1797 Khartoum Medical Journal (2021) Vol. 14, No. 01, pp. 1797 - 1803 Chronic administration of propolis improves plasma levels of nitric oxide, calcium and cyclic guanosine monophosphate in selective serotonin reuptake inhibitors-induced erectile dysfunction in male Wistar rats Ayinde TO,1 Beheiry HM,2 Ojulari LS,1 Hussien MO,3* Afodun AM,4 Oluwasola A,5 Maryoud AH,2 Abdulwahab HM,6 Kardash MM.7 1Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Nigeria. 2Department of Physiology, Faculty of Medicine, International University of Africa, Khartoum, Sudan. 3Department of Microbiology, Central Laboratory, Ministry of Higher Education and Scientific Research, Khartoum, Sudan. 4Department of Anatomy and Cell Biology, Faculty of Health Sciences, Busitema University, Uganda. 5Department of Physiology, Faculty of Health Sciences, Al-Hikmah University, Ilorin, Nigeria. 6Department of Pharmacology, Faculty of Pharmacy, University of Ribat, Khartoum, Sudan. 7Department of Physiology, Faculty of Medicine, Ahlia University, Omdurman, Sudan. ABSTRACT Background Sexual dysfunction is a common adverse effect for 50-80% of patients taking selective serotonin reuptake inhibitors. This could be very annoying and makes the patient scornful of his sexual aggrandizement despite thoughtlessly patronizing several sexual enhancing drugs. It also progressively leads to loss of confidence among couples with the psyche of searching for alternative sexual pleasure. The present study investigated the effect of chronic administration of propolis on plasma levels of nitric oxide, calcium and cyclic guanosine monophosphate which interplay in the physiological mechanism of erectile function. Methods Male Wistar rats (140-190g) that were sexually active and sexually unexposed females (120- 130g) were employed in this study. Induction of erectile dysfunction was done in the male rats in groups II- VII by paroxetine hydrochloride 10mg/kg body weight orally for 2 weeks and confirmed by copulatory test with females. They were then randomly divided into seven groups of six rats (n=6) each and administered sildenafil or graded concentrations of propolis or 0.9% sodium chloride (group I) over a duration of 60 days. Following this, the animals were euthanized and blood samples collected for nitric oxide, calcium and cyclic guanosine monophosphate analysis. Results There was significant (p<0.05) increase in the plasma levels of nitric oxide of sildenafil treated group (III), high dose propolis treated group (VI), propolis-sildenafil combination treated rats (group VII); and significant (p<0.05) reduction in paroxetine-induced untreated rats (group II) and low dose propolis treated rats (group IV) compared to control (group I). However, there was no significant (p>0.05) difference between moderate dose treated rats (group V) compared to control group. There was significant (p<0.05) increase in plasma levels of calcium in group III, VI and VII while there was significant (p<0.05) reduction in calcium level of group II. However, there was no significant (p>0.05) difference in group IV and V. There was significant (p<0.05) reduction of cyclic guanosine monophosphate in group II, IV, and V, while significant (p<0.05) increase was seen in cyclic guanosine monophosphate of groups III, VI and VII compared to control. Conclusion Propolis has a key role to play in sexual functions through enhancement of erectogenic ability if given at high dose for sexual dysfunction by modulation of nitric oxide, calcium and cyclic guanosine monophosphate pathways in the physiological mechanism of penile erection. *Correspondence to [email protected]. Ayinde TO, Beheiry HM, Ojulari LS, Hussien MO, Afodun AM, Oluwasola A,Maryoud AH, Abdulwahab HM, Kardash MM 1798 INTRODUCTION low libido, erectile dysfunction (ED), premature Propolis (PL) is a collection of mixtures from ejaculation, delayed orgasm with other associated 15 different parts of plants harvested by honey bees multifactorial underlying causes. and is currently of much research interests, from Part of the present interest resides in ED, which has both traditional and orthodox perspectives.1,2 It is been documented by some authorities as the most a waxy product which bees utilize for construction common sexual problem in men. It is currently and repairation of their hives,3 and also employed as defined as “the inability to achieve and/or maintain chemical tools by bees against invading organisms. penile erection sufficient to attain satisfactory It has also been explored by humans as antidote sexual intercourse”. ED is a complex multifactorial for several ailments.4 It is a complex biologically disease, and one of the commonest health problems active substance containing more than 80-100 in men, and even more common with increasing identifiable chemical compounds depending on age.16 It has a high worldwide prevalence, with a source of its plant.5 Raw PL is composed of 50% projection of increasing over the next 25 years. resin, flavonoids, and related phenolic acids, In a community-based study ED affected 50-69% 30% wax, 10% essential oils, 5% pollen, and 5% and found to be more in 30% of men between 40 various organic compounds.6 However, a study and 70 years of age.17 It is a globally increasing also discovered that the major phytochemical problem, and because it is not a life threatening components of propolis are caffeic acid phenethyl disease on one hand, and due to its associated ester (CAPE), phenolics, hydrocarbons, aromatic stigma on the other hand, the sufferers seldom seek and aliphatic acids, flavonoids (Pinocembrin, for medical intervention which further deteriorates Galangin and Chrysin).7 Propolis exhibits anti- the situation.18 Thus, ED is known to be hiddenly inflammatory and antioxidant properties8, because associated with high level of psychological trauma it inhibits nuclear factor kappa light chain enhancer in affected men, and this precipitates a low level of activated B cells (NF- B) and subsequently K of self esteem and ecstasy, and poor relationship production of interleukins.9,10,11 among the sufferers, especially with their spouses.15 In another study, the Brazilian green propolis Most of the orthodox oral preparations are of cyclic has been explored to have caused lengthening in nucleotide phosphodiesterases (PDE) which are epididymal epithelium that is free of oxidative enzymes that catalyze the hydrolysis of the cyclic stress as well as sperm production in rats in a nucleotides, cyclic adenosine monophosphate morphometric-stereological study.12,13 PL has (cAMP) and 3’, 5’-cyclic guanosine monophosphate also been observed to increase semen quality and (cGMP); and they appear in different molecular seminal plasma enzymes. In a similar in vitro study, forms such as phosphodiesterase. An important it was discovered that PL can improve the total subtype distributed throughout the body is PDE5. mitochondrial respiratory efficiency in the human Sildenafil (Viagra), vardenafil (Levitra) and spermatozoa, suggesting its potential to improve tadalafil (Cialis) are common PDE5 inhibitors sperm motility,14 which is an important parameter prescription drugs which are taken orally.19 They for the fertilizing power of spermatozoa. Apart work by blocking the action of PDE5, which causes from the sperm produced by the male reproductive degradation of cGMP. Alprostadil (Vitaros) is a system, having a sustained penile erection is a big similar topical cream approved in Canada for erectile psychosexual phenomenon that plays a key role dysfunction.20 Many traditional concoctions from in sociocultural definition of a complete man. The parts of plants and animal secretions have been major shortfall of this system is a constellation used before the advent of PDE5 inhibitors, and of manifestations collectively termed sexual still much prevalent in many African communities dysfunction experienced by men at a point in as antidote for various conditions of sexual life, though of varying degrees which include: Chronic administration of propolis improves plasma levels of nitric oxide, calcium and cyclic guanosine monophosphate in selective 1799 serotonin reuptake inhibitors-induced erectile dysfunction in male Wistar rats dysfunction. For example, some people believe as Sources of kits and drugs folktales that the toxin in the venom of Brazilian Nitric oxide, Calcium and cGMP were products of 21 spider has erectogenic activity. Fortress Diagnostics Limited, Antrim Technology Park, Antrim, BT41 IQ3, United Kingdom and The burden of high cost and desensitization to purchased at Hisam Medical Diagnostic Equipment, availability of current therapies among sufferers in Khartoum, Sudan. our environment, especially in rural communities, necessitates the need for indigenous, inexpensive, Propolis extract was a product of Y.S. Organic Bee natural sources that is almost free of side effects as Farms 2774 N 4351 Rd. Sheridan, IL 60551 USA. intervention. This is a big gap in the knowledge of It is commercially prepared as 1000mg per capsule the present available clinical intervention for the and reconstituted by dissolving in 10ml of normal victims of ED and by extension sexual dysfunction saline and delivered as 100mg/ml. as a stigmatizing menace. The current study was carried out to explore and evaluate the medicinal Paroxetine hydrochloride was a product of activities of propolis using rat model with the Pharaonia Pharmaceuticals, New Borg El- Arab view to justify part of its ethno-medicinal claim City,