TOXIC AND IMMUNOTOXIC EVALUATION OF KETAMINE AND/OR ETHANOL IN RATS DURING 28 DAYS

Objective: Studies have shown that ketamine (K) and ethanol (E) have immunomodulatory activity; however, few studies were performed with concomitant treatments. Thus, we evaluated the toxic and immunotoxic effects of this association.Methods: Wistar rats were distributed into four groups (n=8/group), each receiving one of the following treatments, for 28 d: K group (15 mg/kg of ketamine, intraperitoneally); E group [1.0 ml of ethanol 10% (approximately 0,08g/rat), gavage]; KE group, receiving both treatments; and Control (Co) group, receiving only vehicles. On day 29, animals were euthanized for biochemical, hematological, histopathological and immunological evaluation.Results: Although the experimental conditions did not elicit changes on immune parameters, some biochemical alterations were detected in the different groups. Even in the absence of nutritional and histopathological changes, or renal and hepatic markers that could indicate tissue damage, a reduction on alkaline phosphatase levels in rats from K and KE groups was observed. Moreover, changes in lipid markers [cholesterol, triglycerides and high-density lipoproteins (HDL)] were found in the different groups studied, suggesting that K and E could promote a synergic/antagonistic effect.Conclusion: In conclusion, despite biochemical alterations promoted by K and E, associated or not, the doses here employed did not promote immunotoxic effects on rats treated for 28 d. (response to the suggestion in the end of the paper).Â

Inflammatory, immunological and histopathological parameters of prolonged administration of Ipomoea carnea in rats: 1. Evaluation of adult animals 2. Perinatal study

O presente estudo visou avaliar efeitos da I. carnea e de seus princípios ativos sobre a imunidade natural de ratos e, os efeitos de sua administração durante a gestação ou lactação às mães e os possíveis efeitos imunotóxicos sobre os filhotes quando adultos. Nas o resíduo da planta (RAF) foi diluído na água de bebida nas doses-alvo de 3,0 e 15,0g/kg de folhas secas da planta, durante 14 e 21 dias e por via oral, por gavage, na dose de 15,0g/kg, durante 14 dias, para avaliação da atividade de macrófagos (MO) peritoneais e das inflamações crônica e aguda, induzidas pelo BCG e pela carragenina, respectivamente. Os princípios ativos (suainsonina e calisteginas B1, B2, B3 e C1) foram administrados isoladamente em ratas, nas mesmas concentrações presentes em 15,0g/kg do RAF, durante 14 dias, para então avaliar a atividade macrofágica. Em ratas prenhes ou lactantes empregaram-se as doses de 1,0; 3,0; 7,0 e 15,0g/kg do RAF, por gavage. Ainda no estudo perinatal, foram realizados o cross-fostering para observação da passagem transplacentária da suainsonina, a amniocentese e a coleta de leite para quantificação deste alcalóide. As proles foram avaliadas até os 70 dias de vida, para avaliação da atividade macrofágica e das inflamações crônica e aguda. Foram realizados ensaios de imunotoxicidade, (peso relativo de órgãos linfóides, resposta imune humoral e celular), em ratos jovens e adultos, tratados durante 14 dias. No final da experimentação foram coletados diferentes órgãos para o estudo histopatológico. Em relação à imunidade das ratas adultas houve aumento da fagocitose e da produção de peróxido de hidrogênio de MO, maior processo inflamatório crônico e supressão da resposta inflamatória aguda, apenas nas ratas tratadas com baixas doses do RAF. Dos alcalóides da I.carnea, apenas a suainsonina mostrou-se tóxica. Em relação às ninhadas de mães tratadas durante a gestação ou lactação, verificou-se menor peso ao nascimento e menor peso ao desmame, respectivamente. O emprego do cross-fostering evidenciou a passagem da suainsonina pela placenta, confirmada pela quantificação deste alcalóide no líquido amniótico. A suainsonina também foi quantificada no leite. Em relação à imunidade natural da prole de ratas tratadas durante a gestação ou lactação, não se observou alterações nos parâmetros avaliados, porém filhotes de ratas tratadas com a planta durante a lactação e desafiados com o BCG quando adultos, desenvolveram artrite. Nos ensaios imunotóxicos, ratos jovens apresentaram involução tímica, os adultos esplenomegalia e menor celularidade de medula óssea, e em todos os animais, aumento no título de anticorpos. Dos órgãos coletados, apenas o SNC não apresentou as degenerações vacuolares características da toxicose por I.carnea. Concluindo, baixas doses do RAF promovem aumento da atividade de MO. Dos alcalóides da planta, apenas a suainsonina mostrou-se tóxica. A suainsonina passa a barreira placentária, ocasionando ninhadas menores e com menor peso e, também é excretada no leite, ocasionando lesões degenerativas vacuolares, bem como alterações no desenvolvimento tímico, o que possivelmente resultou em autoimunidade quando do desafio imune na idade adulta. Finalmente, em ratos, mesmo em altas doses, não ocorre lesão vacuolar no SNC.The aim of this study was to evaluate the toxic effect of I. Carnea and its toxins on the immune system of rats, and to evaluate its effects on mothers and offspring when administered to dams during gestation or lactation. An alkaloid-rich plant extract (RAF) was added to drinking water to obtain doses equivalent to 3.0 and 15.0g/kg of dry leaves for 14 and 21 days, and a dose of 15.0 g/kg by gavage for 14 days. Macrophage activity (MO), and chronic and acute inflammation induced by BCG and carragenine, respectively, were evaluated. Each toxin in I. carnea (i.e., swainsonine and calystegines B1, B2, B3 and C1) was administered by gavage to female rats, in similar concentrations as contained in 15.0g/kg of RAF during 14 days to evaluate MO. The RAF was dosed by gavage in pregnant or nursing rats at 1.0, 3.0, 7.0 and 15.0g/kg. Cross-fostering was used to evaluate placental passage of swainsonine; swainsonine concentration was determined in amniotic fluid and in milk. On postpartum day 70 the litters were evaluated for MO and chronic and acute inflammation. Immunotoxic responses were evaluated in young and adult rats treated with RAF for 14 days. Tissue samples were then harvested for histopathology. The immune function of adult rats was enhanced by lower doses of the RAF. Phagocytosis and hydrogen peroxide production were improved, and there was enhancement of chronic immunity, but suppression of acute inflammatory responses. Among the I.carnea alkaloids, only swainsonine showed toxicity. The litters of dams treated with swainsonine during gestation or lactation showed a reduction in body weight at birth and after lactation, respectively. Swainsonine clearly passed through the placenta, and was found in amniotic fluid, and in milk. There were no effects on the immunity of litters from mothers treated during gestation or lactation. However, pups from mothers dosed with swainsonine during lactation had an increased occurrence of arthritis. Further, young rats showed thymus atrophy, whereas adults developed splenomegaly and reduced bone marrow cellularity. Finally, animals of all ages showed enhanced antibody titers. Only CNS tissue did not have the characteristic vacuolar degeneration typical of I. Carnea toxicosis. In conclusion, low doses of RAF enhanced MO activity. Among the I. Carnea alkaloids, only swainsonine showed toxicity. Swainsonine passed the placental barrier, resulting in smaller litters with diminished birth weights. Swainsonine was also excreted in milk, resulting in vacuolar lesions in pups, as well as thymus atrophy, which could cause autoimmunity in adulthood. Finally, even with higher doses, CNS tissue in rats is resistant to the toxic effects of swainsonine

Immunomodulatory effects of swainsonine from Ipomoea carnea in healthy mice

The objective of this study was to more clearly characterize the immunomodulatory effects of swainsonine and an Ipomoea carnea aqueous fraction using two different mouse strains: Swiss outbred mice and C57BL/6 inbred mice. The swainsonine is the main toxic principle found in the Ipomoea carnea a poisonous plant native from Brazil and other tropical countries. Many studies have shown that swainsonine promotes biological response modifications in different cell lines, such as increased murine splenic NK lymphocyte activity, improvement of peritoneal macrophage activity and macrophage cytotoxicity against tumor cells. In addition, it is suggested that swainsonine stimulates bone marrow cell proliferation in inbred mice. Therefore, we evaluated in this study the immunomodulatory effects of swainsonine and I. carnea aqueous fraction using for this analyses of macrophages activities and histology evaluation of lymphoid organ. Thereby, analyses of peritoneal macrophage activities showed decreased phagocytosis of aqueous fraction-treated Swiss mice and enhancement of both the spreading activity and PMA-induced H2O2 production of swainsonine-treated Swiss mice; however, no alterations in these parameters were observed in C57BL/6 mice. In addition, swainsonine and aqueous fraction treatment showed no differences for both Swiss and C57BL/6 mice in the thymus, spleen and bone marrow evaluations and histological analyses of liver and kidney. In conclusion, a clear difference in swainsonine immunostimulant effect was observed when considering mouse strain, while the use of swainsonine alone did not induce bone marrow cellularity in healthy mic

Calcinogenic effects of Solanum malacoxylon. Study in goats

Univ São Paulo, Coll Vet Med, Dept Pathol, Res Ctr Vet Toxicol CEPTOX, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Environm Chem & Pharmaceut Sci, São Paulo, BrazilUniversidade Federal de São Paulo, Inst Environm Chem & Pharmaceut Sci, São Paulo, BrazilWeb of Scienc

Immunomodulatory effects of Pteridium aquilinum on natural killer cell activity and select aspects of the cellular immune response of mice

Pteridium aquilinum (bracken fern) is one of the most common plants. Epidemiological studies have revealed a higher risk of certain types of cancers (i.e., esophageal, gastric) in people who consume bracken fern directly ( as crosiers or rhizomes) or indirectly through the consumption of milk from livestock that fed on the plant. In animals, evidence exists regarding the associations between chronic bracken fern intoxication, papilloma virus infection, and the development of carcinomas. While it is possible that some carcinogens in bracken fern could be responsible for these cancers in both humans and animals, it is equally plausible that the observed increases in cancers could be related to induction of an overall immunosuppression by the plant/its various constituents. Under the latter scenario, normal tumor surveillance responses against nascent (non-bracken-induced) cancers or responses against viral infections ( specifically those linked to induction of cancers) might be adversely impacted by continuous dietary exposure to this plant. Therefore, the overall objective of this study was to evaluate the immunomodulatory effects of bracken fern following daily ingestion of its extract by a murine host over a period of 14 ( or up to 30) days. In C57BL/6 mice administered ( by gavage) the extract, histological analyses revealed a significant reduction in splenic white pulp area. Among a variety of immune response parameters/functions assessed in these hosts and isolated cells, both delayed-type hypersensitivity (DTH) analysis and evaluation of IFN gamma. production by NK cells during T(H)1 priming were also reduced. Lastly, the innate response in these hosts-assessed by analysis of NK cell cytotoxic functionality-was also diminished. The results here clearly showed the immunosuppressive effects of P. aquilinum and that many of the functions that were modulated could contribute to the increased risk of cancer formation in exposed hosts.CAPESFAPESP[07/50313-4

Sodium Salicylate as Feed Additive in Broilers: Absence of Toxicopathological Findings

Antimicrobial growth promoters (AGPs) in animal production have been related to the increase in multidrug-resistant bacteria. The AGP ban in many countries has highlighted the growing need for alternatives for feed additives. Considering the non-antibiotic anti-inflammatory theory of AGPs, chicks received three different doses of sodium salicylate (SS) in feed (10, 30, 90 mg/kg), basal diet (BD) was used as a negative control, and zinc bacitracin (ZB) was used as a positive control. Chicks were individually housed to increase the accuracy of the dose of SS ingested. Performance parameters and footpad dermatitis were evaluated weekly, while haematology, serum biochemistry, histopathology, and tibial dyschondroplasia were determined on Days 21 and 42. A linear dose-dependent decrease in haemoglobin concentration was observed, but the values were within the normal reference range. Among all the other evaluated parameters, no relevant differences between treatments were observed; however, not even the AGP group performed better than the control group. It is possible that the conditions in which the birds were raised were not stressful enough to allow for anti-inflammatories to demonstrate their beneficial effects on performance. Studies should be conducted where the animals are exposed to commercial conditions, as the presence of natural stressors could allow a better evaluation of the efficacy of the anti-inflammatory agent as a growth promoter