MOTILIPERM Ameliorates Immobilization Stress-Induced Testicular Dysfunction via Inhibition of Oxidative Stress and Modulation of the Nrf2/HO-1 Pathway in SD Rats.

Keshab Karna,Kiran Soni,Sung Lee,Jae You,Hye Kim,Chul Kim,Na Choi,Jong Park,Yu Shin

doi:10.3390/ijms21134750

Abstract

It is well established that physiological stress has an adverse effect on the male reproductive system. Experimental studies have demonstrated the promising effects of MOTILIPERM in male infertility. MOTILIPERM extract is composed of three crude medicinal herbs: Morinda officinalis How (Rubiaceae) roots, Allium cepa L. (Liliaceae) outer scales, and Cuscuta chinensis Lamark (convolvulaceae) seeds. The present study aimed to investigate the possible mechanisms responsible for the effects of MOTILIPERM on testicular dysfunction induced by immobilization stress. Fifty male Sprague Dawley rats were divided into five groups (10 rats each): a normal control group (CTR), a control group administered MOTILIPERM 200 mg/kg (M 200), an immobilization-induced stress control group (S), an immobilization-induced stress group administered MOTILIPERM 100 mg/kg (S + M 100), and MOTILIPERM 200 mg/kg (S + M 200). Stressed rats (n = 30) were subjected to stress by immobilization for 6 h by placing them in a Perspex restraint cage, while controls (n = 20) were maintained without disturbance. Rats were administrated 100 or 200 mg/kg MOTILIPERM once daily for 30 days 1 h prior to immobilization. At the end of the treatment period, we measured body and reproductive organ weight; sperm parameters; histopathological damage; reproductive hormone levels; steroidogenic acute regulatory protein (StAR); biomarkers of oxidative stress; and apoptosis markers. MOTILIPERM treatment improved testicular dysfunction by up-regulating (p < 0.05) sperm count, sperm motility, serum testosterone level, StAR protein level, Johnsen score, and spermatogenic cell density in stressed rats. MOTILIPERM decreased oxidative stress by increasing (p < 0.05) testicular superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione peroxidase-4 (GPx 4), catalase, nuclear factor erythroid 2-related factor 2 (Nrf2), and heme oxygenase 1 (HO-1) levels and decreasing (p < 0.05) malondialdehyde (MDA) and reactive oxygen species/reactive nitrogen species (ROS/RNS) levels. Furthermore, MOTILIPERM down-regulated (p < 0.05) cleaved caspase 3 and BCL2 associated X protein (Bax) levels; increased pro caspase-3 and B-cell lymphoma 2 (Bcl-2) levels; and upregulated testicular germ cell proliferation in stressed rats. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL)-positive cells and serum luteinizing hormone (LH) and follicle stimulating hormone (FSH) levels also significantly (p < 0.05) decreased after pretreatment with MOTILIPERM in stressed rats. Collectively, our results suggest that, in immobilization-mediated stress-induced testicular dysfunction, MOTILIPERM sustains normal spermatogenesis via antioxidant and anti-apoptotic activities by activating the NRF/HO-1 signaling pathway.

Highlights

Male reproductive health has markedly deteriorated over the past few decades
The differences were tested by one-way analysis of variance (ANOVA) followed by Tukey’s post hoc test; n = 10 for each group. * p < 0.05 denotes significant difference compared to normal control (CTR) group
Taken together, our data suggest that stress over a long period of time, perhaps surprisingly, is a cause of male infertility, and MOTILIPERM use should be considered as a novel strategy for the treatment of physiological and psychological stress-induced male infertility (Figure 4)

Summary

Introduction

Male reproductive health has markedly deteriorated over the past few decades. In particular, a decline in semen quality around the world has led to an increase in the prevalence of infertility [1]. Infertility can be defined as failure of a couple to conceive after 12 months or more of attempting regular unprotected intercourse [2]. Male infertility has multifactorial causes, such as failure in spermatogenesis, defects in sperm transportation, genetic defects, hormonal dysfunction, aging, and environment and lifestyle factors [4,5,6,7]. Among these factors, physiological and psychological stress appears to be one of the main causes of dysfunction of male reproductive health [8]. The pathophysiology of idiopathic male infertility still needs to be examined

Methods

Results

Discussion

Conclusion