Alejandra Minetti

Evaluation of gastroprotective activity and acute toxicity of Solidago chilensis Meyen (Asteraceae)

Context: Solidago chilensis Meyen (Asteraceae) is widely used in South America in traditional medicine as an anti-inflammatory and diuretic, and to treat gastrointestinal disorders. However, no scientific evidence exists in literature to corroborate the therapeutic use of the plant. Despite its traditional uses, no reports are available on the safety of this utilization or on the relationship between the pharmacological activities and its phytochemical compounds. Objective: This study investigates for the first time the acute toxicity and the gastroprotective effect of the aqueous extract from inflorescences of S. chilensis. Materials and methods: The gastroprotective activity was evaluated in mice subjected to ethanol-induced gastric ulcer model at 125, 250, 400, 800, 1200, and 2000 mg/kg doses. Acute toxicity study was performed at one dose of 2000 mg/kg. At the end of the exposure behavioral and functional parameters and motor activity were assessed in all animals. Results: Results demonstrated that the extract exhibited a significant antiulcer activity when given at 125-2000 mg/kg (P <0.05), but did not show acute toxicity in mice treated with 2000 mg/kg p.o. Discussion and conclusion: This study demonstrated that the oral administration of S. chilensis aqueous extract prevents the formation of gastric lesions caused by an aggressive factor as ethanol but does not produce toxicity by acute exposure in mice. These promising results support a better pharmacological study of S. chilensis as a potential antiulcerogenic species for studies targeted towards the development of antiulcerogenic agents.

Exposure to a glyphosate-based herbicide during pregnancy and lactation induces neurobehavioral alterations in rat offspring.

The impact of sub-lethal doses of herbicides on human health and the environment is a matter of controversy. Due to the fact that evidence particularly of the effects of glyphosate on the central nervous system of rat offspring by in utero exposure is scarce, the purpose of the present study was to assess the neurobehavioral effects of chronic exposure to a glyphosate-containing herbicide during pregnancy and lactation. To this end, pregnant Wistar rats were exposed through drinking water to 0.2% or 0.4% of a commercial formulation of glyphosate (corresponding to a concentration of 0.65 or 1.30g/L of glyphosate, respectively) during pregnancy and lactation and neurobehavioral alterations in offspring were analyzed. The postnatal day on which each pup acquired neonatal reflexes (righting, cliff aversion and negative geotaxis) and that on which eyes and auditory canals were fully opened were recorded for the assessment of sensorimotor development. Locomotor activity and anxiety levels were monitored via open field test and plus maze test, respectively, in 45- and 90-day-old offspring. Pups exposed to a glyphosate-based herbicide showed early onset of cliff aversion reflex and early auditory canal opening. A decrease in locomotor activity and in anxiety levels was also observed in the groups exposed to a glyphosate-containing herbicide. Findings from the present study reveal that early exposure to a glyphosate-based herbicide affects the central nervous system in rat offspring probably by altering mechanisms or neurotransmitter systems that regulate locomotor activity and anxiety.

Neurobehavioural effects of exposure to fluoride in the earliest stages of rat development.

It is known that exposure to high concentrations of Fluoride (F) produces deleterious health effects in human population. However, in the last years it has been concluded that low concentrations of F may have adverse health effects as well. Transplacental passage of F and its incorporation into foetal tissues has been demonstrated. Therefore, the purpose of the present work was to study the effects of the exposure to low levels of F during pregnancy and lactation on the central nervous system functionality. Wistar rats were exposed to low F concentrations (5 and 10 mg/l) during pregnancy and lactation. Sensorimotor reflexes in the each pup were analysed and the postnatal day on which both eyes and auditory canals were opened was recorded. Locomotor activity and anxiety were subsequently analysed in 45- and 90-day-old offspring by an open field test and plus maze test, respectively. A significant delay in the development of eye opening was observed in all offspring whose mothers had been exposed to the two F concentrations tested. Exposure to 5 and 10 mg/l F was also found to significantly decrease locomotor activity only in 90-day-old male and female offspring. A low index of anxiety in the young females and in all adult offspring exposed to the two F concentrations tested was also detected. Taken together, findings from the present study show that exposure to low F concentrations during pregnancy and lactation produces dysfunction in the central nervous system mechanisms which regulate motor and sensitive development, locomotor activity and anxiety

Enhanced Analgesic Properties and Reduced Ulcerogenic Effect of a Mononuclear Copper(II) Complex with Fenoprofen in Comparison to the Parent Drug: Promising Insights in the Treatment of Chronic Inflammatory Diseases

Analgesic and ulcerogenic properties have been studied for the copper(II) coordination complex of the nonsteroidal anti-inflammatory drug Fenoprofen and imidazole [Cu(fen)2(im)2] (Cu: copper(II) ion; fen: fenoprofenate anion from Fenoprofen, im: imidazole). A therapeutic dose of 28 mg/kg was tested for [Cu(fen)2(im)2] and 21 mg/kg was employed for Fenoprofen calcium, administered by oral gavage in female mice to compare the therapeutic properties of the new entity. The acetic acid induced writhing test was employed to study visceral pain. The percentage of inhibition in writhing and stretching was 78.9% and 46.2% for the [Cu(fen)2(im)2] and Fenoprofen calcium, respectively. This result indicates that the complex could be more effective in diminishing visceral pain. The formalin test was evaluated to study the impact of the drugs over nociceptive and inflammatory pain. The complex is a more potent analgesic on inflammatory pain than the parent drug. Ulcerogenic effects were evaluated using a model of gastric lesions induced by hypothermic-restraint stress. Fenoprofen calcium salt caused an ulcer index of about 79 mm2 while the one caused by [Cu(fen)2(im)2] was 22 mm2. The complex diminished the development of gastric mucosal ulcers in comparison to the uncomplexed drug. Possible mechanisms of action related to both therapeutic properties have been discussed.

Evaluation of the acute dermal exposure of the ethanolic and hexanic extracts from leaves of Schinus molle var. areira L. in rats

ETHNOPHARMACOLOGICAL RELEVANCE Schinus molle var. areira L. (Anacardiaceae) is employed in herbal medicine for many conditions, including respiratory, urinary and menstrual disorders, and as a digestive stimulant, diuretic, astringent and antidepressant. It is also known for its topical use as wound healer, antiseptic, for skin disorders and as repellent and insecticide. In the present work, the acute dermal exposure to ethanolic and hexanic extracts from leaves of Schinus molle var. areira was studied in rats. MATERIALS AND METHODS A single dose of 2000 mg/kg of body weight of ethanolic and hexanic extracts from leaves was applied on the shaved skin of male and female rats. After 24h of exposure, the patch was removed and any sign of irritation was recorded. Behavioral and functional parameters in a functional observational battery and motor activity in an open field were assessed after the exposure to the extracts. Then, after 14 days of observation, animals were retested. Finally, histopathological studies were conducted on several organs. RESULTS Slight signs of erythema and edema were observed in the skin site of exposure, but they disappeared after 48 h. The exposure to the hexanic extract produced an increase in parameters of activity, rearing and arousal assessed in the functional observational battery, which reversed after 14 days. On the other hand, the ethanolic extract caused an increase in locomotor activity, reflected in a higher number of rearings performed in the open field in the evaluation carried out on Day 14. No histopathological alterations were detected in the analyzed organs. CONCLUSIONS The results show that the acute dermal exposure of the ethanolic and hexanic extracts from leaves of Schinus molle var. areira only causes a slight and reversible skin irritation, and a mild stimulatory effect in rats. All these indicate that the topical use of these extracts would be safe.

Consequences of subchronic exposure to ethanolic extract from fruits and leaves of Schinus molle var. areira L. in mice

AIM OF THE STUDY Several extracts of Schinus molle var. areira L. plant proved to be useful for the treatment of different pathologies and for the control of insect pest. Due to these potential uses, it is necessary to study their safety. In this work, we evaluated the effects of subchronic exposure to ethanolic extracts from leaves and fruits of Schinus molle var. areira in mice. MATERIALS AND METHODS The plant extract was added to the diet at 1 g/kg body weight/day for 90 days. At the end of the exposure, behavioral and functional parameters in a functional observational battery and motor activity in an open field were assessed. Finally, several biochemical and histopathological studies were realized. RESULTS The exposure to extract from leaves produced an increase in the number of rearings in the open field and of urine pools in the functional observational battery. On the other hand, the exposure to extract from fruits produced an increase in the neutrophil count and a decrease in the lymphocyte count and in the total cholesterol levels. None of the exposures affected the different organs evaluated. CONCLUSIONS Our results suggest that subchronic exposure to ethanolic extracts from leaves and fruits of Schinus molle var. areira should be potentially useful in the treatment of lipid pathologies and safe to use.

Influence of chitosan coating on magnetic nanoparticles in endothelial cells and acute tissue biodistribution

Abstract Chitosan coating on magnetic nanoparticles (MNPs) was studied on biological systems as a first step toward the application in the biomedical field as drug-targeted nanosystems. Composition of MNPs consists of magnetite functionalized with oleic acid and coated with the biopolymer chitosan or glutaraldehyde-cross-linked chitosan. The influence of the biopolymeric coating has been evaluated by in vitro and in vivo assays on the effects of these MNPs on rat aortic endothelial cells (ECs) viability and on the random tissue distribution in mice. Results were correlated with the physicochemical properties of the nanoparticles. Nitric oxide (NO) production by ECs was determined, considering that endothelial NO represents one of the major markers of ECs function. Cell viability was studied by MTT assay. Different doses of the MNPs (1, 10 and 100 μg/mL) were assayed, revealing that MNPs coated with non-cross-linked chitosan for 6 and 24 h did not affect neither NO production nor cell viability. However, a significant decrease in cell viability was observed after 36 h treatment with the highest dose of this nanocarrier. It was also revealed that the presence and dose of glutaraldehyde in the MNPs structureimpact on the cytotoxicity. The study of the acute tissue distribution was performed acutely in mice after 24 h of an intraperitoneal injection of the MNPs and sub acutely, after 28 days of weekly administration. Both formulations greatly avoided the initial clearance by the reticuloendothelial system (RES) in liver. Biological properties found for N1 and N2 in the performed assays reveal that chitosan coating improves biocompatibility of MNPs turning these magnetic nanosystems as promising devices for targeted drug delivery.

Behavioral impairments following repeated intranasal glyphosate-based herbicide administration in mice

Inhalation or intranasal (IN) administration of neurotoxicants could constitute a route of toxin delivery to the brain. Pesticides have been proposed as the main environmental factor associated with the etiology of neurodegenerative disorders. In Argentina, the area used for glyphosate (Gly)-resistant crops are sprayed annually with ~200 million liters of Gly-based herbicides (Gly-BHs). Gly residues are often found in the environment, and considering the frequency and amount of its applications, it is probable that the inhalation of Gly-BHs occurs. The present study investigates the neurobehavioral effects of repeated IN administration of Gly-BH in male CF-1 mice (~2mg/nostrils/day) three days a week, during four weeks (50mg/kg/day). Locomotor activity and anxiety levels were studied by the Open Field (OF) test. Anxiety was also analyzed through the plus maze (PM) test. Novel Object Recognition (NOR) test was used for recognition memory analysis. Repeated IN Gly-BH administration in mice decreased the ambulatory activity. Moreover, Gly-BH treated mice showed a pronounced increase in thigmotaxis, compared to control group, indicating higher anxiety levels. The anxiogenic behavior in Gly-BH treated mice was then confirmed by PM test. The recognition memory was significantly impaired after 6h in the Gly-BH treated group. No differences were observed between both groups when the NOR test was performed 24h after. The present study reveals that repeated IN exposure to Gly-BH in mice affects the central nervous system probably altering neurotransmission pathways that participate or regulate locomotor activity, anxiety and memory.

Locomotor activity and sensory–motor developmental alterations in rat offspring exposed to arsenic prenatally and via lactation

Arsenic (As) is one of the most toxic naturally occurring contaminants in the environment. The major source of human exposure to inorganic As (iAs) is through contaminated drinking water. Although both genotoxicity and carcinogenicity derived from this metalloid have been thoroughly studied, the effects of iAs on the development and function of the central nervous system (CNS) have received less attention and only a few studies have focused on neurobehavioral effects. Thus, in order to characterize developmental and behavioral alterations induced by iAs exposure, pregnant Wistar rats were exposed to 0.05 and 0.10 mg/L iAs through drinking water during gestation and lactation. Sensory-motor reflexes in each pup were analyzed and the postnatal day when righting reflex, cliff aversion and negative geotaxis were recorded. Functional Observational Battery (FOB) and locomotor activity in an open field were assessed in 90-day-old offspring. Results show that rats exposed to low iAs concentrations through drinking water during early development evidence a delay in the development of sensory-motor reflexes. Both FOB procedure and open-field tests showed a decrease in locomotor activity in adult rats. This study reveals that exposure to the above-mentioned iAs concentrations produces dysfunction in the CNS mechanisms whose role is to regulate motor and sensory development and locomotor activity.

Alterations in the memory of rat offspring exposed to low levels of fluoride during gestation and lactation: Involvement of the α7 nicotinic receptor and oxidative stress

Daily exposure to fluoride (F) depends mainly on the intake of this element with drinking water. When administered during gestation and lactation, F has been associated with cognitive deficits in the offspring. However, the mechanisms underlying the neurotoxicity of F remain obscure. In the current study, we investigated the effects of oral exposure to low levels of F during the gestational and lactation periods, on the memory of adult female rat offspring. We also considered a possible underlying neurotoxic mechanism. Our results showed that this exposure reduced step-down latency in the inhibitory avoidance task, and decreased both mRNA expression of the α7 nicotinic receptor (nAChR) and catalase activity in hippocampus. Our data indicates that low F concentrations administrated during gestation and lactation decrease the memory of 90-day-old female offspring. This suggests that the mechanism might be connected with an α7 nAChR deficit in the hippocampus, induced by oxidative stress.