BrdU does not induce hepatocellular damage in experimental Wistar rats.

Bromodeoxyuridine (BrdU) is used in studies related to cell proliferation and neurogenesis. The multiple intraperitoneal injections of this molecule could favor liver function profile changes. In this study, we evaluate the systemic and hepatocellular impact of BrdU in male adult Wistar rats in 30 %-partial hepatectomy (PHx) model. The rats received BrdU 50 mg/Kg by intraperitoneal injection at 0.5, 1, 2, 3, 6, 9 and 16 days after 30 %-PH. The rats were distributed into four groups as follows, control, sham, PHx/BrdU(-) and PHx/BrdU(+). On day 16, we evaluated hepatocellular nuclei and analyzed histopathological features by haematoxylin-eosin stain and apoptotic profile was qualified by caspase-3 presence. The systemic effect was evaluated by liver markers such as alanine transferase (ALT), aspartate aminotransferase (AST), lactate dehydrogenase (LDH), alkaline phosphatase (AP), bilirubin, total proteins and serum albumin content. The statistical analysis consisted of a student t-test and one-way ANOVA. BrdU did not induce apoptosis or hepatocellular damage in male rats. Multiple administrations of BrdU in male rats did not induce significant decrease body weight, but increased serum ALT and LDH levels were found. Our results show that the BrdU does not produce hepatocellular damage.

Pharmacological, Neurochemical, and Behavioral Mechanisms Underlying the Anxiolytic- and Antidepressant-like Effects of Flavonoid Chrysin.

Chrysin (5,7-dihydroxyflavone) is a flavonoid isolated from plants, such as Passiflora coerulea, Passiflora incarnata, and Matricaria chamomilla. This natural molecule exerts diverse pharmacological effects, which includes antioxidant, anti-inflammatory, anti-cancer, neuroprotective, and anti-apoptotic effects. Additionally, in brain structures, such as the hippocampus, prefrontal cortex, raphe nucleus, and striatum, involved in the physiopathology of anxiety and depression disorders, several neuropharmacological activities, including the activation of neurotransmitter systems (GABAergic, serotonergic, dopaminergic, and noradrenergic), neurotrophic factors, such as brain-derived neurotrophic factor and the nerve growth factor, and some signaling pathways are affected. The results showed that the anxiolytic and antidepressant-like effects of chrysin occurs through its interaction with specific neurotransmitter systems, principally the GABAergic and the serotonergic, and activation of other neurotrophic factors. However, it is not possible to discard the antioxidant and anti-inflammatory activities of chrysin while producing its anxiolytic- and antidepressant-like effects. Although these results have been obtained principally from pre-clinical research, they consistently demonstrate the potential therapeutic use of flavonoid chrysin as an anxiolytic and antidepressant agent. Therefore, this flavonoid could be considered as a promising novel therapy for anxiety and depression disorders.

Differential effects of acute and chronic treatment with the flavonoid chrysin on anxiety-like behavior and Fos immunoreactivity in the lateral septal nucleus in rats.

The aim of this study was to compare the effects of acute (a single injection) and chronic (21 consecutive days) treatments with chrysin 2, 4, and 8 µmol kg-1 on anxiety-like behavior and Fos immunoreactivity in the lateral septum nucleus (LSN), a structure that is involved in the regulation of anxiety, in male Wistar rats. These effects were compared with the clinically effective anxiolytic diazepam 7 µmol kg-1. The results showed that acute, but not chronic treatment, with 4 µmol kg-1 chrysin exerted anxiolytic- and anti- depressant-like effects with these effects being similar to that of diazepam. Also, none of the above-mentioned treatments did alter Fos immunoreactivity in the LSN, but a tendency towards the reduction of this variable was detected with chrysin 4 µmol kg-1 and diazepam 7 µmol kg-1. Altogether, results suggest that chrysin exerts anxiolytic-like effects, however, it can produce pharmacological tolerance after repeated use, similar to benzodiazepines.

Genistein as Potential Therapeutic Candidate for Menopausal Symptoms and Other Related Diseases.

Plant-derived compounds have recently attracted greater interest in the field of new therapeutic agent development. These compounds have been widely screened for their pharmacological effects. Polyphenols, such as soy-derived isoflavones, also called phytoestrogens, have been extensively studied due to their ability to inhibit carcinogenesis. These compounds are chemically similar to 17ß-estradiol, and mimic the binding of estrogens to its receptors, exerting estrogenic effects in target organs. Genistein is an isoflavone derived from soy-rich products and accounts for about 60% of total isoflavones found in soybeans. Genistein has been reported to exhibit several biological effects, such as anti-tumor activity (inhibition of cell proliferation, regulation of the cell cycle, induction of apoptosis), improvement of glucose metabolism, impairment of angiogenesis in both hormone-related and hormone-unrelated cancer cells, reduction of peri-menopausal and postmenopausal hot flashes, and modulation of antioxidant effects. Additionally, epidemiological and clinical studies have reported health benefits of genistein in many chronic diseases, such as cardiovascular disease, diabetes, and osteoporosis, and aid in the amelioration of typical menopausal symptoms, such as anxiety and depression. Although the biological effects are promising, certain limitations, such as low bioavailability, biological estrogenic activity, and effects on target organs, have limited the clinical applications of genistein to some extent. Moreover, studies report that modification of its molecular structure may eliminate the biological estrogenic activity and its effects on target organs. In this review, we summarize the potential benefits of genistein on menopause symptoms and menopause-related diseases like cardiovascular, osteoporosis, obesity, diabetes, anxiety, depression, and breast cancer.

Long-term ovariectomy increases anxiety- and despair-like behaviors associated with lower Fos immunoreactivity in the lateral septal nucleus in rats.

In woman, surgical menopause is associated with anxiety and depression symptoms. Ovariectomy in rats has been proposed as an experimental model of surgical menopause, but its long-term effects on anxiety- and depression-like behaviors and relationship with cellular changes in specific brain structures are unknown. The effects of ovariectomy on anxiety- and despair-like behavior 1, 3, 6, 9, 12, and 15-weeks postovariectomy were evaluated. Fos-immunoreactivity was evaluated in the lateral septal nucleus (LSN). The effects were compared with rats in the proestrus-estrus and metestrus-diestrus phases of the ovarian cycle and with ovariectomized rats that received 17ß-estradiol (OVXE). Three weeks postovariectomy, the rats exhibited an increase in anxiety-like behavior compared with PE and OVXE groups. Decreases in the locomotor activity and time spent grooming and rearing were detected in all the ovariectomized rats. In the forced swim test, the rats exhibited an increase in immobility time 6-weeks postovariectomy compared with control groups. The Fos-immunoreactivity in the LSN was significantly lower in all groups of ovariectomized rats compared with control groups. These findings indicate that rats develop anxiety-like behavior 3-weeks postovariectomy. Six weeks postovariectomy, the rats also developed despair-like behavior, which was associated with a reduction of Fos immunoreactivity in the LSN. Long-term ovariectomy may be considered a useful tool for understanding the development of neurobiological changes associated with surgical menopause. This model may also be useful for evaluating potential anxiolytic and antidepressant effects of diverse substances to ameliorate typical emotional and affective disorders during surgical menopause in women.

The Phytoestrogen Genistein Produces Similar Effects as 17ß-Estradiol on Anxiety-Like Behavior in Rats at 12 Weeks after Ovariectomy.

The phytoestrogen genistein produces anxiolytic-like effects in ovariectomized rats, which highlights its potential therapeutic effect in ameliorating anxiety in surgical menopausal women. However, no studies have directly compared the effects of identical doses of genistein and 17ß-estradiol, the main estrogen used in hormone replacement therapy in menopausal women. The present study evaluated the anxiolytic-like effects of identical doses of genistein and 17ß-estradiol (0.045, 0.09, and 0.18 mg/kg/7 days, s.c.) in a surgical menopause model in rats in the elevated plus maze and locomotor activity tests at 12 weeks after ovariectomy. Additionally, the participation of estrogen receptor-ß in the anxiolytic-like effect of genistein and 17ß-estradiol was explored by previous administration of the 5 mg/kg tamoxifen antagonist. Genistein and 17ß-estradiol (0.09 and 0.18 mg/kg) similarly reduced anxiety-like behavior in the elevated plus maze and also increased the time spent grooming and rearing, without affecting crossing in locomotor activity test. These effects were blocked by tamoxifen. Present results indicate that the phytoestrogen genistein has a similar behavioral profile as 17ß-estradiol in rats at 12 weeks after ovariectomy through action at the estrogen receptor-ß. Thus genistein has potential for reducing anxiety-like behavior associated with low concentrations of ovarian hormones, which normally occurs during natural and surgical menopause.