The year 2010 is not gone yet but we already know that this year will be associated with one of the biggest losses in pharmacology and toxicology. On Tuesday, April 13, 2010, at the age of 97, one of the most influential pharmacologists in Eastern Europe, Professor Helena Rašková has left us. Her wisdom, generosity, kindness and hard work made it possible to create a positive environment for research and education, although sometimes she had to fight hard. Her incredible story "How I became a Pharmacologist" wroted by Prof. Rašková herself documents how rich and inspirational her life was [Rašková H. (1997). Pharmacology & Toxicology 80: 255-261]. In this issue you will find mostly works of her colleagues and friends who would like to pay homage to the mother and grandmother of Czecho-Slovak pharmacology and toxicology and to the wonderful person who Prof. Helena Rašková was. She touched many people in her lifetime, affected many and will truly be missed.
Modern society is constantly increasing the volume of chemicals for everyday use, including drugs, additives, food stabilizers, cosmetics or ubiquitous by-products of the industry. More than 65,000 chemicals are in the U.S. Environmental Protection Agency's inventory of toxic chemicals and annually the Agency receives approximately 1,500 notices of intent to manufacture new substances. It is thus important to know what each of this compound can do to the living organism. Thanks to developmental toxicology, it has become evident that even small amounts of potentially toxic compounds introduced to the developing organism may be the cause of later morbidity. This phenomenon is known as developmental origins of health and diseases (DOHaD). It is therefore very important to understand the potential risks. Toxicology is interdisciplinary science utilizing methods and knowledge from a number of scientific fields like biology, pharmacology, biochemistry, pathophysiology, genetics, etc. Understanding the adverse effects of compounds in the environment may influence our everyday decisions and might shift the course of our life toward happiness.
One of the goals of the Slovak Toxicology Society SETOX, together with the Institute of Experimental Pharmacology & Toxicology SASc., Bratislava, is to impart scientific knowledge and experience to the public, and especially to the young generation. This group has definitely the greatest potential to materialize positive changes in our environment and to promote the protection of our planet. Every experience matters, every encounter, knowledge, situation or person might change our perspective. Thus to pass on knowledge and to educate the young generation is a matter of utmost importance.
Communication - Dialogue - Co-operation - Solving problems. These are the words of nowadays Europe. Such approaches should be used in broad spectrum of life as well as in toxicology. It is therefore admirable that EUROTOX commissars, mainly past-president Prof. Liesivuori, invited all heads of European toxicological societies to discuss current issues of toxicology in Europe during IUTOX meeting held in Barcelona in July 2010. Renowned scientists and regulatory officers from Government, Industry and Academia made appearance and talked about contribution of toxicological research to society, importance of communication and education. The strategic meeting was successful. Prof. Liesivuori expressed gratitude to all delegates for the great suggestions and key findings resulting from the brainstorming sessions conducted during the meeting. Majority of delegates agreed that education in toxicology and related fields is the top priority for future. Communication towards society, in the sense of explaining possible risks, should be an important concern as well. Taking a good example from EUROTOX, on the verge of summer the Slovak Toxicology Society SETOX organizes meeting of the toxicological societies from the Central Europe, i.e. Slovak, Czech, Polish, Austrian and Hungarian societies of toxicology. First positive step was done by Visegrad Fund and Federation of European Toxicologists & European Societies of Toxicology, which supported this meeting. It is essential for successful co-operation to establish strong connections, which can be further crucial for meaningful and highly profitable information to society.
Important issues in developmental toxicity testing
Studies of individual development and its possible deterioration have been the concern since the 19th century, when Etienne Geoffroy de Saint-Hilaire (1772-1844) with his pioneer experiments opened the door for future experimental teratologists. Later scientists, focused on environmental agents which can alter embryonic and fetal development, such hyperthermia, malnutrition, pharmaceuticals, microbial toxins etc. Although the history of teratology involves many notable scientists, it has gained prominence after the big thalidomide tragedy in 1961. Principles of teratology were proposed later by James Wilson in his monograph Environment and Birth Defects (Wilson, 1973).
Developmental origin of chronic diseases: toxicological implication
Human epidemiological and experimental animal studies show that suboptimal environments in fetal and neonatal life exerts a profound influence on physiological function and risk of disease in adult life. The molecular, cellular, metabolic, endocrine and physiological adaptations to intrauterine nutritional conditions result in permanent alterations of cellular proliferation and differentiation of tissues and organ systems, which in turn can manifest by pathological consequences or increased vulnerability to chronic diseases in adulthood. Intrauterine growth restriction (IUGR) due to intrauterine development derangements is considered the important factor in development of such diseases as essential hypertension, diabetes mellitus, ischemic diseases of the heart, osteoporosis, respiratory, neuropsychiatric and immune system diseases.
An early life exposures to dietary and environmental exposures can have a important effect on epigenetic code, resulting in diseases developed later in life. The concept of the "developmental programming" and Developmental Origins of Adult Diseases (DOHaD) has become well accepted because of the compelling animal studies that have precisely defined the outcomes of specific exposures. The environmental pollullutants and other chemical toxicants may influence crucial cellular functions during critical periods of fetal development and permanently alter the structure or function of specific organ systems. Developmental epigenetics is believed to establish "adaptive" phenotypes to meet the demands of the later-life environment. Resulting phenotypes that match predicted later-life demands will promote health, while a high degree of mismatch will impede adaptability to later-life challenges and elevate disease risk. The rapid introduction of synthetic chemicals, environmental pollutants and medical interventions, may result in conflict with the programmed adaptive changes made during early development, and explain the alarming increases in some diseases.
Anxiolytic activity of pyridoindole derivatives SMe1EC2 and SMe1M2: behavioral analysis using rat model
Anxiety and mood disorders have become very significant affections in the last decades. According to WHO at least one mental disease occurred per year in 27% of EU inhabitants (more than 82 mil. people). It is estimated that by 2020, depression will be the main cause of morbidity in the developed countries. These circumstances call for research for new prospective drugs with anxiolytic and antidepressive properties exhibiting no toxicity and withdrawal effect and possessing beneficial properties, like antioxidant and/or neuroprotective effects. The aim of this study was to obtain information about psychopharmacological properties of pyridoindole derivatives SMe1EC2 and SMe1M2, using non-invasive behavioral methods in rats.
The battery of ethological tests (open field, elevated plus-maze, light/dark box exploration, forced swim test) was used to obtain information about anxiolytic and antidepressant activity of the pyridoindole derivatives. The substances were administered intraperitoneally 30 minutes before the tests at doses of 1, 10 and 25 mg/kg.
In the behavioral tests, SMe1EC2 was found to exert anxiolytic activity in elevated plus maze with no affection of locomotor activity. The highest dose of SMe1M2 increased the time spent in the lit part of the Light/Dark box, however this result was influenced by inhibition of motor activity of the rats. Similar findings were observed also in elevated plus-maze, although these results were not statistically significant.
In conclusion, from the results of our study it is evident that both pyridoindoles acted on the CNS. In the highest dose, SMe1M2 was found to possess rather sedative than anxiolytic or antidepressant activity.
Experimental modeling of hypoxia in pregnancy and early postnatal life
The important role of equilibrium of environmental factors during the embryo-fetal period is undisputable. Women of reproductive age are increasingly exposed to various environmental risk factors such as hypoxia, prenatal viral infections, use of drugs, smoking, complications of birth or stressful life events. These early hazards represent an important risk for structural and/or functional maldevelopment of the fetus and neonates. Impairment of oxygen/energy supply during the pre- and perinatal period may affect neuronal functions and induce cell death. Thus when death of the newborn is not occurring following intrauterine hypoxia, various neurological deficits, including hyperactivity, learning disabilities, mental retardation, epilepsy, cerebral palsy, dystonia etc., may develop both in humans and in experimental animals. In our animal studies we used several approaches for modeling hypoxia in rats during pregnancy and shortly after delivery, i.e. chronic intrauterine hypoxia induced by the antiepileptic drug phenytoin, neonatal anoxia by decreased oxygen saturation in 2-day-old pups. Using these models we were able to test potential protective properties of natural (vitamin E, melatonin) and synthetic (stobadine) compounds. Based on our results, stobadine was also able to reduce hypoxia-induced hyperactivity and the antioxidant capacity of stobadine exceeded that of vitamin E and melatonin, and contrary to vitamin E, stobadine had no adverse effects on developing fetus and offspring.
Safety assessment of the pyridoindole derivative SMe1EC2: developmental neurotoxicity study in rats
The present study deals with effect of prenatal and neonatal administration of the synthetic pyridoindole derivative SMe1EC2 (2-ethoxycarbonyl-8-methoxy-2,3,4,4a, 5,9b-hexahydro-1H-pyrido-[4,3b] indolinium chloride) on postnatal and neurobehavioral development of the rat offspring. The substance tested was administered to pregnant rats orally in the doses 5, 50 and 250 mg/kg from day 15 of gestation to day 10 post partum (PP). From the day 4 PP, the postnatal development and neurobehavioral characteritics of offspring were evaluated. The following variables were observed: body weight, pinna detachment, incisor eruption, ear opening, eye opening, testes descent and vaginal opening, righting reflex, negative geotaxia, startle reflex, dynamic air righting and exploratory behavior in a new environment. No maternal death, abortion or dead fetuses occurred either in the control or SMe1EC2 groups. Dynamic righting reflex was delayed one day in the groups of animals treated via their mothers with 5 and 50 mg/kg SMe1EC2. The delay in the development of this reflex was only transient. On day 20 PP, all pups tested had a positive score of the reflex. Administration of SMe1EC2 did not reveal any significant changes in other variables of somatic growth and maturation, reflex and neuromotor development and exploratory behavior, either of young or adult animals of both genders, assessed by analysis of variance.
5-hydroxymethyl-2-furfural (5-HMF) is a thermal decomposition product of saccharides. There are two main ways for the formation of 5-HMF. First, 5-HMF is forming during Maillard reaction and second, during thermic dehydration of saccharides under acid conditions. Significant parameters of 5-HMF formation are temperature, time, pH, water activity, type of saccharide and amino acids. It is suspected that 5-HMF has genotoxic, mutagenic and carcinogenic potential. This chemical can be found in many food sources, e.g. honey, dried fruits, fruit juice and concentrates, alcoholic beverages, bakery products, roasted nuts and seeds, brown sugar, and milk. The present study aimed to determine the amount of 5-HMF in children's biscuits. The examined samples were divided into three groups. The first group of biscuits claimed availability for children older than six months, the second for children older than one year. The third group did not give a determined age range.
For the assessment of 5-HMF, a HPLC method with UV/VIS detection was used. In the first group of samples, the amount of 5-HMF ranged from 0.34±0.04 to 1.73±0.03 mg/kg, in the second group from 0.57±0.09 to 1.78±0.07 mg/kg, and in the third group the amounts of 5-HMF were from 1.80±0.05 to 34.99±0.22 mg/kg.
In conclusion, the results showed that the content of 5-HMF in biscuits without age group determination was significantly higher than in biscuits with declared availability for children older than six months or one year. Since the acceptable daily intake is 2 mg/kg bw, the established amount of 5-HMF in all samples cannot be regarded as dangerous in a normal dose of biscuits.
Early assessment of the severity of asphyxia in term newborns using parameters of blood count
Acute perinatal asphyxia is a major cause of death and neurological injury in newborn infants. Severe asphyxia can occur in infants around the time of birth for several reasons. The aim of our study was to find the most sensitive, easily obtainable and fast assessable parameter of the presence and quantification of asphyxia.
In our study 39 term newborns (15 healthy term newborns and 24 asphyxial term newborns), from vaginal deliveries admitted within 24 hours of life were monitored and parameters of blood count from venous blood were assessed. Laboratory findings of blood count parameters revealed significant differences between term asphyxial and healthy newborns in erythrocyte count and hemoglobin and hematocrit values.
Hematological changes observed early after delivery can determine the duration of hypoxemia (acute vs. chronic) and asphyxia of short duration may be accompanied without occurrence of polyglobulia.