Acțiunea selectivă a U-74389G asupra ovarelor în cazul organelor genitale interne feminine la șobolan

Introduction

Although the manufacturing companies⁽¹⁾ have not independently confirmed the accuracy of the quoted methods, it is claimed that U-74389G (L) (PNU74389G meleate) is an antioxidant that can inhibit lipid peroxidation reactions and protect against ischemia-reperfusion injury (IRI). It is widely used in IRI animal models and shows anti-inflammatory activity, inhibiting nitrite production at plasma levels, in endotoxin stimulated peritoneal macrophages and in the supernatants of lipopolysaccharide (LPS)-primed macrophages in a dose-dependent manner. It reduces colonic tumor necrosis factor alpha (TNF-a), the macroscopic index of mucosal damage score (CMDI), and it increases body weight. It significantly protects against LPS-induced lethality, it reduces hypotension, ameliorates liver function, restores the hyporeactivity of aortic rings to their control values, and it inhibits the activity of inducible nitric oxide NO synthase in the liver and aorta.

In the present study, four histologic variables of IRI uteri⁽²⁾, fallopian tubes⁽³⁾ and ovaries⁽⁴⁾ (internal genitalia; GIR) were examined for this purpose. These variables were, for every organ, the epithelium edema (E), epithelium karyorrhexis (K), congestion (C) and inflammation (I) – EKCI. Furthermore, the cytokine (TNF-a) and the oxidative marker malondialdehyde (MDA) were also calculated. The present review work quotes the effect of U-74389G on rat genitalia pathology totally, associated by the two redox markers and a biochemical access⁽⁵⁾.

Materials and method

Since this is a review study, the reader is called to backdate at referenced publications^(2-5) for technical details settings, such as the two ethics committee approvals under the 3693/12-11-2010 and 14/10-1-2012 numbers, fully complying with the requirements of the Declaration of Helsinki; about the granting company, the experiment location, and also the pathology department and the peri-experimental Albino female Wistar rats management. Rats were 16-18 weeks old. Similar details will be found there^(2-5) about the randomization assignment to four groups, consisting in N=10, about the introductory common stage of 45-minute ischemia for all four groups. The groups were: Group A (placebo intravenous reperfusion of 60 minutes); Group B (placebo intravenous reperfusion of 120 minutes), Group C (immediate L intravenous reperfusion of 60 minutes) and Group D (immediate L intravenous reperfusion of 120 minutes). The dose height assessment was described at preliminary studies as 10 mg/kg body mass.

Also, data about perioperational details about the ischemic laparotomic clamping of the inferior aorta over renal arteries with forceps for 45 minutes; its restoration removal for blood patency and reperfusion; as well the iterated L administration at the time of reperfusion; through inferior vena cava catheter for each experimental group can be found at the same sources^(2-5). The EKCI variables, TNF-a, MDA and the blood values were determined at the 60^th minute of reperfusion (for A and C groups) and at the 120^th minute of reperfusion (for B and D groups). Increased relations ever proven between animals’ mass with each EKCI, either marker or serum variables, were included using corrected values. The pathologic score grading was maintained widely the same: lesions-free (0-0.499), mild lesions (0.5-1.499), moderate lesions (1.5-2.499), and serious lesions (2.5-3) damage. It is worth noting that the functional statistical test used in the preliminary studies freed the final findings from strict timepoints and endpoints, so that Table 1 is applicable to any time point within the first two hours. The fourth preliminary study simultaneously examined the effect of U-74389G on 35 blood and plasma substances from the central circulatory system of rats using exactly the same IR methodology in the inferior vena cava and with the same exact timepoints⁽⁵⁾ (Table 2). The aim was to obtain a more accurate and reliable numerical estimate of the direction and severity of the general metabolic disorder caused by this particular antioxidant agent in the body, with the ultimate goal of using it as a basis for comparison with the pathologic deviations of the internal genitalia (Table 3).

Discussion

There are no studies in the literature with U-74389G in GIR experiments; for this reason, the authors resorted to quote other antioxidant substances involved in experiments on GIR. Paksoy and Yumusak⁽⁶⁾ concluded that uterine torsion can lead to endometrial damage, degeneration, inflammation and apoptosis, potentially affecting fertility. High-dose folic acid treatment may protect uterus from these damages, thereby preserving fertility; it may be a safe and beneficial treatment to prevent ischemia-reperfusion (IR) damage and promote uterine health in rats. Folic acid treatment attenuated the caspase-3 activity, an increased marker of apoptosis in response to IR and uterine inflammation also was reduced. It also inhibited TNF-a immunoreactivity; however, it did not activate antioxidant mechanisms to reduce oxidative stress (OS). Nevertheless, it mitigated IR-induced damage by reducing endometrial injury and preventing inflammation and apoptosis.

Lafci et al.⁽⁷⁾ suggested a protective role of subcutaneous enoxaparin at 0.5 mg/kg against OS in uterine IRI two hours before ischemia, although it did not significantly improve the histopathologic injury in female rats. The endometrial glandular and endometrial/myometrial stromal changes were ameliorated according to the histopathologic scoring system (p<0.05) and more to the biochemical ones: catalase (CAT), superoxide dismutase (SOD) enzyme activities and MDA levels measured in uterine tissues (p>0.000).

Zhang et al.⁽⁸⁾ confirmed the scientific basis of snow lotus for its anti-inflammatory, anti-rheumatoid arthritis (RA), antioxidant and antitumor effects. The identified genes provide valuable resources for crop stress resistance improvement and innovative drug development of snow lotus, while underscore the standardizing pharmacopeial criteria. Uyghur medicine employs them for warming kidneys/uterus in cold-type rheumatism. Pharmacologically, active components alleviate arthritis by suppressing NF-kB/MAPK pathways and modulating gut microbiota-metabolite axes; polysaccharides exert antioxidant/photoprotective effects via ARE activation and PI3K/Akt inhibition; ethanol extracts/hispidulin induce tumor apoptosis by regulating caspase/Bax and blocking EGFR/AKT. Gene studies reveal that hypoxia/MeJA up-regulates DNA repair, terpenoid synthesis and cold/drought resistance genes (SiICE1, SikCOR413PM1), enhancing stress tolerance.

Koyam Karadeniz et al.⁽⁹⁾ revealed that biochemical and histopathologic improvement is observed in the fallopian tube tissues gradually when the detorsion procedure is performed for the necrotized tubal tissue instead of salpingectomy in Sprague-Dawley rats. Although there is restoration of epithelial integrity after reperfusion, tubal passage remains absent. Significant difference was observed in the tissue SOD, GSH-Px, MDA and 8-OHdG values. Among the histopathologic parameters, epithelial changes, vascular congestion and the total fallopian tube mean damage score showed a significant decrease. The values of the methylene blue transition after ischemia-reperfusion injury (IRI) were significantly decreased, whereas the postoperative serum AMH values were found significantly increased.

Hizal et al.⁽¹⁰⁾ revealed that vigabatrin – an antiepileptic agent – has been shown to increase the levels of gamma-aminobutyric acid (GABA) which has the potential to increase the ATP levels. It may represent a novel strategy for the prevention of ovarian IRI in vigabatrin + ovarian IR group (VOIR) female Wistar albino rats. VOIR demonstrated a decline in oxidants and proinflammatory cytokines, an augmentation in antioxidants and a reduction in histopathologic damage (p<0.05); also in MDA, TNF-a, IL-1b and IL-6 levels, total glutathione (GSH), SOD and CAT in ovaries (p<0.001); follicle numbers, congestion, dilatation of the vessels, edema, and an increase in inflammatory cells (p<0.05).

Refaie et al.⁽¹¹⁾ revealed that eplerenone (EPL; 100 mg/kg) and/or fenofibrate (FEN; 300 mg/kg) had ameliorative properties against ovarian ischemia/reperfusion (OIR) induced harmful effects. They revealed significant increases of the cardiac enzymes and MDA levels but decreases of total anti-oxidant capacity (TAC) and reduced GSH levels. Moreover, there were increases in toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MYD88), activation protein 1 (AP1), IL-6, nuclear factor kappa B (NF-kB) and cleaved caspase-3 with abnormal histological features. However, EPL or FEN coadministration alone or in combination reversed the OIR damaging effects by antagonizing aldosterone action by EPL, anti-inflammatory, antioxidant and antiapoptotic features with modulation of peroxisome proliferator activated receptor alpha (PPAR-a) by FEN and TLR4/MYD88/NF-kB/AP1/IL-6 pathway. Interestingly, the coadministration of both drugs showed a better improvement than each one given alone.

Xie et al.⁽¹²⁾ demonstrated that melatonin (25 mg/kg and 50 mg/kg) daily administered until the fourth postope­rative day mitigates oxidative stress and inflammatory damage in intact transplanted ovaries through the MT1/Nrf2/ARE signaling axis, thereby preserving ovarian function post-transplantation in Lewis rats. The treatment with high-dose melatonin (50 mg/kg) exhibited accelerated estrous cycle recovery, reduced the follicular loss, improved serum hormone levels, enhanced the antioxidant capacity in serum and ovarian tissue, and decreased the levels of inflammatory cytokines. Furthermore, melatonin exerted its antioxidant and anti-inflammatory effects through the activation of the Nrf2/ARE signaling pathway via the MT1 receptor.

The present experiment shows that U-74389G attenuates the cytokine TNF-a levels involved in systemic inflammation, one of the cytokines that make up the acute phase reaction, stimulates phagocytosis and the production of IL-1 oxidants, and, thus, attenuates all of these processes by 4.69%±8.40% (p=0.5749).

Also, U-74389G significantly attenuates the MDA levels, which is a marker of oxidative stress, and specifically of lipid peroxidation in tissues, thus providing membrane protection by 9.85%±2.66% (p=0.0005).Also, the synthesis presented in Table 3 about the resultant metabolic vector on 35 serum variables of complete blood count and blood chemistry tests, no significantly (p=0.2016) advocates a more general catabolic effect of U-74389G, compatible with that on ovaries.

Conclusions

U-74389G appears to be a promising factor, especially in ovarian tissue, with a wide range of applications, such as the immune pathogenesis of different ovarian disorders, including ovarian torsion, common during surgical manipulation, or within ovarian masses, affecting not only the ovaries, but also remote different organs, particularly the cardiac tissue. Cryopreservation and transplantation of intact ovaries offer a promising approach to fertility restoration in cancer patients. Larger studies may prove its usefulness on cases involving the rest of internal genitalia, such as uterine torsion, a pregnancy pathology that poses risks to both maternal and fetal health when the uterus rotates around its own axis, resulting in ischemia, which, if left untreated, may progress to necrosis and fetal loss. Finally, warmed cold-type rheumatic uterus and tubal patency may be benefited after U-74389G administration.

Acknowledgement. Acknowledged in preliminary studies.

Autor corespondent:  Tsompos N. Constantinos E-mail: constantinos1tsompos@gmail.com

CONFLICT OF INTEREST: none declared.

FINANCIAL SUPPORT: none declared.

This work is permanently accessible online free of charge and published under the CC-BY.