Protective Effects of Antioxidants on Cyclophosphamide-Induced Ovarian Toxicity.

The most common limitation of anticancer chemotherapy is the injury to normal cells. Cyclophosphamide, which is one of the most widely used alkylating agents, can cause premature ovarian insufficiency and infertility since the ovarian follicles are extremely sensitive to their effects. Although little information is available about the pathogenic mechanism of cyclophosphamide-induced ovarian damage, its toxicity is attributed to oxidative stress, inflammation, and apoptosis. The use of compounds with antioxidant and cytoprotective properties to protect ovarian function from deleterious effects during chemotherapy would be a significant advantage. Thus, this article reviews the mechanism by which cyclophosphamide exerts its toxic effects on the different cellular components of the ovary, and describes 24 cytoprotective compounds used to ameliorate cyclophosphamide-induced ovarian injury and their possible mechanisms of action. Understanding these mechanisms is essential for the development of efficient and targeted pharmacological complementary therapies that could protect and prolong female fertility.

Epigallocatechin-3-gallate attenuates cyclophosphamide-induced damage in mouse ovarian tissue via suppressing inflammation, apoptosis, and expression of phosphorylated Akt, FOXO3a and rpS6.

This study was conducted to evaluate the protective effects of epigallocatechin-3-gallate (EGCG) against ovarian toxicity in cyclophosphamide-treated mice and to verify the possible involvement of phosphorylated Akt, FOXO3a and rpS6 in the EGCG actions. Mice received saline solution (i.p.; control) or a single dose of cyclophosphamide (200 mg/kg body weight, i.p.) or mice were pretreated with N-acetylcysteine (150 mg/kg body weight, i.p.; positive control) or with EGCG (5, 25 or 50 mg/kg body weight, i.p.) once daily for three days followed by injection with single dose of cyclophosphamide (200 mg/kg body weight, i.p.). Thereafter, the mice were euthanized, and the ovaries were harvested and destined to histological (follicular morphology and activation), immunohistochemistry (cleaved caspase-3 and TNF-α) and fluorescence (mitochondrial activity and GSH concentrations) analyses. Furthermore, we examined the participation of p-Akt, p-FOXO3a and p-rpS6 in the protective effects of EGCG in cyclophosphamide-induced ovarian damage by immunohistochemical staining. The results showed that pretreatment with N-acetylcysteine or EGCG at 25 and 50 mg/kg before cyclophosphamide administration preserved the normal follicular morphology, prevented primordial follicle loss, reduced atresia, inflammation, and mitochondrial damage, and increased GSH concentrations compared to the only cyclophosphamide treatment. Additionally, pretreatment with 25 mg/kg EGCG regulated phosphorylated Akt, FOXO3a and rpS6 after cyclophosphamide treatment. In conclusion, short-time pretreatment with 25 mg/kg EGCG can prevent follicle loss in cyclophosphamide-treated mice by reducing oxidative damage, inflammation, and apoptosis, and regulating of p-Akt, p-FOXO3a and p-rpS6.

Involvement of serotonergic pathways in gastric dysmotility induced by fat burning nutritional supplements in mice.

Fat burners are a category of nutritional supplements that are claimed to increase the metabolism and promote greater energy expenditure, leading to weight loss. However, little is known about the side effects on gastrointestinal motility. In this study, we evaluated the effect of ingestion with a fat burner named Thermbuterol® (THERM) on the gastric motility and food behavior of mice. THERM compounds were identified using nuclear magnetic resonance (NMR). Mice received variable doses of THERM (10, 50, 100 or 300 â€‹mg/kg, p.o.) or NaCl 0.15 â€‹M (control). Gastric emptying (GE) was assessed using the phenol red technique. Another set of mice was pretreated with intraperitoneal administration of hexamethonium (HEXA, 10 â€‹mg/kg), prazosin (PRAZ, 0.25 â€‹mg/kg), propranolol (PROP, 2 â€‹mg/kg), parachlorophenylalanine (PCPA, 300 â€‹mg/kg) or ondansetron (ONDA, 50 â€‹µg/kg) 30 â€‹min before THERM treatment for evaluation of GE. We assessed the gastrointestinal responsiveness in vitro as well as THERM's effects on food behavior. Caffeine was the major compound of THERM, identified by NMR. THERM 100 and 300 â€‹mg/kg decreased GE compared to the respective controls. Pretreatment with PRAZ or PROP did not prevent gastric dysmotility induced by THERM 100 â€‹mg/kg. However, the pretreatment with HEXA, ONDA or PCPA prevented GE delay induced by THERM. In vitro, THERM relaxed contractions in strips of longitudinal gastric fundus and duodenum. THERM also increased food intake, which was prevented by PCPA and ONDA treatments. THERM decreased GE of a liquid and increased food intake in mice, a phenomenon mediated by the autonomic nicotinic receptors and serotoninergic receptor.

Antinociceptive and anti-inflammatory activities of the ethanolic extract of Annona vepretorum Mart. (Annonaceae) in rodents.

BACKGROUND: Annona vepretorum Mart. (Annonaceae) is a native tree from Caatinga (Brazilian Northeastern savanna biome), popularly known as "araticum" and "pinha da Caatinga". In this study, we investigated the effects of the crude ethanolic extract (Av-EtOH) in models of pain and inflammation in rodents. METHODS: The evaluation of antinociceptive activity was carried out by the acetic acid-induced writhing, formalin, hot plate and tail flick tests, while paw edema induced by carrageenan or histamine, and leukocyte migration to the peritoneal cavity were used for anti-inflammatory profile. Histological analyses also were carried out. RESULTS: Av-EtOH (25, 50 and 100 mg/kg, p.o) significantly reduced the number of writhing (P < 0.01) and decreased (P < 0.01) the paw licking time in both phases of the formalin test. In the hot plate and tail flick tests, this extract increased the reaction time, consequently reduced painful behavior. The effects in the formalin and hot plate tests were antagonized by naloxone. Av-EtOH inhibited significantly (P < 0.01) the increase in the edema volume after administration of carrageenan and histamine. In the peritonitis test, acute pre-treatment with Av-EtOH inhibited leukocyte migration. Histological analysis showed less inflammation in the groups treated with the extract when the inflammation was induced by carrageenan or histamine. CONCLUSION: Thus, Av-EtOH has significant antinociceptive and anti-inflammatory properties, which are related probably with the activation of opioid receptors and inhibition of release of mediators of the inflammatory process. This specie is a potential target for drug discovery.

Sodium bicarbonate treatment prevents gastric emptying delay caused by acute exercise in awake rats.

Physical exercise, mainly after vigorous activity, may induce gastrointestinal dysmotility whose mechanisms are still unknown. We hypothesized that physical exercise and ensuing lactate-related acidemia alter gastrointestinal motor behavior. In the present study, we evaluated the effects of short-term exercise on gastric emptying rate in awake rats subjected to 15-min swimming sessions against a load equivalent to 5% of their body weight. After 0, 10, or 20 min of exercise testing, the rats were gavage fed with 1.5 ml of a liquid test meal (0.5 mg/ml of phenol red in 5% glucose solution) and euthanized 10 min postprandially to measure fractional gastric dye recovery. In addition to inducing acidemia and increasing blood lactate levels, acute exercise increased (P < 0.05) gastric retention. Such a phenomenon presented a positive correlation (P < 0.001) between blood lactate levels and fractional gastric dye recovery. Gastric retention and other acidbase-related changes were all prevented by NaHCO3 pretreatment. Additionally, exercise enhanced (P < 0.05) the marker's progression through the small intestine. In anesthetized rats, exercise increased (P < 0.05) gastric volume, measured by a balloon catheter in a barostat system. Compared with sedentary control rats, acute exercise also inhibited (P < 0.05) the contractility of gastric fundus strips in vitro. In conclusion, acute exercise delayed the gastric emptying of a liquid test meal by interfering with the acid-base balance.