Neonatal action of the dipeptidyl peptidase iv inhibitor diprotin A leads to a hyperactive phenotype formation and a prolonged increase in aggressiveness in rats

Введение. Ингибиторы пролинспецифической сериновой протеазы дипептидилпептидазы IV (ДПП-IV, CD26, EC 3.4.14.5), способные модулировать широкий спектр физиологических процессов, находят применение в клинике. В наших работах получены свидетельства влияния ингибиторов ДПП-IV при их введении в раннем постнатальном периоде на эмоционально-мотивационное поведение взрослых крыс. Более сильные изменения в поведении отмечались у крыс при действии ингибитора ДПП-IV дипротина А. Однако не ясно, как долго сохраняются такие изменения. Цель работы - изучение отсроченных эффектов ингибитора ДПП-IV дипротина А на выраженность эмоционально-мотивационных расстройств, индуцированных действием ингибитора в раннем постнатальном периоде, в динамике взросления крыс от 2 до 7 мес. Методика. Дипротин А вводили крысятам ежедневно в 5-18-й постнатальные дни внутрибрюшинно (2 мг/кг), в объеме 0.1 мл на 10 г массы тела. Крысята контрольной группы получали инъекции физиологического раствора. Поведение взрослых крыс оценивали в возрасте 2 и 7 мес в тестах автоматизированного «открытого поля», «Приподнятый крестообразный лабиринт» (ПКЛ), принудительного плавания и социального взаимодействия. Уровень кортикостерона в сыворотке крови определяли методом твердофазного иммуноферментного анализа ELISA. Для статистической обработки результатов использовали двухфакторный дисперсионный анализ Two Way ANOVA и непараметрический U-критерий Манна-Уитни с поправкой на множественность сравнений. Результаты. У крыс опытной группы по сравнению с контрольной группой в возрасте 2 и 7 мес была повышена двигательная активность и скорость перемещения в тесте ПКЛ. В возрасте 7 мес у них также была увеличена вертикальная исследовательская активность. Признаков повышения тревожности не выявлено. У крыс опытной группы выявлены признаки депрессивно-подобного поведения по нарушению биоритмологической структуры плавания, более выраженные в возрасте 7 мес. Неагрессивное социальное взаимодействие у крыс, получавших неонатально дипротин А, было снижено по сравнению с контролем в возрасте 2 мес, а в возрасте 7 мес, напротив, увеличено. У этих животных число и длительность агрессивных социальных контактов были увеличены по сравнению с контролем как в возрасте 2, так и в возрасте 7 мес. Уровень кортикостерона в сыворотке крови у крыс опытной группы в возрасте 7.5 мес был выше, чем в контроле. Заключение. Данные настоящего исследования свидетельствуют о развитии гиперактивного фенотипа и длительных психоэмоциональных нарушений в виде повышенной агрессивности наряду с активацией гипоталамо-гипофизарно-адреналовой оси у взрослых крыс, подвергнутых действию дипротина А в 5-18-й постнатальные дни, и поддерживают представления об участии дипептидилпептидазы-IV в генезе психоэмоциональных расстройств. Background. Inhibitors of the proline-specific serine protease dipeptidyl peptidase IV (DPP-IV, CD26, EC 3.4.14.5) may modulate a wide range of physiological processes and are used in the clinic. In our studies, we obtained evidence for the impact of DPP-IV inhibitors on adult rats’ emotional and motivational behavior when administered in the early postnatal period. Diprotin A exhibited the most significant impact on the animals’ behaviors. However, it is not clear how long the changes persist. Aim. To study the delayed effects of the DPP-IV inhibitor diprotin A on the severity of emotional and motivational disorders induced by the inhibitor action in the early postnatal period, in the dynamics of rats maturation from 2 to 7 months. Methods. Diprotin A was administered to rat pups daily on postnatal days 5-18, intraperitoneally, at a dose of 2 mg/kg, in a volume of 0.1 ml per 10 g of body weight. The rat pups of the control group received saline. The behavior of adult rats was assessed at the age of 2 and 7 months in the automated “open field,” “Elevated Plus Maze” (EPM), forced swimming, and social interaction tests. Serum corticosterone levels were determined by ELISA. The results were statistically processed using Two Way ANOVA and nonparametric Mann-Whitney U-test adjusted for multiple comparisons. Results. Experimental rats increased motor activity and travel speed in the EPM test compared with the control group at 2 and 7 months of age. At the age of 7 months, experimental rats also increased vertical (rearing) activity. There were no signs of increased anxiety. Experimental rats demonstrated depression-like behavior judged by the biorhythmologic structure of swimming, more pronounced at 7 months. Non-aggressive social interaction in rats treated neonatally with diprotin A was reduced compared with controls at the age of 2 months and, on the contrary, increased at the age of 7 months. In these animals, the number and duration of aggressive social contacts were increased compared with controls at the ages of 2 and 7 months. Serum corticosterone levels in experimental rats at the age of 7.5 months were higher than in control. Conclusion. The present study results testify to the development of a hyperactive phenotype and prolonged psychoemotional disorders as increased aggressiveness along with hypothalamic-pituitary-adrenal axis activation in adult rats exposed to the action of diprotin A on postnatal days 5-18. The data support the dipeptidyl peptidase IV involvement in the genesis of psychoemotional disorders.

Maternal anxiety symptoms associated with increased behavioral synchrony in the early postnatal period

The presence of perinatal mood and anxiety disorders (PMAD) has typically been associated with decreases in the quality of mother-infant interactions. However, maternal anxiety symptoms during the postpartum period have been less studied than other mental health disorders like depression. In the current study we examined associations among symptoms of maternal anxiety, maternal perceived stress, and mother-infant behavioral synchrony in the early postnatal period. Eighty one mother-infant dyads participated in this study when the infants were 3 months old. Surveys were given to obtain demographic information and current maternal mental health symptoms, and dyads completed a 5-minute free play task to measure behavioral synchrony. Results indicated that maternal anxiety symptoms were positively associated with behavioral synchrony, but only for mothers reporting moderate levels of perceived stress. These findings highlight the differential impact of maternal postpartum mental health on behavioral synchrony and suggest that higher maternal anxiety symptoms during the postnatal period may play an adaptive role in fostering more dynamic parent-child interactions.

Formation of colostral immunity in calfs on the background of the application of immunostimulators to cows

A scientific and practical substantiation of the need for the timely formation of colostral immunity in calves to create nonspecific protection of the body and adaptation of newborns to new environmental conditions is given, which is the most important problem of modern veterinary science and practice. Colostral immunity is immunity that develops in newborns due to colostral immunoglobulins during the first 24-36 hours of life. For some newborn farm animals (horses, ruminants and pigs), antibodies are transmitted to offspring only through colostrum in the early postnatal period. In order to increase the nonspecific defenses of the body of mothers cows, the formation of colostral immunity in newborn calves and the realization of the biological resource potential of the body, immunostimulants were used, developed by scientists of the Chuvash State Agrarian University: Prevention-N-B-S and Salus-PE.

Anatomy and histology of the thymus of American mink genotypes Standard, Sapphire, Lavander in the early postnatal period of ontogenesis

Data are presented on the thymus structure of American Mink of the Standard, Sapphire, Lavender colouring genotypes in the early postnatal period from birth to 180 days. The thymus is known to be a fully formed organ at birth. The anatomical structure of the thymus and its topography are not determined by genotype. At 45 days of age, the changes are manifested by an increase in the thymic lobule area and the brain matter therein, a decrease in the cortex area; the most intense growth of the thymus due to the rise in the number of lobules is noted. The thymus of mink at 45 to 90 days of age is characterised by an equalisation between the genotypes, increasing cortical area values to about the level of newborn mink with a corresponding increase in the cortical-brain index. The thymus of minks at the age of 90 to 180 days retains the typical morphological structure. Still, the signs of age involutive processes are seen – reduction of the lobule area, enlargement of the medulla, changes in the form of the organ (lobule fusion), increased signs of fat transformation thymus. Hassall’s corpuscles were found in the medulla in all periods of investigation. The number of Hassall’s bodies and their morphology depends on the functional activity of the thymus. In newborns, unicellular, young and juvenile forms predominate. In 45-day-old minks, young and immature forms predominate. In 90-day-old female and male Standard burros, young and quite often unicellular bodies are visualised, while mature and juvenile records are less common. In mink of the coloured genotypes, immature and youthful Hassall’s corpuscles are predominant. By 180 days, the number of mature and young corpuscles with signs of central cell destruction with detritus accumulation and cavity formation increases.

Serum protein electrophoretic pattern in piglets during the early postnatal period

The pattern of serum proteins, the typical features of the electrophoretogram in newborn piglets and during their postnatal development is not completely described. Therefore, the aim of this study was to characterize the changes in serum protein electrophoretic pattern and features of the electrophoretograms during the early postnatal period. Significant changes during the monitored period were found in all evaluated parameters (P < 0.001). The most marked changes were observed mainly in the period before weaning. The concentrations of total proteins, albumin and γ-globulins were before colostrum intake low, γ-globulins represented the smallest proportion of protein fractions. The proportion of α1-globulins was after birth a dominant protein fraction. Significant increase of total proteins, α2-, β- and γ-globulins and decrease of α1-globulins was found 2 days after colostrum intake. The albumin and A/G values increased after birth gradually until weaning. After weaning a significant changes were found in absolute concentrations of total protein and albumin, and in relative values of β-globulin fractions. Presented results showed marked developmental alterations in the serum protein pattern in piglets along with the age. The study also brings new knowledge in the field of description of typical features of electrophoretograms in the observed period of piglet’s life.

MAPKs Are Highly Abundant but Do Not Contribute to α1-Adrenergic Contraction of Rat Saphenous Arteries in the Early Postnatal Period

Previously, the abundance of p42/44 and p38 MAPK proteins had been shown to be higher in arteries of 1- to 2-week-old compared to 2- to 3-month-old rats. However, the role of MAPKs in vascular tone regulation in early ontogenesis remains largely unexplored. We tested the hypothesis that the contribution of p42/44 and p38 MAPKs to the contraction of peripheral arteries is higher in the early postnatal period compared to adulthood. Saphenous arteries of 1- to 2-week-old and 2- to 3-month-old rats were studied using wire myography and western blotting. The α1-adrenoceptor agonist methoxamine did not increase the phosphorylation level of p38 MAPK in either 1- to 2-week-old or 2- to 3-month-old rats. Accordingly, inhibition of p38 MAPK did not affect arterial contraction to methoxamine in either age group. Methoxamine increased the phosphorylation level of p42/44 MAPKs in arteries of 2- to 3-month-old and of p44 MAPK in 1- to 2-week-old rats. Inhibition of p42/44 MAPKs reduced methoxamine-induced contractions in arteries of 2- to 3-month-old, but not 1- to 2-week-old rats. Thus, despite a high abundance in arterial tissue, p38 and p42/44 MAPKs do not regulate contraction of the saphenous artery in the early postnatal period. However, p42/44 MAPK activity contributes to arterial contractions in adult rats.

Urinary Tetrahydrocortisol/Tetrahydrocortisone Ratio at Early Postnatal Period Predict Steroid Dependency and Neonatal Condition in Preterm Infant

Insufficient adrenal function in preterm infants affects poor neonatal outcome, owing to the immaturity of their adrenal enzyme. While 11β-hydroxysteroid dehydrogenase (11βHSD) type 1 and type2 act as gatekeepers for cell steroid action. This study aimed to investigate the effects of early postnatal urinary tetrahydrocortisol/tetrahydrocortisone (F/E) ratio, used as an alternative indicator of 11βHSDs activity, in preterm infants on their subsequent clinical course. In 80 preterm infants of ≤ 34 weeks gestational age admitted to our hospital, urinary F/E ratio was measured within 24 hours of birth. Furthermore, the relationship between this ratio and neonatal outcomes was estimated. Univariate analysis revealed that the high F/E ratio group had significantly higher morbidity in terms of duration of ventilatory support for more than 14 days, hypotension requiring inotropes and hydrocortisone, and symptomatic patent ductus arteriosus. On multivariate analysis, the incidence of hypotension requiring hydrocortisone was higher in the high F/E group, despite the absence of elevated dehydroepiandrosterone, a precursor of cortisol.Conclusion: The urinary F/E ratio in the early postnatal period in preterm infants may contribute to the understanding of the pathogenesis of infant condition after birth by estimating the amount of local steroid action in the organs.