Histopathological changes in androgenized ovaries are recovered by melatonin treatment

Nandrolone decanoate (ND) is a synthetic steroid, which promotes adverse effects on the ovarian tissue, and melatonin (MLT) exhibits a number of beneficial properties in the reproductive system. This study evaluated the general features of the ovarian tissue and the immunoexpression of sex steroid receptors in ND‐treated rats that were submitted to short‐term melatonin treatment. Adult rats received mineral oil (control group) and ND at doses of 7.5 mg/kg for 15 days (ND‐treated group). The treatment with MLT (10mg/kg for 7 days) was given alone, before or in combination with ND. All ND‐treated animals showed persistent dioestrus. In the androgenized groups that received MLT, ovarian morphology and size, and the number/area of corpora lutea were recovered. The number of healthy and atretic follicles was recovered when MLT was administered prior to ND; this was similar to the ovaries of control and MLT groups. There was a decrease in estrogen receptors immunostaining in the follicles of androgenized rats that were treated with MLT, and pretreatment with MLT reduced the expression of androgen receptor in atretic follicles and corpora lutea, when compared with ND‐treated group. We conclude that MLT treatment recovered the histopathological aspects of the androgenized ovaries, and MLT pretreatment was the most effective.     

In Utero Exposure to Benzo[a]pyrene Induces Ovarian Mutations at Doses That Deplete Ovarian Follicles in Mice

Polycyclic aromatic hydrocarbons like benzo[a]pyrene (BaP) are ubiquitous environmental contaminants formed during incomplete combustion of organic materials. Our prior work showed that transplacental exposure to BaP depletes ovarian follicles and increases prevalence of epithelial ovarian tumors later in life. We used the MutaMouse transgenic rodent model to address the hypothesis that ovarian mutations play a role in tumorigenesis caused by prenatal exposure to BaP. Pregnant MutaMouse females were treated with 0, 10, 20, or 40 mg/(kg day) BaP orally on gestational days 7–16, covering critical windows of ovarian development. Female offspring were euthanized at 10 weeks of age; some ovaries with oviducts were processed for follicle counting; other ovaries/oviducts and bone marrow were processed for determination of lacZ mutant frequency (MF). Mutant plaques were pooled within dose groups and sequenced to determine the mutation spectrum. BaP exposure caused highly significant dose-related decreases in ovarian follicles and increases in ovarian/oviductal and bone marrow mutant frequencies at all doses. Absence of follicles, cell packets, and epithelial tubular structures were observed with 20 and 40 mg/(kg day) BaP. Depletion of ovarian germ cells was inversely associated with ovarian MF. BaP induced primarily G > T and G > C transversions and deletions in ovaries/oviducts and bone marrow cells and produced a mutation signature highly consistent with that of tobacco smoking in human cancers. Overall, our results show that prenatal BaP exposure significantly depletes ovarian germ cells, causes histopathological abnormalities, and increases the burden of ovarian/oviductal mutations, which may be involved in pathogenesis of epithelial ovarian tumors. Environ. Mol. Mutagen. 60:410–420, 2019. © 2018 Her Majesty the Queen in Right of Canada     

Angiogenesis of the Frozen‐Thawed Human Fetal Ovarian Tissue at the Early Stage after Xenotransplantation and the Positive Effect of Salviae miltiorrhizae

Cryopreserving ovarian tissue followed by transplantation has been suggested to preserve fertility for young cancer survivors. However, ischemia in the early stage after transplantation causes massive follicle loss. The aim was to investigate the histological and ultrastructural characteristics of the frozen‐thawed human fetal ovarian tissue after xenotransplantation and the effects of Salviae miltiorrhizae (SM) on the angiogenesis. The human fetal ovarian tissues were frozen‐thawed, xenografted into the immunodeficient nu/nu mice, and then collected 2, 7, and 28 days after transplantation. SM was administered. Compared with that of the frozen‐thawed ovarian tissue, the total follicle number of the grafts was greatly reduced. Nearly half of the primordial follicles were damaged at different levels on day 2. Moreover, edema was prevalent in the stroma during the first week after the graft, especially on day 2. The microvessel density of the grafts was increased on day 2, reached a peak on day 7, and then declined on day 28. Both healthy primordial follicle proportion and the total healthy primordial follicles pool in the SM group were significantly higher than those of the control group (P = 0.003 and P = 0.001). We found a statistically significant difference of microvessel density between the two groups on day 2 (P < 0.001). In the frozen‐thawed fetal ovarian grafts, angiogenesis has been begun on day 2, and the first week is the critical time for the grafts to regain their function, in which SM can facilitate graft vascularization and improve the preservation of primordial follicles. Anat Rec, 2010. © 2010 Wiley‐Liss, Inc.     

Chronic valproate treatment influences folliculogenesis and reproductive hormones with possible ameliorating role for folic acid in adult albino rats

Sodium Valproate (VPA) is known to have deleterious consequences on ovarian function and folliculogenesis. Folic acid (FA) is associated with the quality of many parameters in folliculogenesis. Therefore, we aimed to investigate the effects of chronic Valproate administration on ovarian morphology, folliculogenesis, reproductive hormones, and the possible protective effect of Folic acid supplementation. Forty adult female albino rats were divided into four groups and treated orally for 90 days as follows: Control group received distilled water; FA group received (folic acid 400 μg/day); VPA group received (Na Valproate 200 mg/kg/day) and VPA + FA group received (Na Valproate 200 mg/kg/day + folic acid 400 μg/day). In addition, ovaries were processed for routine histology and immunohistochemistry (TGFβ1 and PCNA) and reproductive hormones levels were measured. Results showed a significant decrease in number of follicles in VPA group, while atretic follicles increased compared with control group (P < 0.001). Interestingly, the number of follicles significantly increased in VPA + FA group compared with VPA group (P < 0.001). Also, number of atretic follicles significantly decreased in the VPA + FA group compared to the VPA group. Histochemistry score decreased for TGFβ1 and PCNA staining in VPA group compared with control group (P < 0.01). Moreover, Valproate demonstrated a significant increase in testosterone levels in VPA group than control group (P < 0.001). However, VPA group demonstrated a significant decrease in levels of estradiol, progesterone, FSH and LH levels compared with control group. These changes were partially improved in VPA + FA group. In conclusion, FA co-treatment can modulate ovarian follicular and hormonal disturbances induced by valproate, which needs further investigations to identify the precise mechanisms.     

Effects of different doses of nandrolone decanoate on estrous cycle and ovarian tissue of rats after treatment and recovery periods

This study tested the hypothesis that different doses of nandrolone decanoate (ND) will cause changes in the estrous cycle and ovarian tissue of adult rats; and investigated the duration of the recovery period that is sufficient to restore the damage in the animals treated with different doses. Wistar rats were treated with ND at doses of 1.87, 3.75, 7.5 and 15 mg/kg body weight, or received mineral oil (control group) for 15 days, subcutaneously. All animals were divided into three groups according to the treatment periods: (i) ND treatment for 15 days; (ii) ND treatment followed by a 30‐day recovery; and (iii) ND treatment followed by a 60‐day recovery. Estrous cycle was monitored daily, and at the end of each period, the animals were euthanized for histopathological analysis. During ND treatment and after 30‐day recovery, all animals exhibited persistent diestrus. After a 60‐day recovery, persistent diestrus was only maintained in the group that had received the highest dose. Ovarian weight was decreased significantly after the 30‐day recovery, regardless of ND doses, compared with the control group. There was a reduction (P < 0.05) in the number of corpora lutea and antral and growing follicles, in contrast to an increase (P < 0.05) in atretic follicles in a dose‐ and time‐dependent manner. Remarkable histopathological changes occurred in the ovaries of all ND‐treated groups. In conclusion, the different doses of ND caused changes in the estrous cycle and ovarian tissue of rats, and recovery periods (30 and 60 days) were insufficient to completely restore the damage in the animals treated with the highest dose.     

Decrease of the electroacupuncture-induced analgesic effects in nuclear factor-kappa B1 knockout mice

We investigated whether pre-treatment with melatonin, a potent free radical scavenger and antioxidant, would protect against permanent focal cerebral ischemia without reperfusion in a rat middle cerebral artery occlusion (MCAO) model. A single dose of melatonin at 5, 15, or 50 mg/kg or the vehicle alone was given via an intraperitoneal injection at 0.5 h before permanent MCAO. Relative infarction volumes on day 3 were significantly reduced in the groups treated with melatonin at 5 (mean+/-SEM, 17.0+/-6.5%), 15 (18.1+/-5.8%), or 50 (20.6+/-5.0%) mg/kg when compared with the vehicle-treated group (37.1+/-2.8%) and so melatonin treatment achieved a relative reduction in infarct volume by 54.2, 51.2 and 44.5%, respectively. Melatonin did not affect the hemodynamic parameters. Thus, pre-treatment with melatonin at a dose between 5 and 50 mg/kg protects against focal cerebral ischemia without reperfusion.     

Nuclear localization of E-cadherin but not beta-catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma

Ohishi Y, Oda Y, Kurihara S, Kaku T, Kobayashi H, Wake N & Tsuneyoshi M
(2011) Histopathology 58 , 423–432
Nuclear localization of E‐cadherin but not beta‐catenin in human ovarian granulosa cell tumours and normal ovarian follicles and ovarian stroma Aims: The role of misregulated Wnt/beta‐catenin signalling in human ovarian granulosa cell tumour (GCT) has not been well characterized. The aim of this study was to confirm subcellular localization of key molecules of Wnt signalling (beta‐catenin and E‐cadherin) in human ovarian GCTs. Methods and results: Tissue samples taken from 32 human ovarian GCTs and 19 human normal ovaries containing 68 follicles were stained immunohistochemically using monoclonal anti‐beta‐catenin and anti‐E‐cadherin antibodies. None of the 32 GCTs and none of the 68 ovarian follicles showed beta‐catenin nuclear expression (0%). On the other hand, 28 of 32 GCTs (88%) and 53 of 68 normal ovarian follicles (78%) showed nuclear expression of E‐cadherin in granulosa cells. The ovarian stroma in all 19 normal ovaries showed nuclear expression of E‐cadherin but not beta‐catenin. Membranous and cytoplasmic expression was observed variously in ovarian GCT, follicles and stroma. Conclusions: We have confirmed frequent nuclear localization of E‐cadherin but not beta‐catenin in human ovarian GCT, ovarian follicles and stroma. There is no evidence of misregulated Wnt/beta‐catenin signalling (represented by nuclear expression of beta‐catenin) in human ovarian GCT. Nuclear translocation of E‐cadherin might contribute to ovarian folliculogenesis or granulosa/stromal cell differentiation.     

Does circadian rhythm disruption induced by light-at-night has beneficial effect of melatonin on sciatic nerve injury?

Melatonin stimulates peripheral nerve regeneration. However, the precise effect of Melatonin on nerve repair in dark period have not been clarified. The aim of the present study was to investigate the effect of melatonin on sciatic nerve injury after melatonin was given to rats in the morning or evening by means of combined analysis. This is the first study to investigate the influence of melatonin on sciatic nerve in cut injury two different times of the day. 60 adult female Wistar rats were divided into 4 groups: control (Group 1), sham-operated (Group 2), sciatic nerve cut + melatonin treatment in light (Group 3), sciatic nerve cut + melatonin treatment in dark (Group 4). Melatonin was administered intraperitoneally at dose of 50 mg/kg/day for six weeks. Recovery of function was analyzed by structural (biochemical properties of the antioxidant levels and ultrastructural analysis) and functional analyses (Sciatic function index, pinch test). The data demonstrated beneficial effect of melatonin in light period. However significant beneficial effect of melatonin was detected on the recovery of the cut sciatic nerve in dark period. Melatonin treatment was unable to influence on the recovery of the cut sciatic nerve in dark period. This means that the effect of melatonin the recovery of the cut injured sciatic nerve depends on the time of treatment may be attributed to its circadian rhythm.     

Protective effect of melatonin on beta-cell damage in streptozotocin-induced diabetes in rats

The aim of the present study was the evaluation of possible protective effects of melatonin against beta-cell damage in streptozotocin-induced diabetes in rats. Malondialdehyde levels and glutathione peroxidase activity were measured in pancreatic homogenates. Pancreatic beta-cells were examined by immunohistochemical methods. Streptozotocin was injected intraperitoneally at a single dose of 60 mg/kg for induction of diabetes. Melatonin (200 microg/kg/day, ip) was injected for 3 days prior to administration of streptozotocin; these injections were continued until the end of the study (4 weeks). Streptozotocin induced a significant increase in malondialdehyde levels (p < 0.01) and a significant decrease in glutathione peroxidase activity (p < 0.05) in pancreatic tissue. Degeneration of islet cells and weak immunohistochemical staining of insulin was observed in diabetic rats. Treatment of diabetic rats with melatonin markedly reduced malondialdehyde production (p < 0.05) and increased glutathione peroxidase activity (p < 0.01) without affecting hyperglycemia. Increased staining of insulin and preservation of islet cells were apparent in the melatonin-treated diabetic rats. These data suggest that melatonin treatment has a therapeutic effect in diabetes by reduction of oxidative stress and preservation of pancreatic beta-cell integrity.     

Role of exogenous melatonin in reducing the cardiotoxic effect of daunorubicin and doxorubicin in the rat

The aim of the studies was to examine the cardioprotective effect of melatonin during the anthracycline administration (daunorubicin, doxorubicin) in rats. Application of these drugs in chemotherapy is limited because of their cardiotoxicity. Rats of Buffalo strain were divided into groups according to the cytostatic drug used, its dose and sequence of administration (single intravenous [i.v.] dose of 10 mg/kg b.w., i.e., acute intoxication; 3 mg/kg b.w. weekly for 3 weeks, subchronic intoxication). Melatonin was administered subcutaneously before and after every injection of a cytostatic drug at a dose of 10 mg/kg b.w. The degree of cardiac muscle cell alterations was examined either histologically (Mean Total Score technique and the Billingham scale), or biochemically (levels of lipid peroxidation markers, malonyldialdehyde, and 4-hydroxyalkenals). Statistically significant decrease in cardiac muscle cell damage was noted with an aid of the Billingham scale after melatonin administration in acutely intoxicated doxorubicin-treated rats (p < 0.001). The similar phenomenon was observed using the Mean Total Score technique in case of acute daunorubicin or doxorubicin (p < 0.01 and p < 0.001, respectively) intoxications. A significant reduction in cardiac muscle cell lesions was detected either by the Billingham scale or by the Mean Total Score technique during subchronic intoxication with either of the anthracyclines when melatonin was given. Biochemical assays revealed significant decreases in malonyldialdehyde and 4-hydroxyalkenals levels following application of melatonin during either acute doxorubicin (p < 0.05) or subchronic daunorubicin (p < 0.01) intoxication. In summary, melatonin was found to exert a protective effect on the cardiac muscle cells, which was particularly evident after acute doxorubicin or subchronic daunorubicin intoxication, using either histological or biochemical methods.     

褪黑素体内外对胃癌Th1/Th2/Th17型细胞因子表达的影响

目的 探讨褪黑素（MLT）体内外对胃癌Th1/Th2/Th17型细胞因子干扰素（IFN）-γ、肿瘤坏死因子（TNF）、白细胞介素（IL）-2、IL-4、IL-6、IL-10、IL-17a表达的影响。 方法 1.构建荷胃癌小鼠模型,共32只雄性615小鼠全部荷小鼠前胃癌（MFC）细胞后随机分为4组,分别用0、25、50、100 mg/kg剂量褪黑素进行腹腔注射并测量肿瘤长短径。干预1周后取外周血,剥离肿瘤组织进行称重和测量。2.将MFC接种于6孔细胞培养板中,贴壁24 h后分别用0、2、4、6、8、10 mmol/L浓度褪黑素干预,24 h后形态学观察并收集相应上清液。3.采用ELISA检测外周血清中褪黑素的浓度变化。采用流式液相多重蛋白定量技术流式微珠阵列（CBA）分别检测外周血清、细胞上清液中Th1/Th2/Th17型相关细胞因子的浓度变化。 结果 1.成功建立荷胃癌小鼠模型。与阴性对照组相比, 褪黑素中、高剂量组小鼠外周血清褪黑素浓度明显升高,肿瘤体积明显下降。与阴性对照组相比,中剂量组血清中IL-10浓度明显增加;高剂量组血清IFN-γ、IL-2、IL-10浓度均明显增加。2.褪黑素干预MFC细胞实验中,与空白对照组相比,6、10 mmol/L 褪黑素组中IFN-γ浓度显著降低;4、6、8、10 mmol/L 褪黑素组中IL-6浓度明显降低,而 6 mmol/L 褪黑素组IL-10浓度明显升高。以上差异均具有统计学意义（P<0.05）。 结论 褪黑素体内外对胃癌细胞均有抑制作用且可能通过调节Th1/Th2/Th17细胞相关因子IFN-γ、IL-2、IL-6及IL-10的表达起增强肿瘤免疫作用。     

Dual effects of melatonin on barbiturate-induced narcosis in rats

Melatonin affects the circadian sleep/wake cycle, but it is not clear whether it may influence drug-induced narcosis. Sodium thiopenthal was administered intraperitoneally into male rats pre-treated with melatonin (0.05, 0.5, 5 and 50 mg/kg). Melatonin pre-treatment affected in a dual manner barbiturate narcosis, however, no dose-effect correlation was found. In particular, low doses reduced the latency to and prolonged the duration of barbiturate narcosis. In contrast, the highest dose of melatonin (50 mg/kg) caused a paradoxical increase in the latency and produced a sustained reduction of the duration of narcosis, and a reduction in mortality rate. Melatonin 0.5 and 5 mg/kg influenced the duration but not the latency of ketamine- or diazepam-induced narcosis. Thus, the dual action of melatonin on pharmacological narcosis seems to be specific for the barbiturate mechanism of action.     

Phospholipid composition of granulation and fibrous tissues in rats after local application of melatonin

We studied the effect of melatonin applied locally in doses of 1.5 and 15 mg/ml on the phospholipid composition of granulation and fibrous tissues in rats at various stages of regeneration. Melatonin (especially in a dose of 1.5 mg/ml) increased the total phospholipid content on day 8 of regeneration, which was primarily related to accumulation of ethanolamine- and serine-containing fractions. Melatonin in a dose of 15 mg/ml increased the concentration of choline-containing fractions on day 5 of regeneration.     

The ameliorative effect of propolis against methoxychlor induced ovarian toxicity in rat

A study was designed to evaluate ameliorative effect of propolis against methoxychlor (MXC) induced ovarian toxicity in rat. The organochlorine pesticide (MXC) is a known endocrine disruptor with estrogenic, anti-estrogenic, and anti-androgenic properties. To investigate whether chronic exposure to MXC could cause ovarian dysfunction, two groups of Sprague–Dawley adult female rats were exposed to MXC alone in a dose of 200 mg/kg, twice/weekly, orally or MXC dose as previous plus propolis in a dose of 200 mg/l/day, in drinking water for 10 months. Another two groups of rat were given corn oil (control) or propolis. Multiple reproductive parameters, ovarian weight, serum hormone levels, ovarian oxidative status and ovarian morphology were examined. In MXC-exposed group, there is a significant decrease in body and ovarian weight vs. control. MXC decreases serum estradiol and progesterone levels. A significant increase in the levels of lipid peroxidation was obtained while a significant decrease of the total antioxidant was recorded. Ovarian histopathology showed primary, secondary and vesicular follicles displaying an atretic morphology. Increase in the ovarian surface epithelium height accompanied with vacuolated, pyknotic oocytes were obtained. The previous toxic effects were neutralized by the administration of propolis in MXC + propolis group. The present results suggest that propolis may be effective in decreasing of MXC-induced ovarian toxicity in rat.     

Immune Stimulation by Exogenous Melatonin During Experimental Endotoxemia

Melatonin has been shown to enhance the immune response under immune-compromised conditions. However, its immune-modulatory effects under inflammatory conditions are unclear at present. Both pro- and anti-inflammation has been reported. To study time-dependent effects of melatonin on the general immune response during endotoxemia in more detail, we used two models in male rats: per-acute endotoxemia was induced by lipopolysaccharide (LPS) bolus injection (2.5 mg/kg), sub-acute endotoxemia by LPS infusion (2.5 mg/kg × h). Melatonin was applied directly before and 2 h after LPS administration (3 mg/kg, each). The LPS-induced formation of the pro-inflammatory cytokines tumor necrosis factor alpha, interferon-gamma, interleukin (IL)-1α/β, IL-5, and IL-6 and of the anti-inflammatory cytokine IL-10 was further amplified by melatonin, although it was only significant during per-acute endotoxemia. In both models, melatonin had no effect on the LPS-induced nitric oxide release. These findings show that exogenous melatonin is capable of enhancing the general immune response under inflammatory conditions.     

Polarized Ovaries of the Long‐tongued Bat,Glossophaga soricina: A Novel Model for Studying Ovarian Development,Folliculogenesis, and Ovulation

Glossophaga soricina is a spontaneously ovulating, monovular, polyestrous bat with a simplex uterus, exhibiting true menstruation. Studies conducted on reproductively active, captive‐maintained animals established that G. soricina also has polarized ovaries, with the ovarian surface epithelium (OSE) restricted to the medial side of the ovary, and primordial follicles limited to an immediately adjacent zone. Follicles selected for further development are recruited from the medullary side of this zone, and ovulation is restricted to the portion of the ovary covered by the OSE. To further develop G. soricina as a model for studying ovarian development and physiology, ovaries were collected from fetal, neonatal, and adult females and processed for morphological and immunohistochemical analyses. The latter included staining for factor VIII‐related antigen (von Willebrand factor) to assess regional differences in ovarian vascularity. The ovarian structure in fetal and neonatal animals was very similar to that in other species that do not have polarized ovaries at comparable stages of development. This indicated that polarization of the ovary does not occur during fetal development, but rather sometime between the neonatal period and adulthood. Vascular elements were abundant in areas of the ovary surrounding early growing follicles, but sparse in the zone of the ovary containing primordial follicles. The polarized nature of the ovaries in G. soricina suggests that this species might be used as a model to investigate the formation, long‐term maintenance, and activation of primordial follicles, and the role of the OSE in ovulation and folliculogenesis. Anat Rec, 290:1439–1448, 2007. © 2007 Wiley‐Liss, Inc.     

Role of CD4+CD25+ Regulatory T Cells in Melatonin‐Mediated Inhibition of Murine Gastric Cancer Cell Growth In Vivo and In Vitro

Melatonin is an important immune modulator with antitumor functions, and increased CD4⁺CD25⁺ regulatory T cells (Tregs) have been observed in tumor tissues of patients and animal models with gastric cancer. However, the relationship between melatonin and Tregs remains unclear. To explore this potential connection, we performed an in vivo study by inoculating the murine foregastric carcinoma (MFC) cell line in mice and then treated them with different doses of melatonin (0, 25, 50, and 100 mg/kg, i.p.) for 1 week. The results showed that melatonin could reduce the tumor tissue and decrease Tregs numbers and Forkhead box p3 (Foxp3) expression in the tumor tissue. An in vitro study was also performed to test the effects of purified Tregs on melatonin‐mediated inhibition of MFC cells. The cell cultures were divided into three groups: 1) MFC+ Tregs; 2) MFC only; and 3) MFC+CD4⁺CD25^? T cells. After treatment with different concentrations of melatonin (0, 2, 4, 6, 8, and 10 mM) for 24 h, a dose‐dependent apoptosis and cell cycle arrest at the G2/M phase was detected in melatonin‐treated MFC at melatonin concentration higher than 4 mM. There were no significant differences in the rates of apoptosis and cell cycle distributions of MFC among the three groups. In conclusion, the antigastric cancer effect of melatonin is associated with downregulation of CD4⁺CD25⁺ Tregs and its Foxp3 expression in the tumor tissue. Anat Rec, 2011. © 2011 Wiley‐Liss, Inc.     

Lipid peroxidation in the brain and liver of rats during acute stress and melatonin treatment

We studied the effects of acute stress and exogenous melatonin in various doses on the intensity of lipid peroxidation in emotiogenic structures of the brain and liver of rats with different activity in the open field. Stress had no effect on the content of malonic dialdehyde in the hypothalamus, sensorimotor cortex, and liver of active and passive rats receiving physiological saline. The influence of melatonin on malonic dialdehyde content depended on the dose of this substance. The amount of malonic dialdehyde in brain structures (active and passive rats) and liver (active rats) increased after administration of exogenous melatonin in doses of 0.5 and 2 mg/kg, but decreased after treatment with the hormone in a dose of 1 mg/kg. Melatonin in various doses decreased malonic dialdehyde content in the liver of passive rats. The effects of melatonin are partly related to modulation of lipid peroxidation in central and peripheral tissues of the organism. Translated fromByulleten’ Eksperimental’noi Biologii i Meditsiny, Vol. 138, No. 7, pp. 19–23, July, 2004     

Inhibitory Effect of Imiquimod‐Induced Psoriasis‐Like Skin Inflammation in Mice by Histamine H4 Receptor Agonist 4‐Methylhistamine

Psoriasis is a chronic inflammatory immune‐mediated autoimmune skin disorder. The histamine H4 receptor (H4R) agonist 4‐methylhistamine (4‐MH) plays an important role in immunomodulation of inflammatory responses associated with allergic inflammatory diseases. In this study, we investigated the effects of H4R agonist 4‐MH on the development of imiquimod (IMQ)‐induced psoriasis‐like skin inflammation in mice and explored the immunoregulatory mechanism involved. The total clinical severity scores were significantly ameliorated by treatment with 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg). Histological analysis of the skin revealed that 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg) significantly attenuated the psoriatic phenotypes, including epidermal hyperplasis, hyperkeratosis and lymphocytes infiltration. Treatment with 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg) led to reductions in the levels of Th1 cytokines (TNF‐α, IFN‐α, and IL‐27) in the serum and dorsal skin, whereas Th17 cytokines levels (IL‐17A and IL‐23) did not change in response to treatment with 4‐MH (20 mg/kg) and 4‐MH (40 mg/kg). Furthermore, the number of CD4⁺CD25⁺FoxP3⁺ regulatory T (Treg) cells was significantly increased by treatment with 4‐MH (40 mg/kg). Taken together, these results imply that H4R agonist 4‐MH might be an effective immunomodulatory approach for treatment of patients with psoriasis and the effects may be related to inhibited epidermal alteration, selectively reduced Th1 pro‐inflammatory cytokines, and recruited CD4⁺CD25⁺FoxP3⁺ Treg cells.