Function	Effect on Heart	Mechanism of action
Afobazole	Sigma- 1	Agonist	Ischemic area shrinkage in the heart, prevention of post- infarction remodeling of the left ventricle (LV), prevents cardiac fibrillation	Interaction with sigma-1 receptor, anti-arrhythmic effect as an agonist of cytosolic σ_1-receptors in myocytes
Dehydroepi- androsterone	Sigma1/2	Agonist	LVH prevented with functional recovery induced by PO in thoracic aorta and significantly increased σ₁-receptors expression in thoracic aorta	Upregulation of σ_1- receptor and stimulation of σ_1-mediated Akt- Enos signaling
Fluvoxamine	Sigma-1	Agonist	Attenuation of TAC-induced hypertrophy in myocardium along with sigma-l receptor mediated of LV expression	Via upregulation of σ₁-1 receptor and stimulation of σ_1-receptor mediated Akt- eNOS signaling
Paroxetine	Sigma- 1	Agonist	Enhances βAR-dependent cardiomyocyte contractility and LV contractility, ionotropic effect in vivo with minimal effect on heart	Increase β adrenergic mediated consistent with direct increase GRK2 inhibition cultured myocytes and in vivo
SA4503	Sigma-1/2	Agonist	Ameliorates cardiac hypertrophy and dysfunction by restoring both mitochondrial Ca²⁺ mobilization and ATP production via sigma-1 receptor stimulation	Mitochondrial and calcium mobilization restoration, ATP production
BD737	Sigma-1	Agonist	BD737 show the positive inotropic and chronotropic effects	PLC stimulation and intracellular IP₃ level elevation via sigma receptors
Berberine	Sigma-1	Agonist	Lowers the level of CK, LDH, IL-6 TNF-α, malondialdehyde (MDA), ST elvation increase SOD, attenuate myocardial poptosis and improved mitochondrial dysfunction	Antioxidative and anti-inflammatory
Imipramine	Sigma1	Agonist	Cause hypotension as well as suppress arrhythmias after 15 min following coronary artery ligation	Hypotension due to peripheral vasodilation
Haloperidol	Sigma1/2	Antagonist	Positive inotropic effect in left atria of rat cardiomyocytes and papillary muscles expressing sigma-1 and IP₃ receptors	Likely to be mediated via increase in genes of inward rectifying potassium channels