Barinderjit Kaur, Muthuraman A., Surya P Gautam
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Barinderjit Kaur1,2, Muthuraman A.3, Surya P Gautam4*
1Department of Pharmaceutical Sciences, I. K. Gujral Punjab Technical University, Kapurthala, Punjab, India.
2Department of Pharmaceutical Sciences, Lovely Professional University, Jalandhar, Punjab, India.
3Pharmacology Unit, Faculty of Pharmacy, AIMST University, Bedong, Kedah Darul Aman, Malaysia.
4Department of Pharmacology, CT Institute of Pharmaceutical Sciences, Jalandhar, Punjab, India.
Volume - 14,
Issue - 12,
Year - 2021
Cardiovascular diseases (CVDs) are primary reason of mortality and morbidity worldwide. Angina pectoris (AP), myocardial infarction (MI), silent myocardial ischemia and sudden cardiac death occur due to blockage in the coronary artery by atherosclerotic clot. Atherosclerotic clot is a systemic inflammatory process characterised by the accumulation and subsequent thickening of the wall by blood borne materials like low-density lipoproteins and macrophages/lymphocytes within the intima of arteries. These initial fatty streak lesions may also evolve into vulnerable plaques susceptible to rupture or erosion. Plaque rupture initiates both platelet adhesion and aggregation as well as the activation of the clotting cascade leading to so-called athero-thrombotic process and leads to coronary artery blockade. Coronary artery blockage interrupts the coronary blood supply leading to damage of myocardium. Multiple factors such as intra cellular (Ca2+, pH) and inter cellular (adhesion molecules) factors, inflammation, environmental toxins as well as metals and oxygen free radicals are involved in the pathogenesis of coronary artery diseases. Furthermore, certain sigma receptor ligands have been reported to show protective action against coronary artery diseases. Sigma receptor, a transmembrane protein, is expressed in many tissues including cardiovascular, liver and central nervous system. Sigma ligands significantly prevented the deviated biochemical parameters such as cardiac marker enzymes, lipid profile and antioxidant parameters to near normal status. Therefore, sigma receptor stimulation represents a new therapeutic strategy to prevent heart from ischemic and hypertrophic dysfunction in case of cardiovascular disorders. This review summarises the sigma receptors and cardioprotective potential of sigma receptor ligands. The article also provides a comprehensive account of structure, types and medical efficacy of cardioprotective sigma agonists.
Cite this article:
Barinderjit Kaur, Muthuraman A., Surya P Gautam. Sigma Receptors Ligands: New insights into the Cardioprotective Potential. Research Journal of Pharmacy and Technology. 2021; 14(12):6753-0. doi: 10.52711/0974-360X.2021.01166
Barinderjit Kaur, Muthuraman A., Surya P Gautam. Sigma Receptors Ligands: New insights into the Cardioprotective Potential. Research Journal of Pharmacy and Technology. 2021; 14(12):6753-0. doi: 10.52711/0974-360X.2021.01166 Available on: https://rjptonline.org/AbstractView.aspx?PID=2021-14-12-96
1. Sanchis-Gomar F, Perez-Quilis C, Leischik R and Lucia A. Epidemiology of coronary heart disease and acute coronary syndrome. Annals of translational medicine. 2016; 4(13).
2. Moradi-Arzeloo M, Farshid AA, Tamad E and Asri-Rezaei S. Effects of histidine and vitamin C on isoproterenol-induced acute myocardial infarction in rats. In Veterinary Research Forum 2016; 7(1): 47-54.
3. Al-Nozha MM, Ismail HM and Al Nozha OM. Coronary artery disease and diabetes mellitus. Journal of Taibah University Medical Sciences. 2016; 11(4): 330-8.
4. Gao K, Shi X and Wang W. The life-course impact of smoking on hypertension, myocardial infarction respiratory diseases. Scientific reports. 2017; 7(1): 1-7.
5. Khalil M, Ahmmed I, Ahmed R, Tanvir EM, Afroz R, Paul S, Gan SH and Alam N. Amelioration of isoproterenol-induced oxidative damage in rat myocardium by Withania somnifera leaf extract. BioMed research international. 2015; 2015.
6. Tagashira H, Bhuiyan S, Shioda N, Hasegawa H, Kanai H and Fukunaga K. σ1-Receptor stimulation with fluvoxamine ameliorates transverse aortic constriction-induced myocardial hypertrophy and dysfunction in mice. American Journal of Physiology-Heart and Circulatory Physiology. 2010; 299(5): H1535-45.
7. Raja S, Ramya I and Ravindranadh K. A review on protective role of phytoconstituents against isoproterenol induced myocardial necrosis. Int J Pharmacogn Phytochem Res. 2016; 8: 848-64.
8. Hirano K, Tagashira H and Fukunaga K. Cardioprotective effect of the selective sigma-1 receptor agonist, SA4503. Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan. 2014; 134(6): 707-13.
9. Hayashi T. Sigma-1 receptor: the novel intracellular target of neuropsychotherapeutic drugs. Journal of pharmacological sciences. 2015; 127(1): 2-5.
10. Hayashi T and Su TP. The sigma receptor: evolution of the concept in neuropsychopharmacology. Current neuropharmacology. 2005; 3(4): 267-80.
11. Shimizu I, Kawashima K, Ishii D and Oka M. Effects of (+)-pentazocine and 1, 3-di-o-tolylguanidine (DTG), sigma (σ) ligands, on micturition in anaesthetized rats. British journal of pharmacology. 2000; 131(3): 610.
12. Rousseaux CG and Greene SF. Sigma receptors [σ Rs]: biology in normal and diseased states. Journal of Receptors and Signal Transduction. 2016; 36(4): 327-88.
13. Su TP. Evidence for sigma opioid receptor: binding of [3H] SKF-10047 to etorphine-inaccessible sites in guinea-pig brain. Journal of Pharmacology and Experimental Therapeutics. 1982; 223(2): 284-90.
14. Su TP, Hayashi T and Vaupel DB. When the endogenous hallucinogenic trace amine N, N-dimethyltryptamine meets the sigma-1 receptor. Science signaling. 2009; 2(61): 12-17
15. Su TP, London ED and Jaffe JH. Steroid binding at sigma receptors suggests a link between endocrine, nervous, and immune systems. Science. 1988; 240(4849): 219-21.
16. Su TP and Hayashi T. Understanding the molecular mechanism of sigma-1 receptors: towards a hypothesis that sigma-1 receptors are intracellular amplifiers for signal transduction. Current medicinal chemistry. 2003; 10(20): 2073-80.
17. Derbez AE, Mody RM and Werling LL. ς2- Receptor Regulation of Dopamine Transporter via Activation of Protein Kinase C. Journal of Pharmacology and Experimental Therapeutics. 2002; 301(1): 306-14.
18. Nováková M. Effects of sigma receptor ligand BD737 in rat isolated hearts. Scr Med (Brno). 2007; 80: 255-62.
19. Novakova M, Ela C, Bowen WD, Hasin and Eilam Y. Highly selective σ receptor ligands elevate inositol 1, 4, 5-trisphosphate production in rat cardiac myocytes. European journal of pharmacology. 1998; 353(2-3): 315-27.
20. Van Waarde A, Ramakrishnan NK, Rybczynska AA, Elsinga PH, Ishiwata K, Nijholt IM, Luiten PG and Dierckx RA. The cholinergic system, sigma-1 receptors and cognition. Behavioural brain research. 2011; 221(2): 543-54.
21. Ela C, Barg J, Vogel Z, Hasin Y and Eilam Y. Sigma receptor ligands modulate contractility, Ca++ influx and beating rate in cultured cardiac myocytes. Journal of Pharmacology and Experimental Therapeutics. 1994; 269(3): 1300-9.
22. Novakova M, Ela C, Barg J, Vogel Z, Hasin Y and Eilam Y. Inotropic action of σ receptor ligands in isolated cardiac myocytes from adult rats. European journal of pharmacology. 1995; 286(1): 19-30.
23. Stracina T, Slaninova I, Polanska H, Axmanova M, Olejnickova V, Konecny P, Krizanova O and Novakova M. Long-term haloperidol treatment prolongs QT interval and increases expression of sigma 1 and IP3 receptors in guinea pig hearts. The Tohoku Journal of Experimental Medicine. 2015; 236(3): 199-207.
24. Schmidt HR, Zheng S, Gurpinar E, Koehl A, Manglik A and Kruse AC. Crystal structure of the human σ 1 receptor. Nature. 2016; 532(7600): 527-30.
25. Aydar E, Palmer CP, Klyachko VA and Jackson MB. The sigma receptor as a ligand-regulated auxiliary potassium channel subunit. Neuron. 2002; 34(3): 399-410.
26. Jamin N, Neumann JM, Ostuni MA, Vu TK, Yao ZX, Murail S, Robert JC, Giatzakis C, Papadopoulos V, Lacapere JJ. Characterization of the cholesterol recognition amino acid consensus sequence of the peripheral-type benzodiazepine receptor. Molecular endocrinology. 2005;19(3): 588-94.
27. Hayashi T and Su TP. Sigma-1 receptor chaperones at the ER-mitochondrion interface regulate Ca2+ signaling and cell survival. Cell. 2007; 131(3): 596-610.
28. Chu U B and Ruoho AE. Biochemical pharmacology of the sigma-1 receptor. Molecular pharmacology. 2016; 89(1): 142-53
29. Seth P, Ganapathy ME, Conway SJ, Bridges CD, Smith SB, Casellas P and Ganapathy V. Expression pattern of the type 1 sigma receptor in the brain and identity of critical anionic amino acid residues in the ligand-binding domain of the receptor. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2001; 1540(1): 59-67.
30. Cobos EJ, Entrena JM, Nieto FR, Cendan CM and DelPezo E. Pharmacology and therapeutic potential of sigma (1) receptor ligands. Curr. Curr Neuropharmacol. 2008; 6, 344-366.
31. Garcés-Ramírez L, Flores G and De la Cruz FL. Effect of sigma agonist 1, 3 di-o-tolyl-guanidine (DTG) on squizophrenia and immobility responses. Therapeutic Targets for Neurological Diseases. 2015; 2: 1-6.
32. Matsumoto RR. Targeting sigma receptors: novel medication development for drug abuse and addiction. Expert review of clinical pharmacology. 2009; 2(4): 351-8.
33. Matsumoto RR, Bowen WD and Su TP. Sigma Receptors. Springer Science. Business Media, LLC. 2007.
34. Kitaichi K, Chabot JG, Moebius FF, Flandorfer A, Glossmann H and Quirion R. Expression of the purported sigma1 (σ1) receptor in the mammalian brain and its possible relevance in deficits induced by antagonism of the NMDA receptor complex as revealed using an antisense strategy. Journal of chemical neuroanatomy. 2000; 20(3-4): 375-87.
35. Hiranita T. Identification of Antagonists Selective for Sigma Receptor Subtypes that are Active In vivo. Journal of alcoholism and drug dependence. 2016; 4(4).
36. Kourrich S, Su TP, Fujimoto M and Bonci A. The sigma-1 receptor: roles in neuronal plasticity and disease. Trends in neurosciences. 2012; 35(12): 762-71.
37. Ito K, Hirooka Y and Sunagawa K. Brain sigma-1 receptor stimulation improves mental disorder and cardiac function in mice with myocardial infarction. Journal of cardiovasc pharmacol. 2013; 62(2): 222-8.
38. Hashimoto K and Ishiwata K. Sigma receptor ligands: possible application as therapeutic drugs and as radiopharmaceuticals. Current pharmaceutical design. 2006; 12(30): 3857-76.
39. Dumont M and Lemaire S. Interaction of 1, 3-di (2-[5-3H] tolyl) guanidine with σ2 binding sites in rat heart membrane preparations. European journal of pharmacology. 1991; 209(3): 245-8.
40. Largent BL, Gundlach AL, Snyder SH. Pharmacological and autoradiographic discrimination of sigma and phencyclidine receptor binding sites in brain with (+)-[3H] SKF 10,047,(+)-[3H]-3-[3-hydroxyphenyl]-N-(1-propyl) piperidine and [3H]-1-[1-(2-thienyl) cyclohexyl] piperidine. Journal of Pharmacology and Experimental Therapeutics. 1986 Aug 1;238(2):739-48.
41. Bhuiyan MS, Tagashira H, Shioda N and Fukunaga K. Targeting sigma-1 receptor with fluvoxamine ameliorates pressure-overload-induced hypertrophy and dysfunctions. Expert opinion on therapeutic targets. 2010; 14(10): 1009-22.
42. Fialova K, Krizanova O, Jarkovsky J and Novakova M. Apparent desensitization of the effects of sigma receptor ligand haloperidol in isolated rat and guinea pig hearts after chronic treatment. Canadian journal of physiology and pharmacology. 2009; 87(12): 1019-27.
43. Bhuiyan MS and Fukunaga K. Stimulation of sigma- 1 receptor signaling by dehydroepiandrosterone ameliorates pressure overload-induced hypertrophy and dysfunction in ovariectomized rats. Expert Opin Ther Targets. 2009; 13(11): 1253-1265.
44. Fontanilla D, Johannessen M, Hajipour AR, Cozzi NV, Jackson MB and Ruoho AE. The hallucinogen N, N-dimethyltryptamine (DMT) is an endogenous sigma-1 receptor regulator. Science. 2009; 323(5916): 934-7.
45. Kockskämper J, Zima AV, Roderick HL, Pieske B, Blatter LA and Bootman MD. Emerging roles of inositol 1, 4, 5-trisphosphate signaling in cardiac myocytes. Journal of molecular and cellular cardiology. 2008; 45(2): 128-47.
46. Johannessen M, Ramachandran S, Riemer L, Ramos-Serrano A, Ruoho AE and Jackson MB. Voltage-gated sodium channel modulation by σ-receptors in cardiac myocytes and heterologous systems. American Journal of Physiology-Cell Physiology. 2009; 296(5): C1049-57.
47. Maurice T and Su TP. The pharmacology of sigma-1 receptors. Pharmacology and therapeutics. 2009; 124(2): 195-206.
48. Voronin MV and Kadnikov IA. Contribution of Sigma‐1 receptor to cytoprotective effect of afobazole. Pharmacology research and perspectives. 2016; 4(6): e00273.
49. Stoliaruk VN, Vititnova MB, Tsorin IB and Kryzhanovskiĭ SA. Afobasol antifibrillation activity in animals with the intact and denervated myocardium. Vestnik Rossiiskoi akademii meditsinskikh nauk. 2010; 4: 45-8.
50. Kryzhanovskyi SA, Sorokina AV, Stolyaruck VN, Vititnova MB, Miroshkina IA, Tsorin IB, Durnev AD and Seredenin SB. Study of anti-ischemic effect of Afobazole in experimental myocardial infarction. Bulletin of experimental biology and medicine. 2011; 150(3): 316.
51. Tagashira H, Zhang C, Lu YM, Hasegawa H, Kanai H and Han F and Fukunaga K. Stimulation of σ1-receptor restores abnormal mitochondrial Ca2+ mobilization and ATP production following cardiac hypertrophy. Biochimica et Biophysica Acta (BBA)-General Subjects. 2013; 1830(4): 3082-94.
52. Tagashira H and Fukunaga K. Cardioprotective effect of fluvoxamine, sigma-1 receptor high affinity agonist. Yakugaku zasshi: Journal of the Pharmaceutical Society of Japan. 2012; 132(2): 167-72.
53. Muto T, Usuda H, Yamamura A, Yoshida K, Ohashi A, Mitsui-Saitoh K, Sakai J, Sugimoto Y, Mizutani H, Nonogaki T and Hotta Y. Protective effects of fluvoxamine against ischemia/reperfusion injury in isolated, perfused guinea-pig hearts. Biological and Pharmaceutical Bulletin.2014;37(5):731-9.
54. Ehmke H. The sigma-1 receptor: a molecular chaperone for the heart and the soul?. 2012; 93: 6-7.
55. Eschenhagen T. β-adrenergic signaling in heart failure—adapt or die. Nature medicine. 2008; 14(5): 485-7.
56. Tian X, Wang Q, Guo R, Xu L, Chen QM and Hou Y. Effects of paroxetine-mediated inhibition of GRK2 expression on depression and cardiovascular function in patients with myocardial infarction. Neuropsychiatric Disease and Treatment. 2016;12: 2333.
57. Hata JA, Williams ML and Koch WJ. Genetic manipulation of myocardial β-adrenergic receptor activation and desensitization. Journal of molecular and cellular cardiology. 2004; 37(1): 11-21.
58. Guo S, Carter RL, Grisanti LA, Koch WJ and Tilley DG. Impact of paroxetine on proximal β-adrenergic receptor signaling. Cellular signalling. 2017; 38: 127-33.
59. Thal DM, Homan KT, Chen J, Wu EK, Hinkle PM, Huang ZM, Chuprun JK, Song J, Gao E, Cheung JY and Sklar LA. Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility. ACS chemical biology. 2012; 7(11): 1830-9.
60. Lever JR, Gustafson JL, Xu R, Allmon RL and Lever SZ. σ1 and σ2 receptor binding affinity and selectivity of SA4503 and fluoroethyl SA4503. Synapse. 2006; 59(6): 350-8.
61. Zhang YJ, Yang SH, Li MH, Iqbal J, Bourantas CV, Mi QY, Yu YH, Li JJ, Zhao SL, Tian NL and Chen SL. Berberine attenuates adverse left ventricular remodeling and cardiac dysfunction after acute myocardial infarction in rats: role of autophagy. Clinical and Experimental Pharmacology and Physiology. 2014; 41(12): 995-1002.
62. Watanabe H, FURUKAWA Y, Chiba S. Cardiovascular effects of imipramine in intact dogs and isolated dog atria. Japanese heart journal. 1981;22(6):977-85.
63. Bril A and Rochette L. Antiarrhythmic properties of antidepressant drugs after coronary artery occlusion and reperfusion in rats. Pharmacology. 1988; 36(1): 16-26.
64. Cobos EJ, Pozo ED and Baeyens JM. Irreversible blockade of sigma‐1 receptors by haloperidol and its metabolites in guinea pig brain and SH‐SY5Y human neuroblastoma cells. Journal of neurochemistry. 2007; 102(3): 812-25.
65. Colabufo NA, Berardi F, Contino M, Niso M, Abate C, Perrone R and Tortorella V. Antiproliferative and cytotoxic effects of some σ 2 agonists and σ 1 antagonists in tumour cell lines. Naunyn-Schmiedeberg's archives of pharmacology. 2004; 370(2): 106-13.
66. Zhang T, Yang S and Du J. Protective effects of berberine on isoproterenol-induced acute myocardial ischemia in rats through regulating HMGB1-TLR4 axis. Evidence-Based Complementary and Alternative Medicine. 2014; 1: 1-8.
67. Yu L, Li Q, Yu B, Yang Y, Jin Z, Duan W, Zhao G, Zhai M, Liu L, Yi D and Chen M. Berberine attenuates myocardial ischemia/reperfusion injury by reducing oxidative stress and inflammation response: role of silent information regulator 1. Oxidative Medicine and Cellular Longevity. 2016; 2016.
68. Wang Y, Liu J, Ma A and Chen Y. Cardioprotective effect of berberine against myocardial ischemia/reperfusion injury via attenuating mitochondrial dysfunction and apoptosis. International journal of clinical and experimental medicine. 2015; 8(8):14513.
69. Tagashira H, Bhuiyan S, Shioda N and Fukunaga K. Distinct cardioprotective effects of 17β-estradiol and dehydroepiandrosterone on pressure overload–induced hypertrophy in ovariectomized female rats. Menopause. 2011; 18(12): 1317-26.
70. Stracina T and Novakova M. Cardiac sigma receptors-an update. Physiological Research. 2018; 2:67.