Objectives: Opioid analgesics have been used for a long time in the treatment of acute and chronic pain. However, they have many side effects including tolerance development to a significant extent. Agomelatine, an atypical antidepressant, has been demonstrated to be effective in experimental studies on pain. However, the effect of agomelatine on morphine tolerance development and its mechanism of action are unknown. The antinociceptive effects of agomelatine, morphine and their combination were assessed in a mice model for painful diabetic neuropathy. The roles of glutamate ionotropic receptor N-methyl-D-aspartate (NMDA) type subunit-1 (GluN1) in raphe nucleus and periaqueductal gray (PAG) in the effect of agomelatine on neuropathic pain were also investigated in diabetic mice. Methods: Agomelatine (10 mg/kg), morphine (10 mg/kg) and agomelatine + morphine were administered intraperitoneally for 15 consecutive days (twice per day), and the analgesic responses were assessed at days 1, 3, 6, 9, 12 and 15 in healthy and diabetic mice. Real time polymerase chain reaction (RT-PCR) was used to determine the changes in GluN1 expression. Results: The tolerance development for morphine was evident, started at 6th day and remained thereafter, but not for agomelatine. GluN1 in raphe nucleus and PAG was upregulated in morphine treated but not in agomelatine-treated groups. Discussion: The combination of agomelatine with morphine alone causes outlasting analgesic effects of repeated treatment, which can be interpreted as attenuated tolerance. Moreover, we also pointed out for the first time the modulatory effects of agomelatine on GluN1 expression in raphe nucleus and PAG after chronic morphine treatment. Abbreviations: Ca²⁺: Calcium; D2DR: Dopamine D2 receptor; GAPDH: Glyceraldehyde-3-phosphate dehydrogenase; GluN1: Glutamate ionotropic receptor N-methyl-D-aspartate type subunit-1; 5-HT: 5-hydroxytryptamine; i.p.: intraperitoneal injection; MPE: Maximal possible effect; MT: Melatonin; NMDA: N-methyl-D-aspartate; NMDAR1: NMDA receptors-1; PAG: Periaqueductal grey; PKCγ: Protein kinase C gamma; RT-PCR: Real time polymerase chain reaction; STZ: Streptozotocin

Prenatal tobacco-smoke exposure negatively affects the reproductive functions of female offspring and oxidative stress plays a major role at this point. Alpha-lipoic acid (ALA), well known as a biological antioxidant, has been used as a nutritional supplement and as a therapeutic agent in the treatment of certain complications during pregnancy. We aimed to investigate the effects of maternal tobacco-smoke exposure and/or ALA administration on puberty onset, sexual behavior, gonadotrophin levels, apoptosis-related genes, apoptotic cell numbers and oxidative stress markers in the adult female rat offspring. Sprague-Dawley rats were divided into four groups; control, tobacco smoke (TS), TS+ALA and ALA groups. Animals were exposed to TS and/or ALA for 8 weeks before pregnancy and throughout pregnancy. All treatments ended with birth and later newborn female rats were selected for each experimental group. The experiment ended at postnatal day 74–77. Maternal tobacco smoke advanced the onset of puberty in the female offspring of the TS group (p < 0.05). In all treatment groups; the mean number of anogenital investigations and lordosis quality scores showed a decline, serum luteinizing hormone levels significantly increased (p < 0.05) and several histopathological changes in ovaries were observed compared to the control group. In addition, an increase in apoptotic marker levels and apoptotic cell numbers was detected in the ovaries of all treatment groups. Decreased TAS and increased TOS levels were detected in all treatment groups compared to control. These findings suggested that maternal tobacco smoke and/or ALA administration may be leading to the impaired reproductive health of female offspring. Abbreviations: ALA: alpha-lipoic acid; LH: luteinizing hormone; FSH: follicle-stimulating hormone; TAS: total antioxidant status; TOS: total oxidant status; Apaf1: apoptotic protease-activating factor 1; Casp3: caspase 3; Casp9: caspase 9; CF: cyst follicles; 4-HNE: 4-Hidroxynonenal; 8-OHdG: 8-hydroxydeoxyguanosine; TUNEL: terminal deoxynucleotidyl transferase-mediated deoxyuridine-biotin nick end labeling; ROS: reactive oxygen species; GnRHR: gonadotropin-releasing hormone receptor; HPG: hypothalamic–pituitary–gonadal; AMPK: AMP-activated protein kinase; ELISA: enzyme-linked immunosorbent assay; cDNA: complementary DNA; qPCR: quantitative real-time PCR; FC: follicular cysts; PF: primary follicle; SF: secondary follicle; GF: graafian follicle; CL: corpus luteum; DF: degenerated follicle; AF: atretic follicle

Exercise hormone irisin, a thermogenic adipo-myokine, promotes energy expenditure by white adipose tissue browning. Considering that irisin improves the white adipose tissue metabolic profile and increases whole-body energy expenditure, it is thought that irisin may be a potential new therapeutic target for the treatment of the growing epidemic of obesity. The roles of mast cells and angiogenesis in the pathogenesis of obesity are known, and the importance of loss of mast cell function and antiangiogenic agents in the treatment of obesity has gained prominence in recent years. In addition, the therapeutic efficacy of oxytocin for obesity, by inducing browning and stimulating thermogenesis, is also noteworthy. To understand better the mechanisms involved in the therapeutic effect of irisin on obesity, the present study evaluated the effects of irisin treatment on high-fat diet-induced, obese female rats, focusing on the number of ovary mast cells, and ovarian angiogenesis and serum oxytocin levels. Our findings showed that ovary mast cell numbers, corpus luteum angiogenesis, and vascular endothelial growth factor (VEGF) immunoreactivity in ovarian tissues increased with obesity and then significantly decreased with irisin administration. Also, it was determined that the increased serum oxytocin levels with obesity, increased markedly depending on irisin administration in obese female rats. Taken together, our findings revealed that irisin can well be considered as a potential therapeutic agent in the treatment of obesity by reducing mast cells and angiogenesis, and promoting oxytocin secretion.

Paroxetine, a selective serotonin reuptake inhibitor commonly used to treat various psychiatric disorders, may adversely affect female reproductive function. Although apigenin has been shown to ameliorate reproductive abnormalities and ovarian dysfunction, its effect on paroxetine-induced reproductive toxicity in females remains unclear. Therefore, this study investigated the potential protective effects of apigenin against paroxetine-induced reproductive alterations in female rats. Female rats with regular estrous cycles were randomly assigned to four groups (n = 9 per group): control, apigenin, paroxetine, and paroxetine + apigenin. The rats received saline, apigenin (20 mg/kg), paroxetine (10 mg/kg), or their combination by oral gavage once daily for about 29 consecutive days. Compared with paroxetine treatment alone, apigenin co-administration restored decreased serum anti-Müllerian hormone (AMH) levels, enhanced PAS reactivity in the zona pellucida, reduced ovarian iNOS immunoreactivity, increased follicle and corpus luteum numbers, and increased ovarian VEGF immunoreactivity. However, apigenin administration alone was associated with reduced testosterone levels and alterations in certain ovarian and uterine histological features in female rats. In conclusion, the findings suggest that apigenin may ameliorate paroxetine-induced reproductive alterations in female rats by modulating AMH levels, follicle and corpus luteum numbers, and ovarian histochemical and molecular parameters.

Exercise provides significant benefits for most women, but adverse effects on reproduction can and do occur. Increased frequency, duration, and intensity of exercise are associated with a higher risk of female infertility. In particular, exercise-induced reproductive dysfunction is linked to alterations in the hypothalamic-pituitary-gonadal (HPG) axis. However, the role of meteorin-like protein (metrnl), as an exercise-induced myokine, in female reproductive function and the HPG axis is not yet fully understood. In this study, we investigated the effects of metrnl, compared with a swimming exercise protocol, on sexual motivation and the HPG axis in female rats. Female rats with regular estrous cycles were randomly allocated into three groups (n = 9 per group), and subjected to deionized water (1 mL/kg), metrnl (1 µg/day) or swimming-based moderate-intensity exercise (30 min/day, 5 days/week) for about 19 consecutive days. The results showed that metrnl administration reduced the time spent near the male rat and the male preference ratio, indicators of sexual motivation. It also decreased hypothalamic GnRH expression (in the median eminence and preoptic area), serum concentrations of reproductive hormones (follicle-stimulating hormone and anti-Müllerian hormone), and the numbers of ovarian follicles (primordial and primary follicles), similar to the effects observed after the swimming exercise protocol. Furthermore, metrnl concentrations in serum remained unchanged in female rats treated with metrnl and exercise. In conclusion, metrnl treatment reduced sexual incentive motivation and altered HPG axis regulation in female rats. These findings suggest that exercise-induced metrnl may be a potential exerkine associated with changes in female sexual motivation and HPG axis regulation due to exercise.

Psychological stress can affect female reproductive function through behavioral, endocrine, ovarian, and oxidative mechanisms. Antioxidant supplements have therefore attracted attention for their potential to mitigate stress-related reproductive alterations. Coenzyme Q10 (CoQ10) is a lipid-soluble quinone involved in mitochondrial energy metabolism and is widely used as a dietary supplement. However, whether CoQ10 modulates female reproductive responses to repeated psychological stress remains unclear. Although water avoidance stress (WAS) is a well-established psychogenic stress model, its effects on female reproductive outcomes are still not fully defined. In this study, we examined how repeated WAS affects female reproductive outcomes and whether CoQ10 modifies these effects. Twenty-eight regularly cycling female rats were assigned to sham control, WAS, CoQ10, or WAS + CoQ10 groups. WAS was applied for 1 h/day for 10 days, and CoQ10 was administered orally at 100 mg/kg/day. Repeated WAS did not significantly alter sexual incentive motivation parameters, reproductive hormones, corticosterone, total antioxidant capacity (T-AOC), 8-hydroxy-deoxyguanosine (8-OHdG), or mast cell count under the present experimental conditions (all p > 0.05). However, WAS reduced male-directed active investigation time (p = 0.008) and male investigation preference ratio (p = 0.024), increased absolute ovarian and adrenal gland weights (p = 0.035 and p = 0.016, respectively), reduced primordial follicle number (p = 0.030), decreased germinative epithelium thickness (p = 0.017), lowered VEGF histoscore (p = 0.033) regardless of CoQ10 treatment, and reduced corpus luteum angiogenesis in animals not receiving CoQ10 (p = 0.030). CoQ10 reduced total investigation time toward the male (p = 0.032), male investigation preference ratio (p = 0.037), 17-β estradiol (E2) (p = 0.003), testosterone (p = 0.021), and germinative epithelium thickness (p < 0.001) regardless of WAS exposure. CoQ10 also decreased kisspeptin-1 levels under non-stressed conditions (p = 0.010), while increasing corpus luteum angiogenesis under stress conditions (p = 0.003). Overall, repeated WAS produced selective behavioral and ovarian alterations rather than broad reproductive dysfunction. CoQ10 was not associated with a broadly protective or uniformly beneficial profile in this model, and its endocrine, behavioral, and ovarian effects should be interpreted with caution.