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In experiments on 3-day-old rats to identify the possible involvement of adrenoreceptors (AR) in the development of pathologic heart rhythm with high-amplitude (> 0.5 s) bradycardic complexes (PHRBC) occurring in newborn rats after NiCl2 administration, a comparative analysis of changes in heart rate variability (HRV), heart rate, and respiration after injection of nickel chloride and a high dose of the β-AR agonist isoproterenol was carried out. Injection of NiCl2, which blocks T-type voltage-dependent Ca2+ channels (T-VDCC), causes in 100% of rats the occurrence of PHRBC accompanied by a decrease in the role of neural influences and an increase in the role of neurohumoral factors in the mechanisms of heart rate regulation. Activation of β-AR causes shifts of physiological parameters qualitatively and quantitatively similar to those observed after NiCl2 poisoning in rats, but PHRBC does not occur. Pharmacological analysis with premedication of rats with β-AR antagonists (propranolol, atenolol) or α-AR antagonists (phentolamine) followed by NiCl2 administration showed that β-AR blockade with the nonselective adrenolytic propranolol prevents the development of PSRBC in half of the rats. In animals with pathologic arrhythmia occurring after NiCl2 injection, a rapid increase in the load on the sympathoadrenal system is noted, and the initial (background) instability of the mechanisms of heart rhythm regulation is revealed. Blockade of α- and β1-AR does not prevent the development of PHRBC during subsequent NiCl2 administration, which suggests the participation of β2-AR in the development of arrhythmia. Administration of the selective β2-AR agonist clenbuterol to rats leads to a decrease in HRV, including neurohumoral regulation and the appearance of low-amplitude (< 0.1 s) bradycardic complexes (BC) in 22% of rats. The results obtained by us together with the analysis of the literature suggest that β-AR plays an important role in the complex changes in the balance of regulatory influences in the occurrence of PHRBCs. Activation of β1-AR contributes to increased release of catecholamines by adrenal chromaffin cells, increased role of neurohumoral component of heart rhythm regulation and causes activation of β2-AR. Blockade of β2-AR, on the contrary, reduces the release of catecholamines and prevents the development of pathological arrhythmia. The second necessary factor leading to the development of arrhythmias with high-amplitude BCs is blockade of T-type calcium channels. [ABSTRACT FROM AUTHOR]

A comparative analysis of heart rate variability (HRV) indices after injection of the acetylcholinesterase inhibitor (AChE) physostigmine (3/4 LD50) and the T-type calcium channel blocker (T-VDCC) Ni2+ (ED100) into animals was performed in experiments on 3-day-old newborn rats. Both drugs cause phenomenologically similar pathological heart rhythm with significant bradycardia complexes (PHRBC). Analysis of HRV indices showed that the disturbance of heart rhythm regulation mechanisms in NiCl2 poisoning of rats and in cholinoreactive structure activation caused by AChE inhibition develop according to a similar pattern. In both cases there is a decrease in the total power of the spectrum and the absolute power values of the LF (predominantly sympathetic) and HF (parasympathetic influences) bands. Significant decrease in the level of nerve influences leads to the fact that the dominant role in the regulation of heart rhythm begins to play neurohumoral factors (VLF-band). It was found that under conditions of premedication with N- or M-cholinolytics, when rats do not develop cardiac rhythm disturbances, the initial decrease in the severity of neurohumoral and subsequent increase in sympathetic and, to a lesser extent, parasympathetic influences is common. In this case, vagosympathetic balance is not decisive. In case the influence of neurohumoral factors increases after premedication, then later there is a decrease in the proportion of nerve influences and the occurrence of PHRBC. The obtained data suggest that in newborn rats both direct blockade of T-VDCC and changes in ICaT current mediated through M3-subtype muscarinic cholinoreceptors lead to disruption of pacing and development of PHRBC. [ABSTRACT FROM AUTHOR]

Medicinal plants received special attention due to their biological and medicinal activities, aspects of safety in their use, and low cost. This study aimed to prove gum Arabic (GA) extract’s preventive and therapeutic role against furosemide toxicity. Moreover, histological findings, renal functions, and the level of MDA and GSH in the serum and kidney tissues of newborn rats were assessed. Thirty pregnant rats were divided into six groups (n = 5 per group). The first group is the control group, with no treatment. The second is the GA group, administered 15% w/v GA in drinking water daily from conception day 0 until the end of pregnancy. The third group is the furosemide group; furosemide (20 mg/k, ip) was taken daily from conception day 0 until the end of pregnancy. The fourth group is the protective group (preventive group); GA was taken daily (15% w/v in drinking water) from conception day 0 to day 10, followed by furosemide (20 mg/kg, ip) daily until the end of pregnancy. The fifth group is the therapeutic group; furosemide (20 mg/kg, ip) was taken daily from conception day 0 to day 10, followed by GA (15% w/v in drinking water) daily until the end of pregnancy. The sixth group is the mixed group; GA and furosemide were administered together from conception day 0 until the end of pregnancy. [ABSTRACT FROM AUTHOR]

Abstract The objective of this study was to examine whether ultrasound can examine the development of cerebral vascular structure and cerebral blood flow in Sprague–Dawley (SD) rats by ultrasound in a noninvasive manner, which provides a reference for ultrasound research of SD rats. Thirty‐nine SD rats (7–16 days old) were divided into seven groups according to age, and the number of SD rats in each group was, respectively, 7, 17, 1, 3, 2, 8, and 1. Ultrasound was used to detect cerebral blood vessels, cerebrovascular flow velocity, and heart rate in SD rats in the sagittal and coronal positions, and images were obtained in B‐mode ultrasound. The cerebral vascular structure of 39 SD rats (7–16 days) was dynamically observed under B‐ultrasound. We found that the cerebral vascular structure of the rats aged 7–10 days was clear and detectable. Rats aged 11–16 days of cerebral vascular structures became thinner and undetectable. Quantitative analysis of cerebrovascular flow rate and heart rate in rats found that there was no significant difference in cerebrovascular blood flow rate and heart rate between 7 and 8 days. Ultrasound can also be used in rat animal studies, that is, the cerebral blood flow in rats of different ages can be monitored in real‐time by ultrasound in a noninvasive way.

Early life nutrition fundamentally influences neonatal development and health. Human milk oligosaccharides (HMO) are key components of breast milk but not standard infant formula that support the establishment of the newborn gut microbiota. Using an artificial rearing system, our objective was to test the effect of two HMO on the whole body and organ growth, adiposity, glucose tolerance and faecal microbiota in young rat pups. From postnatal days 4 to 21, Sprague–Dawley rats were randomised to receive one of: (1) CTR (rat milk substitute); (2) 2′FL (CTR + 1·2 g/l 2′-fucosyllactose); (3) 3′SL (CTR + 1·2 g/l 3′-sialyllactose) and (4) 2′FL + 3′SL (CTR + 0·6 g/l 2′-FL + 0·6 g/l 3′-SL). Body weight (BW), bowel movements and food intake were monitored daily, faecal samples collected each week and oral glucose tolerance, body composition and organ weight measured at weaning. No significant differences were observed between groups in growth performance, body composition, organ weight and abundance of dominant faecal microbes. A decreased relative abundance of genus Proteus in week 1 faecal samples and Terrisporobacter in week 3 faecal samples (P < 0·05) was suggestive of a potential pathogen inhibitory effect of 3′SL. Longitudinal changes in the faecal microbiota of artificially reared suckling rats were primarily governed by age (P = 0·001) and not affected by the presence of 2′-FL and/or 3′-SL in rat milk substitutes (P = 0·479). Considering the known protective effects of HMO, further investigation of supplementation with these and other HMO in models of premature birth, extremely low BW or malnutrition may show more pronounced outcomes. [ABSTRACT FROM AUTHOR]

Behavioral changes in newborn 3-day-old rats (n=44) with modeled hypoxic-ischemic brain injury (HIBI) were observed, and the expression of CDK8 in brain tissues was detected to clarify the significance of CDK8. In 30 min, 3 h, and 3 days after HIBI, the left (ischemic) hemisphere was taken for examination. In 3 days after HIBI, the rat pups were examined in the behavioral tests. In rat pups with HIBI, changes of CDK8 expression were detected by Western blotting and real-time PCR and changes in the righting reflex and forelimb grip strength test (p<0.05) were revealed in comparison with sham-operated animals. The expression of CDK8 increased 30 min after HIBI and decreased in 3 h and 3 days. Hypoxia and ischemia of the left brain may affect locomotion, but not sensation. Since CDK8 is involved in the immune response after cerebral hypoxia and ischemia, this kinase can be used as an early diagnostic index. [ABSTRACT FROM AUTHOR]

The effect of Ni2+, a T-type low-threshold calcium channel (T-VDCC) and Na+/Ca2+ exchanger (NCX) blocker, on cardiac and respiratory rhythm parameters was studied in newborn rats aged 3–16 days (P3–16). A distinct age dependence of the intensity of the arrhythmogenic effect evoked by calcium channel blockade was found. In 3-day-old rats injected with NiCl2 at a dose of 109 mg/kg (ED100), a transient atypical heart rhythm, representing the alternating periods of moderate bradycardia with a pathologically slow (up to 20–60 bpm) heart rhythm, occurs in 100% of animals. In parallel, a pronounced respiratory system dysfunction with burst breathing develops. This symptom complex occurs in 75% of 10–14-day-old rats and is completely absent in 15–16-day-old animals. Phenomenologically similar heart rhythm disorders are observed in newborn rats after NiCl2 injection, during poisoning with acetylcholinesterase inhibitors, and upon activation of the central N-cholinergic structures. The obtained data suggest that in the early period of rat postnatal ontogenesis, impaired mechanisms of calcium metabolism may play a certain role in the development of arrhythmogenic disorders. [ABSTRACT FROM AUTHOR]

Disease of the digestive system occupies one of the first places in the structure of morbidity and mortality in the population of Ukraine and EU countries. The alimentary factor (diet with an excess or deficiency of nutrients) is of leading importance Among the factors that cause liver damage in the mother-fetus system. The purpose of this study was to establish the effect of excess or insufficient content of nutrients in the mother's diet on the structural and functional state of the liver of newborn rats. Materials and Methods. To achieve this goal, 20 female rats of the WAG population were used; they were divided into 3 groups: group 1 (control) - rats were in standard vivarium conditions and received a basic diet; animals of the 2nd group received a diet with excess nutrients; rats of the 3rd group received a nutrient deficient diet. The offspring of rats were hatched from experiment through decapitation straightaway after birth. Was a complex of morphological and biochemical studies of liver tissue was carried out. Results. When analysing micro preparations of liver tissue, a similarity in the nature of the induced changes in the organ rats of the 2nd and 3rd groups in the form of moderately pronounced discomplexation of beamed-radiary structure and expansion sinusoids were revealed. The difference was that in rats of the 2nd group, mainly around the zone of portal tracts, small extramedullary hematopoiesis foci; and in rats of the 3rd group, multiple small extramedullary hematopoiesis foci that indicated more pronounced hypoxia were determined. Thus, it can be noted that the greatest damage to the fetus liver was caused by nutritional deficiency in the mother's diet. When studying the fractional composition of lipids in liver homogenates of newborn rats, the following dynamics of changes was discovered: in animals of the 2nd group - an increase of cholesterol and triglycerides levels, with a decrease of PL level, and in rats of the 3rd group, a decrease in almost all fractions of lipids cholesterol, triglycerides, and NEF A (non-esterified fatty acid). The obtained data suggested that, most likely, such dynamics of changes in lipid metabolism parameters is associated with the inclusion of epigenetic programming mechanisms in the mother-fetus complex. Conclusions. Therefore, based on conducted research, we can do conclusion about the negative impact of the alimentary factor (nutrient deficiency) on the structural and functional state of the liver of newborn offspring of rats. [ABSTRACT FROM AUTHOR]

Background: Mitochondrial $\beta $ -oxidation of fatty acids is the primary energy source for the heart and carried out by Hydroxy Acyl-CoA Dehydrogenase (HADH) encoded trifunctional protein. Mutations in the genes encoding mitochondrial proteins result in functionally defective protein complexes that contribute to energy deficiencies, excessive reactive oxygen species (ROS) production, and accumulation of damaged mitochondria. We hypothesize that a dramatic alternation in redox state and associated mitochondrial dysfunction is the underlying cause of Fatty Acid Oxidation (FAO) deficiency mutant, resulting in heart failure. Mitochondrial co-enzymes, NADH and FAD, are autofluorescent metabolic indices of cells when imaged, yield a quantitative assessment of the cells’ redox status and, in turn, that of the tissue and organ. Method: We utilized an optical cryo-imager to quantitively evaluate the three-dimensional distribution of mitochondrial redox state in newborn rats’ hearts and kidneys. Redox ratio (RR) assessment shows that mitochondrial dysfunction is extreme and could contribute to severe heart problems and eventual heart failure in the mutants. Results: Three-dimensional redox ratio (NADH/FAD) rendering, and the volumetric mean value calculations confirmed significantly decreased cardiac RR in mutants by 31.90% and 12.32%, in renal mitochondrial RR compared to wild-type control. Further, histological assessment of newborn heart myocardial tissue indicated no significant difference in myocardial tissue architecture in both control and severe (HADHAe4−/−) conditions. Conclusion: These results demonstrate that optical imaging can accurately estimate the redox state changes in newborn rat organs. It is also apparent that the FAO mutant’s heart tissue with a low redox ratio is probably more vulnerable to cumulative damages than kidneys and fails prematurely, contributing to sudden death.

Anesthetic-induced toxicity in early life may lead to risk of cognitive decline at later ages. Notably, multiple exposures to isoflurane (ISO) cause acute apoptotic cell death in the developing brain and long-term cognitive dysfunction. This study is the first to investigate whether levosimendan (LVS), known for its protective myocardial properties, can prevent anesthesia-induced apoptotic response in brain cells and learning and memory impairment. Postnatal day (P)7 Wistar albino pups were randomly assigned to groups consisting of an equal number of males and females in this laboratory investigation. We treated rats with LVS (0.8 mg/kg/day) intranasally 30 min before each ISO exposure (1.5%, 3 h) at P7+9+11. We selected DMSO as the drug vehicle. Also, the control group at P7+9+11 received 50% O2 for 3 h instead of ISO. Neuroprotective activity of LVS against ISO-induced cognitive dysfunction was evaluated by Morris water maze. Expression of apoptotic-related proteins was detected in the whole brain using western blot. LVS pretreatment significantly prevented anesthesia-induced deficit in spatial learning (at P28-32) and memory (at P33, P60, and P90). No sex-dependent difference occurred on any day of the training and probe trial. Intranasal LVS was also found to significantly prevent the ISO-induced apoptosis by reducing Bax and cleaved caspase-3, and by increasing Bcl-2 and Bcl-xL. Our findings support pretreatment with intranasal LVS application as a simple strategy in daily clinical practice in pediatric anesthesia to protect infants and children from the risk of general anesthesia-induced cell death and cognitive declines. [ABSTRACT FROM AUTHOR]

Background: Accumulating evidence suggests a connection between the gut microbiota and neonatal diseases. Hypoxia may play an important role in the intestinal lesions in neonates.Objective: This study aims to determine whether the gut microbiota differs between intrauterine hypoxic rats and healthy controls and to identify the factors that influence the changes in the gut microbiota.Methods: We constructed an intrauterine hypoxia model in rats and collected the intestinal contents of intrauterine hypoxic newborn rats and normal newborn rats within 4 h and on the seventh day after birth. They were divided them into the intrauterine hypoxia first-day group (INH1), intrauterine hypoxia seventh-day group (INH7), normal first-day group (NOR1), and normal seventh-day group (NOR7). The contents of the intestines were sequenced with 16S rRNA sequencing, the sequencing results were analyzed for biological information, and the differences in the diversity, richness, and individual taxa among the groups were analyzed.Results: The abundance of the gut microbiota of neonatal rats with intrauterine hypoxia was higher than that of the control group rats. Intrauterine hypoxia altered the structural composition of the gut microbiota in neonatal rats. The INH1 group showed increased species richness, phylogenetic diversity, and β-diversity, and altered relative abundance in several taxa compared to those in the control group. The differences in the microbiota among the four groups were significantly higher than those within the group, and the differences in the abundance and diversity of the INH7 and NOR7 groups decreased after 7 days of suckling. Functional analysis based on the Cluster of Orthologous Groups (COG) suggested that 23 functional COG categories. There was no significant difference in the functional categories between the hypoxia group and the normal group.Conclusion: Intrauterine hypoxia changed the initial colonization of the gut microbiota in neonatal rats. It could increase the species richness and β-diversity of the gut microbiota, and altered relative abundances of several taxa.

This study investigates the effect of the overexpression of the placental growth factor (PGF) and hyperoxia on lung development and determines whether anti-PGF antibody ameliorates hyperoxia-mediated impairment of lung development in newborn rats. After exposure to normoxic conditions for seven days, newborn rats subjected to normoxia were intraperitoneally or intratracheally injected with physiological saline, adenovirus-negative control (Ad-NC), or adenovirus-PGF (Ad-PGF) to create the Normoxia, Normoxia+Ad-NC, and Normoxia+Ad-PGF groups, respectively. Newborn rats subjected to hyperoxia were intraperitoneally injected with physiological saline or anti-PGF antibodies to create the Hyperoxia and Hyperoxia+anti-PGF groups, respectively. Our results revealed significant augmentation in the levels of PGF and its receptor Flt-1 in the lung tissues of newborn rats belonging to the Normoxia+Ad-PGF or Hyperoxia groups. PGF overexpression in these groups caused lung injury in newborn rats, while anti-PGF antibody treatment significantly cured the hyperoxia-induced lung injury. Moreover, PGF overexpression significantly increased TNF-α and Il-6 levels in the bronchoalveolar lavage (BAL) fluid of the Normoxia+Ad-PGF and Hyperoxia groups. However, their levels were significantly reduced in the BAL fluid of the Hyperoxia+anti-PGF group. Immunohistochemical analysis revealed that PGF overexpression and hyperoxia treatment significantly increased the expression of the angiogenesis marker, CD34. However, its expression was significantly decreased upon administration of anti-PGF antibodies (compared to the control group under hyperoxia). In conclusion, PGF overexpression impairs lung development in newborn rats while its inhibition using an anti-PGF antibody ameliorates the same. These results provided new insights for the clinical management of bronchopulmonary dysplasia in premature infants.

Autofluorescence of the bone extracellular matrix (ECM) has not been widely explored although the ECM plays a very important role in bone development. In our research we focused on examining the bone matrix of very young animals due to the intense growth process during the first month of life. Structure images and fluorescence spectra of the bone surface were carried out using confocal fluorescence microscope Eclipse Ti-S inverted CLSM (NIKON, Japan) for compact tibia of healthy 7-, 14- and 28-day-old rat newborns after prenatal zidovudine administration in comparison with control. Spectral features of ECM autofluorescence were analyzed statistically by taking into consideration p < 0.05. The CLSM technique allows for simultaneous examination of the structure and autofluorescence from selected areas of the bone surface. Excessive autofluorescence of ECM after prenatal zidovudine administration influences bone growth incommensurably to the newborns' age. Therefore the possibility of an additional non-enzymatic mechanism of collagen cross-linking in the first two weeks of life of newborn rats prenatally treated with zidovudine has been considered. Our results suggest that ECM autofluorescence can be an indicator of bone development in the normal and pathological state. [ABSTRACT FROM AUTHOR]

Highlights • We review the respiratory effects of progesterone in newborns rats. • Progesterone acts through nuclear and membrane receptors. • New data show that progesterone receptors have age- and sex-specific effects. • These data might help design new therapeutic approaches for apnea of prematurity. Abstract The steroid hormone progesterone is well-known for its role in neuroprotection, in the pre- and postnatal brain development, and is also recognized as a potent respiratory stimulant that reduces the frequency of sleep apnea in adult female subjects. Over the past few years, we have used newborn rats or mice to provide convincing evidence that the respiratory effect of progesterone involves a balance between excitation mediated by progesterone receptors, and an inhibition due to the fast conversion of progesterone to allopregnanolone, a positive allosteric modulator of GABA A receptors. This review focuses on the sex- and age- specific roles of nuclear and membrane progesterone receptors (nPR or mPR), and highlight the clinical potential of these receptors for the treatment of apnea of prematurity. We present original data showing that in newborn rats, selective nPR or mPR agonists are more efficient to reduce apnea frequency at postnatal days 12 than at postnatal day 1, and appear more efficient in males than in females. Furthermore, new results obtained by using intra-cisternal injection of specific siRNA targeting mPRα, mPRβ (two mPR with high brain expression) or nPR suggest that mPRβ regulates the stability of the breathing pattern in males, while effects of nPR appear in females. While several important questions remain to be addressed before a safe clinical use could be proposed, these results highlight the potential role of these drugs as complementary, and sex-specific tools for the treatment of apnea in preterm neonates. [ABSTRACT FROM AUTHOR]

To evaluate the risk of residual cellular DNA in vaccines manufactured in tumorigenic cell lines, we have been establishing in vivo assays to quantify the oncogenic activity of DNA. We had generated three oncogene-expression plasmids: pMSV-T24-H- ras , which expresses activated H- ras ; pMSV-c- myc, which expresses c- myc ; and pMSV-T24-H- ras /MSV-c- myc , which expresses both oncogenes. Tumors were induced in mice by pMSV-T24-H- ras plus pMSV-c- myc or by pMSV-T24-H- ras /MSV-c- myc. Because newborn hamsters and newborn rats have been recommended for oncogenicity testing of the DNA from tumorigenic mammalian cell-substrates used for vaccine production, we evaluated their sensitivity. Newborn hamsters and rats were inoculated with different doses of pMSV-T24-H- ras /MSV-c- myc to determine their sensitivity to tumor induction and with the single-oncogene-expression plasmids to determine whether single oncogenes could induce tumors. Newborn rats were more sensitive than newborn hamsters, and activated H- ras but not c- myc induced tumors in newborns of both rodent species. DNA from four cell lines established from tumors induced by pMSV-T24-H- ras /MSV-c- myc was inoculated into newborn rats. Because no tumors were induced by this cellular DNA, which should be optimal as it contains both oncogenes linked and present in several copies, we conclude that available in vivo models are not sensitive enough to detect the oncogenicity of cellular DNA. [ABSTRACT FROM AUTHOR]

Objective: To assessment the effect of camel milk on ethanol induced hepatotoxicity in newborn rats. Material and Methods: The study was conducted on 5 groups of 6 rats each, including healthy group (0.5ml normal saline (NS),gavage),ethanol group (3g/kg/day ethanol by gavage),camel milk group (1mL/kg/day/orally camel milk),ethanol(3g/kg/day/orally) plus camel milk (1mL/kg/day/orally)group, 1mL/kg/day/orally camel milk for fifteen days before gestation (as a prophylactic) and then given ethanol(3g/kg/day/orally) group. The duration of treatment lasted from conception to birth. Results: According to our findings in this study, the treatment of rats with ethanol during pregnancy leads to a significant increase in the level of MDA and to a significant decrease in the activity of SOD, CAT and GSH-PX enzymes in liver tissues of newborn rats, and histological changes in the liver tissue. In addition to a significant increase in the activity of serum liver enzymes compared to the control group. Conclusion: We conclude from this study that camel milk has a protective and prophylactic effects against ethanol induced hepatotoxicity in newborn rats. [ABSTRACT FROM AUTHOR]

New Findings: What is the central question of this study? What are the contributions of allopregnanolone, the neuroactive metabolite of progesterone, and nuclear (nPR) and membrane (mPR) progesterone receptors to the respiratory effect of progesterone in newborn rats? What is the main finding and its importance? Acute progesterone injection increases the apnoea frequency, whereas finasteride (which blocks the conversion of progesterone to allopregnanolone) reduces apnoea frequency. An nPR agonist decreases apnoea frequency in males and an mPR agonist decreases apnoea frequency in males and females. Chronic injection of progesterone decreases the frequency of apnoea more efficiently in males than in females. We tested the hypothesis that the effects of progesterone on apnoea frequency in newborn rats are the result of a balance between its neuroactive metabolite, allopregnanolone (GABAA receptor modulator), and progesterone receptors. We used male and female rats between 10 and 12 days of age and recorded respiratory and metabolic parameters (whole‐body plethysmography), and assessed the frequency and duration of apnoeas in normoxia. We tested the effects of a single injection of progesterone (4 mg kg−1, i. p.), finasteride (10 mg kg−1, i. p.; a 5α‐reductase antagonist, which blocks the conversion of progesterone to allopregnanolone), finasteride plus progesterone, or agonists of the nuclear or membrane progesterone receptors (R5020 or Org‐od‐02‐0, 4 mg kg−1). To test the hypothesis that chronic exposure to progesterone reduces the frequency of apnoeas, we used male and female rats treated daily with progesterone between postnatal days 3 and 12. The acute injection of progesterone reduced minute ventilation and metabolic rate and increased the frequency of apnoeas. Finasteride decreased the frequency of apnoeas, and finasteride plus progesterone did not increase apnoea frequency but decreased minute ventilation in female rats. Although R5020 decreased apnoea frequency only in males, Org‐od‐02‐0 decreased apnoea frequency in males and females and decreased respiratory frequency in females. Chronic progesterone treatment reduced apnoea frequency more efficiently in males than in females, but in females (not in males) an acute injection of caffeine (the gold standard for the treatment of apnoea in preterm neonates) further reduced apnoea frequency. Apnoea frequency in newborn rats is, in part, determined by a sex‐specific balance between allopregnanolone, GABAA receptors and progesterone receptors. [ABSTRACT FROM AUTHOR]

Features of microelement maintenance (iron, zinc, copper, manganese, and cobalt), conditionally toxic chrome and toxic lead were studied in newborn rat's brain tissues at experimental hypoxia of different degree. Tissues of newborn rat’s brain are characterized by high level of saturation and considerable dynamism of microelement maintenance. Till the end of the first week of life, the maintenance of these microelements decreases in 1,5 – 10 times. The level of the toxic lead decreases more than in 2,5 times. The hypoxia of easy degree of newborn rats invokes reduction cobalt level 3 times, iron level 2 times, manganese – on 27,65 %, chrome – on 25,84%, zinc – on 16,43%. It means that considerable deficiency and disbalance of microelement maintenance rat's brain tissues. The heavy degree of hypoxia is characterized by further increase of deficiency and disbalance of microelements.

Organs of newborn rats (cerebrum, heart, liver, kidneys) are characterized by a high contains of microelements. Review of toxic and ultramikroelements in the tissues of vital organs in case of severity is essential for understanding hypoxic-ischemic lesions in neonatology. In this paper we used hypobaric model of hypoxia, the study conducted on 60 laboratory rats for the first and seventh day of life. By the seventh day of life the content of chrome and manganese decreases. In cerebrum contain of lead is the most. Hypoxia leads to a considerable decrease of the level of manganese. Severe hypoxia leads to the decrease of contain of chrome and cobalt. Hypoxia causes increase of accumulation of lead in heart and kidneys in 8 times, in liver – in 3 times, and also in cerebrum (28, 2%).

In this study, we analyzed the time-depended scenario of stress response cascade preceding and accompanying brain hemorrhages in newborn rats using an interdisciplinary approach based on: a morphological analysis of brain tissues, coherent-domain optical technologies for visualization of the cerebral blood flow, monitoring of the cerebral oxygenation and the deformability of red blood cells (RBCs). Using a model of stress-induced brain hemorrhages (sound stress, 120 dB, 370 Hz), we studied changes in neonatal brain 2, 4, 6, 8 h after stress (the pre-hemorrhage, latent period) and 24 h after stress (the post-hemorrhage period). We found that latent period of brain hemorrhages is accompanied by gradual pathological changes in systemic, metabolic, and cellular levels of stress. The incidence of brain hemorrhages is characterized by a progression of these changes and the irreversible cell death in the brain areas involved in higher mental functions. These processes are realized via a time-depended reduction of cerebral venous blood flow and oxygenation that was accompanied by an increase in RBCs deformability. The significant depletion of the molecular layer of the prefrontal cortex and the pyramidal neurons, which are crucial for associative learning and attention, is developed as a consequence of homeostasis imbalance. Thus, stress-induced processes preceding and accompanying brain hemorrhages in neonatal period contribute to serious injuries of the brain blood circulation, cerebral metabolic activity and structural elements of cognitive functio These results are an informative platform for further studies of mechanisms underlyin stress-induced brain hemorrhages during the first days of life that will improve the futur generation's health. [ABSTRACT FROM AUTHOR]

Objective To establish a simple and convenient method for primary culture and to identify its validity. Methods The cortical tissues of SD rats born within 24 h were collected, and we got the neuronal cell suspension by trypsin digestion, explanted onto poly-L-lysine-coated plates with DMEM + HG + 10% FBS culture medium for 4 h, then the medium was replaced with neuronal culture medium with Neurobasal 2% B27 + 0. 5 mmol / L glutamine. We observed the neuronal morphological changes for 8 days through inverted phase contrast microscope. Under the laser scanning confocal microscopy, neurons were cultured for 7 to 8 days, and the cells were identified by immunofluorescence staining. The density and purity of neurons were calculated. Results When the cortex neurons were inoculated, they were small, bright, translucent, round,and scattered in the distribution. After inoculation,a small amount of cells adhered to the wall, 2 hours later,more cells adhered to the wall, and a few cells produced short neurites; 4 hours later, most cells adhered to the wall, and a large number of cells produced neurites around the halo. After 3 days of cluture, the neurites were elongated, intertwined, transparent, and had strong three-dimensional sense with the round, oval and fusiform shapes. After 5 to6 days, the cell bodies of the neurons increased, and the processes of the neurons wove into a network. After 7 to 8 days, the body of neuronal cell was full, cytoplasm was translucent, nucleus was large and obvious,the cell body had strong refraction, three-dimensional sense was good, and the processes wove into a network structure. The neuron density was 1. 5 ×106/ m L and the purity was more than 90%. Conclusion A simple and convenient method for primary culture was established with high purity and high density, which can provide a good cell model for the related scientific research. [ABSTRACT FROM AUTHOR]

Rats exhibit a sensitive period from the time of birth until postnatal day 10 during which they develop preferences for odors even if those odors are paired with a moderately aversive stimulus. It is still unknown whether pre-exposure to an odor produces alterations on intake responses of basic tastants, and on other patterns that indicate a change in the hedonic value of reward, such as nipple grasping behavior. The current study assessed the effect of pre-exposure to an odor immediately after birth on intake responses of appetitive and aversive tastants. The objectives were to assess if 3-hour-old rats adjust their behaviors to obtain different values of appetitive and aversive rewards in the presence of a familiar odor. Specifically we wanted to determine whether the intake of saccharin or quinine, administered through the artificial nipple, increases in the presence of the familiar odor. Results showed that 3-hour-old rats differentially respond to two different concentrations of saccharin and two concentrations of quinine. In the presence of the pre-exposed odor newborn rats increased intake and grasp responses to the artificial nipple containing quinine. This effect disappeared with a higher concentration of quinine. These results suggest that the pre-exposed odor generated a change in the hedonic value of the aversive reward. [ABSTRACT FROM AUTHOR]

Objectives To investigate the nerve protective effect and mechanism of baicalin on newborn rats with hypoxic ischemic brain damage (HIBD). Methods A total of 64 SD newborn rats were randomly divided into control group, model group, nerve growth factor group and baicalin group, with 16 in each group. Left carotid artery ligation method was adopted to establish the HIBD model except for in control group, which was treated with intraperitoneal injection of salin e10 mL/kg for 3 d. After oxygen recovery on hypoxia ischemia rats, intraperitoneal injection of saline 10 mL/kg was adopted in model group for 3 d. Intraperitoneal injection of nerve growth factor injection 50 μg/kg per day was adopted in nerve growth factor group for 3 d; intraperitoneal injection of radix scutellariae 16 mg/kg per day was adopted in baicalin group for 3 d after modeling. Four rats of each group were sacrificed at Day 1, 2, 3, 7 for microscopic observation of pathological morphological changes in brain tissue after HE staining, S-P immunohistochemical method was used for observation of Fas and FasL expression in brain cells. Results Neat structure of cells was observed in control group; edema cells in disordered arrangement was observed in model group, with some cells necrosis and cavity change; tissue injury in nerve growth factor group and baicalin group was significantly lighter than that in model group; Fas and FasL expression in model group, nerve growth factor group and baicalin group were significantly higher than that in control group at different time points ( P <0.05); Fas and FasL expression in nerve growth factor group and baicalin group were significantly lower than that in model group at different time points ( P <0.05); There was no statistical difference of Fas, FasL expression at each time point between nerve growth factor group and baicalin group ( P >0.05). Conclusions Baicalin can reduce expression of Fas and FasL in HIBD rats, inhibit apoptosis of nerve cells, thus achieve the protective effect on HIBD rat nerves. [ABSTRACT FROM AUTHOR]

Aim. To study the influence of fetal bovine serum and serum of adult rats on behavior of newborn rat isolated neural cells during their cultivation in vitro. Methods. The isolation of neural cells from neonatal rat brain. The determination of the dynamics of cellular monolayer formation. Immunocytochemical staining of cells for β-tubulin III, nestin and vimentin. Results. It has been determined that the addition of serum of adult rats to the cultivation medium creates more favorable conditions for survival, attachment and spread of differentiated, and proliferation of the stem/progenitor neural cells of newborn rats during cultivation in vitro compared with the fetal bovine serum. Conclusions. Using the serum of adult rats is preferable for the cultivation of isolated neural cells of newborn rats compared with the fetal bovine serum. [ABSTRACT FROM AUTHOR]

ABSTRACT This study investigated the benefits of Cu preexposition on Hg effects on behavioral tests, acetylcholinesterase (AChE) activity and Hg, and essential metal contents in the cerebrum and cerebellum of neonate rats. Wistar rats received (subcutaneous) saline or CuCl2·2H2O (6.9 mg/kg/day) when they were 3 to 7 days old and saline or HgCl2 (5.0 mg/kg/day) when they were 8 to 12 days old. Mercury exposure reduced the performance of rats in the negative geotaxis (3-13 days) and beaker test (17-20 days), inhibited cerebellum AChE activity (13 days), increased cerebrum and cerebellum Hg (13 days), cerebrum Cu (13 days), and cerebrum and cerebellum Zn levels (33 days). The performance of rats in the tail immersion and rotarod tests as well as Fe and Mg levels were not altered by treatments. Copper prevented all alterations induced by mercury. These results are important to open a new perspective of prevention and/or therapy for mercury exposure. [ABSTRACT FROM AUTHOR]

Abstract: Ghrelin was initially related to appetite stimulation and growth hormone secretion. However, it also has a neuroprotective effect in neurodegenerative diseases and regulates cognitive function. The cellular basis of these processes is related to synaptic efficacy and plasticity. Previous studies indicated that ghrelin has an excitatory effect on neuronal activity, and stimulates synaptic plasticity in vivo. Plasticity in the adult brain occurs in many different ways, including changes in synapse morphology and number. Therefore, we used in vitro neuronal cultures to investigate how ghrelin affects synaptogenesis. We used dissociated cortical cultures of newborn rats, chronically treated with different doses of ghrelin (0.5, 1, 1.5 and 2μM). After one-, two-, three- or four weeks cultures were immunostained for the presynaptic marker synaptophysin. In parallel, additional groups of non-treated cultures were immunostained for detection of ghrelin receptor (GHSR1). During development, GHSR1was increasingly expressed in all type of neurons, as well as the synaptophysin. Synaptic density depended on ghrelin concentration, and was much higher than in controls in all age groups. In conclusion, ghrelin leads to earlier network formation in dissociated cortical networks and an increase in number of synapses. The effect is probably mediated by GHSR1. These findings suggest that ghrelin may provide a novel therapeutic strategy for the treatment of disorders related to synaptic impairment. [Copyright &y& Elsevier]

Aim: During reperfusion period of hypoxia-ischemia, cyclooxygenase and xanthine oxidase pathways are induced. A xanthine oxidase inhibitor, allopurinol has been shown to be neuroprotective in hypoxic- ischemic encephalopathy. Caspase-8 and caspase-3 have a key role in neuronal apoptosis. We aimed to test repeated doses of allopurinol's effect on caspase-3 and caspase-8 activities in newborn rats with hypoxic-ischemic encephalopathy. Material and Method: Seven days old newborn rats were taken and there were 10 rats in each group. After Ethical Committee was approved (TIBDAM-25), rats were subjected to left carotid artery ligation and hypoxia (8% oxygen and 92% nitrogen) for two and half hours. Hypoxic ischemic rats treated with 24 mg/kg allopurinol 30 minutes and 12 hours (AL48 group), and 30 minutes, 12 and 24 hours (AL72 group) after hypoxic- ischemic insult. Twenty four hours after last dose, rats were decapitated. The others groups were sham and saline-treated hypoxic-ischemic (H-l) group. Caspase-3 and caspase-8 activities were measured in both hemispheres. Results: There was no difference in caspase-3 and caspase-8 activities between right and left brain hemispheres in each group (p>0.05). Caspase-3 and caspase-8 activities were significantly lower in sham group when compared to H-l group, AL48 and AL72 groups (all of it, p=0.0001). Even though there were no difference activities of caspase-3 and caspase-8 between H-l group and AL48 group (p>0.05), activities of caspase-3 and caspase-8 in AL72 group were significantly lower than H-l group and AL48 group (respectively p= 0.0001, p=0.001). Conclusions: Decreased activities of caspase-3 and caspase-8 in AL72 group may suggest that totally dosage of 72 mg/kg allopurinol may be effective for reducing neuronal apoptosis in newborn rats with hypoxic-ischemic insult. [ABSTRACT FROM AUTHOR]

Abstract: We used whole-body plethysmography and pulse oximetry to assess the effects of acute administration of progesterone (4mg/kg, i.p.) on normoxic ventilation, hypoxic ventilatory response (HVR: FiO2 =12% over 20min), metabolism, and apnea frequency in rats on postnatal (P) days P1, P4, P7, and P12. Arterial oxygen saturation was continuously measured, and apneas were discriminated based on the degree of associated desaturation, at least 5 units less than the value before the desaturation. In normoxia, progesterone did not alter ventilation, metabolism or the coefficient of variation of minute ventilation at any age studied when compared with the control group (saline). However, it decreased apnea frequency and apnea associated with desaturation only in P1 rats. In hypoxia: progesterone increased the peak HVR in P4 and P7 rats, increased the steady-state HVR (mean at 15–20min of exposure) in P1, P4 and P7 without affecting the rats’ metabolic rate, decreased the coefficient of variation of minute ventilation in P4 and P7 rats, and finally, decreased apnea frequency only in the P1 rats with no effect on apnea associated with desaturation at any age. We conclude that acute administration of progesterone has no effect on baseline ventilation, but it increases HVR in rats younger than 7days, and decreased the frequency of apnea only in P1 rats. [Copyright &y& Elsevier]

Abstract: In human neonates, caffeine therapy for apnoea of prematurity, especially when associated with hypoxemia, is maintained for several weeks after birth. In the present study, we used newborn rats and whole-body plethysmography to test whether chronic exposure to neonatal caffeine treatment (NCT), alone or combined with neonatal intermittent hypoxia (n-IH) alters: (1) baseline ventilation and response to hypoxia (12% O2, 20min); and (2) response to acute i.p. injection of caffeine citrate (20mg/kg) or domperidone, a peripheral dopamine D2 receptor antagonist (1mg/kg). Four groups of rats were studied as follows: raised under normal conditions with daily gavage with water (NWT) or NCT, or exposed to n-IH (n-IH+NWT and n-IH+NCT) from postnatal days 3 to 12. In n-IH+NCT rats, baseline ventilation was higher than in the other groups. Caffeine or domperidone enhanced baseline ventilation only in NWT and n-IH+NWT rats, but neither caffeine nor domperidone affected the hypoxic ventilatory response in these groups. In n-IH+NWT rats, the response during the early phase of hypoxia (<10min) was higher than in other groups. During the late response phase to hypoxia (20min), ventilation was lower in n-IH+NWT and n-IH+NCT rats compared to NWT or NCT, and were not affected by caffeine or domperidone injection. NCT or caffeine injection decreased baseline apnoea frequency in all groups. These data suggest that chronic exposure to NCT alters both carotid body dopaminergic and adenosinergic systems and central regulation of breathing under baseline conditions and in response to hypoxia. [Copyright &y& Elsevier]

The article presents a study which examines the impact of environmental enrichment (EE) intervention on the development of newborn rats with hypoxic-ischemic brain damage (HIBD). The study performs light and electron microscopy and morphometry to examine the effects of EE on improving synaptic deficits in frontal cortex and neural remodeling in HIBD neonatal rats. Result shows that EE reduces brain edema and neuronal injury, increases neuronal plasticity, and promotes neuronal repair.

Abstract: Previously, it was proposed that sedative and anesthetic effects of alpha2-adrenergic receptor (alpha2-AR) agonists may be exerted via neuronal networks normally implicated in the regulation of wakefulness. The aim of this study was to evaluate the role of A subtype of alpha2-ARs in the development of drug-independent anesthetic state induced by hypothermia in newborn rats. Using short interfering RNA (siRNA) gene-targeting strategy, we found that down-regulation of the brainstem alpha2A-AR expression resulted in a delay in the onset of hypothermia-induced anesthesia assessed by loss of righting reflex. Involvement of the brain alpha2A-ARs in this delay was confirmed by inability of clonidine, a subtype-nonselective alpha2-AR agonist, to prolong duration of hypothermia-induced anesthesia in siRNA-treated animals, while significant prolongation of this anesthetic state by the alpha2A-AR agonist was observed in control pups. The data suggest that negative regulation of the animal''s waking state is an intrinsic function of the brainstem alpha2A-ARs activated by exogenous agonists, as well as by endogenous noradrenaline, also. [Copyright &y& Elsevier]

Differential scanning microcalorimetry (DSC) and UV–VIS absorption spectroscopy were used to obtain the characteristics of blood serum from newborn rat’ after maternal treatment with cyclophosphamide in comparison with control. The obtained DSC curves reveal a complex endothermic peak due to the unfolding process of various serum proteins. Thermal profiles and absorption spectra of blood serum are sensitive to the age of newborns as well as to effect of maternal administration of cyclophosphamide. The most significant disturbances in serum proteome were observed for 14-day old newborns. The thermodynamic parameters: enthalpy change (∆ H), the normalized first moment (M) of the thermal transition with respect to the temperature axis and the ratio of C at 70 and 60 °C describing denaturation contributions of globulin forms in respect to unliganded albumin with haptoglobin was estimated. Moreover, the second derivative spectroscopy in the UV region was used to resolve the complex protein spectrum. The differences in blood serum detected by DSC and UV–VIS confirm a potential usefulness of these methods for diagnostic and monitoring changes with age as well as the pathological state of blood serum. [ABSTRACT FROM AUTHOR]

Abstract: Spontaneous regeneration of the lateral olfactory tract (LOT) was re-evaluated in newborn rats using a fluorescent retrograde neuronal tracer as objective indicators of complete LOT transection. Complete LOT transection was evidenced by the loss of the white myelinated band characteristic for adult LOT and the total lack of retrograde neuronal labeling of mitral cells by Fast Blue that was injected during LOT transection. In completely LOT-transected young adult rats, mitral cells were retrogradely labeled consistently only by Fluoro-Gold that was injected into the olfactory cortex at the adult stage. Moreover, an anterograde neuronal tracer, biotinylated dextran amine (BDA), was demonstrated to pass from the neonatally LOT-transected bulb, through the transected retrobulbar site, towards the olfactory cortex, far caudally at a level near the optic chiasm. The regenerated structures lacked immunoreactivity for myelin basic protein and electron-dense myelinated axon bundles, and were also characterized by the thinness of the BDA(+) terminal zone within the olfactory cortex and the lack of its caudal extension. Young adult rats subjected to unilateral bulbectomy contralateral to the neonatally LOT-transected side showed perfect ability to discriminate cycloheximide solution by olfaction. From these findings, we conclude that the spontaneously regenerated olfactory system is functional despite structural incompleteness. [ABSTRACT FROM AUTHOR]

Abstract: The effect of tachykinin neurokinin NK2 receptors activation on intestinal propulsion and colorectal sensitivity was studied in 7–15days old newborn rats. In a first set of experiments investigating the intestinal transit, the selective NK2 receptor agonist, [βAla8]NKA-(4-10) was used. It produced an increase of the small intestinal transit measured by charcoal test of 54%, that was inhibited in a dose-dependent manner by nepadutant ([N4-(2-acetamido-2-deoxy-β-d-glucopyranosyl)-l-asparaginyl-l-aspartyl-l-tryptophyl-l-phenylalanyl-l-2,3-diaminopropionyl-l-leucyl]-C-4.2-N-3.5-lactam-C-1.6-N-2.1-lactam), a known selective NK2 receptor antagonist, orally administered 2–48h before the challenge with the NK2 receptor agonist. Nepadutant did not affect the basal intestinal propulsion and showed a good oral bioavailability and long duration of action. In another set of experiments investigating visceral sensitivity, a fixed distension volume of a balloon inserted intrarectally in 14–15days old newborns rats produced abdominal contractions (AC) that were increased after colonic application of acetic acid (50μl, 0.5%). In this latter condition nepadutant, at 0.5 and 2.5mg/kg p.o., significantly reduced the resulting AC. In control rats, untreated with acetic acid, nepadutant did not affect AC evoked by colorectal distension. These findings show for the first time two models to assess intestinal motility and visceral sensitivity in newborn rats and indicate nepadutant as a valuable tool to assess the role of NK2 receptors in the intestinal propulsive and nociceptive activity in infants. [Copyright &y& Elsevier]

Abstract: We tested the hypothesis that the function of cholinergic-nicotinic receptors on respiration is age dependent. To this end, we used whole body plethysmography to measure breathing frequency (fR), tidal volume (V T) and minute ventilation under normoxia (21% O2) in rats at 1, 4, 7, 12 and 21 postnatal days before and after administration of epibatidine (nicotinic agonist 5μg/kg, i.p.). In normoxia, epibatidine increased fR and in a proportionally age-dependent manner (p for age <0.001), without affecting V T. We then focused on P4 and P12 rats, as representative of this developmental pattern, to measure ventilatory response to moderate hypoxia (12% O2, 20min) after i.p. injection of saline (control), epibatidine (5μg/kg), or (nicotinic antagonist, 1mg/kg). At these doses, both drugs selectively target peripheral nicotinic receptors. Epibatidine enhanced the hypoxic ventilatory response while hexamethonium significantly reduced it. These effects were significantly greater in P12 than in P4 rats (p for age <0.001). In P12 rats, in vitro recordings of carotid sinus nerve activity showed that superfusion with nicotine enhanced chemosensory discharge rate in normoxia and hexamethonium reduced the discharge rate in hypoxia. We also identified the nicotinic receptor α7 subunit by immunohistochemistry in carotid bodies from P12 rat. These data show that the role of cholinergic-nicotinic receptor on hypoxic chemoreflex is age dependent and this effect likely implicates carotid body nicotinic receptor activation. [Copyright &y& Elsevier]

Abstract: Scorpion envenoming is a public health problem. In Brazil, the scorpion Tityus serrulatus is considered the most dangerous, but a large number of exposures also occur with Tityus bahiensis. There are quite a few studies in literature about the toxic effects of this venom but it is not known if the venom causes malformations or behavioral defects to the offspring of mothers exposed to the venom during pregnancy. The objective of this work was to determine, in rats, the possible toxic effects of T. bahiensis venom on offspring when injected into rats during different periods of fetal development. Rats were assigned to one of three groups: one control group and two experimental groups that were subcutaneously injected with venom (2.5mg/kg) on the 10th (GD10) or on 16th day (GD16) of gestation. Pups were evaluated for changes in physical and behavioral development. GD10 treatment group offspring showed an increase in body weight gain, earlier ear unfolding, incisor tooth eruption and vaginal opening. A decrease in the time of palmar grasp and surface-righting reflexes was observed only for males. In GD16 treatment group, earlier ear unfolding, incisor tooth eruption, and delay in eye opening were observed in the offspring. In female pups a decrease in weight gain and in time for palmar grasp reflex, and an increase in time for negative geotaxis were observed. In male pups a delay in the testis descent, decrease in the time of palmar grasp, increase in the time of negative geotaxis reflex and in the general and locomotor activities could be noticed. Therefore, we concluded that a moderate dose of scorpion venom administered to pregnant rats was able to elicit alterations in physical and behavioral development in the offspring during the postnatal period. [Copyright &y& Elsevier]

A protocol for the isolation, purification and culture of motor neurons from newborn rat spinal cord was described and the effect of glial cell line-derived neurotrophic factor (GDNF) on the growth of neurite of motor neurons was investigated in vitro. Spinal motor neurons (SMNs) were dissociated from ventral spinal cord of postnatal day 1 rats. The culture system for SMNs was established by density gradient centrifugation, differential adhesion, and use of serum-free defined media and addition of exogenous GDNF. After 72-h culture, the cells displayed the characteristic morphology of motor neurons, exhibited extensive neuritic processes and were positive for choline acetyltransferase (ChAT) expression. The neurite length of SMNs in GDNF groups was significantly longer than that in control group ( P<0.05). This protocol can be adapted for various postnatal motor neurons studies. [ABSTRACT FROM AUTHOR]

In this study, we investigated the sequential changes in the development of renal tubular cysts in newborn rats treated with p-cumylphenol (PCP). Fifteen animals per sex were treated orally with 300 mg/kg/day of PCP for up to 18 days from postnatal day (PND) 4 and were sacrificed on PNDs 8, 12, 19 and 22 and after a 7 day recovery period. On PNDs 8 and 12, slight dilatation of the collecting ducts was frequently observed in the medulla and slight papillary necrosis was also noted in some cases. These dilated collecting ducts were lined with slightly hyperplastic epithelial cells. On PNDs 19 and 22, multiple large cystic changes arising from the collecting ducts in the outer medulla were seen. These cystically dilated ducts were also lined with hyperplastic epithelial cells. During the dosing period, the labeling index of proliferating cell nuclear antigen in the collecting duct epithelium was higher in the PCP-treated group than in the control group at all time points. After a 7 day recovery period, the cystic change still remained, although the cell density was decreased and the epithelial cells became flattened. On the other hand, basophilic tubules with peritubular lymphoid cell infiltration were multifocally observed in the cortex. In conclusion, PCP induced multiple renal cysts that developed in the collecting ducts of the outer medulla in neonatal rats, and it is suggested that epithelial cell proliferation may play some roles in the induction of cystic lesions. [ABSTRACT FROM AUTHOR]

Oxidative stress due to free radical formation and initiation of abnormal oxidative reactions is involved in several diseases of newborns, such as hypoxic–ischemic encephalopathy. Melatonin, an endogenously produced indoleamine primarily formed in the pineal gland, is a potent free radical scavenger as well as an indirect antioxidant. The present study was conducted to evaluate the formation of oxidative damage mediators and the possible effect of melatonin treatment in a model of hypoxic–ischemic encephalopathy in 7-day-old rats. Pups were subjected to permanent ligation of the right common carotid artery and exposed for 2.5 hr to a nitrogen–oxygen mixture (92% and 8%, respectively) (hypoxia–ischemia, HI). Melatonin was injected intraperitoneally to a group of rats at the dose of 15 mg/kg 30 min before starting the ischemic procedure (HI–Melatonin). After 24 hr of treatment, in homogenized cerebral cortex, desferoxamine (DFO)-chelatable free iron, total F2-isoprostanes and total F4-neuroprostanes, originating from the free radical-catalyzed peroxidation of arachidonic and docosahexaenoic acids, respectively, were determined. HI induced a significant increase in DFO-chelatable iron, total F2-isoprostanes and F4-neuroprostanes in both right and left side of the cerebral cortex. In HI–Melatonin-treated animals the levels of free iron, F2-isoprostanes, and F4-neuroprostanes were significantly lower than that in HI rats and the values were similar to controls. These data show the important neuroprotective role of melatonin in reducing oxidative damage resulting from HI. Melatonin could represent a potential safe approach to perinatal brain damage in humans. [ABSTRACT FROM AUTHOR]

Abstract: We tested the hypothesis that postnatal exposure to progesterone or estradiol exerts distinct effects on respiratory control, apnea frequency, and on hypoxic ventilatory response (HVR). To this aim, we assessed breathing pattern using whole body plethysmography in normoxia and during a sustained hypoxic exposure (10% O2—30min) in 10-day-old male rats raised by dams implanted with osmotic minipumps delivering either estradiol (E2, 7.0μgday−1), estradiol+progesterone (E2 +P, 7.0+70μgday−1) or vehicle (propylene glycol) at a regular flow rate throughout postnatal days 1–14. Compared to vehicle, E2 and E2 +P pups had a reduced ventilation, metabolic rate and rectal temperature. HVR was specifically increased in E2 +P pups compared to controls and E2 pups. On the contrary, both E2 and E2 +P pups did not reduced metabolism as much as controls during hypoxic exposure, and the decrease in rectal temperature was abolished. Surprisingly, E2 +P pups showed a dramatic elevation of sigh frequency, while progesterone (in E2 +P compared to E2 and Veh pups) reduced apnea frequency. These findings are relevant to better understand the role of placental steroids on respiratory and metabolic control during early development in rats, and could ultimately contribute to a better understanding of specific respiratory control disorders in preterm neonates, which are chronically deprived from placental steroids exposure. [Copyright &y& Elsevier]

Among the main factors responsible for perinatal brain injury, inflammation, hypoxia-ischemia and formation of free radicals (FR) appear to play key roles. Melatonin, an endogenously produced indoleamine formed in higher amounts in adults than in neonates, is a potent FR scavenger as well as an indirect antioxidant. Herein, we examined whether melatonin provides significant protection against brain damage and its long-term consequences in a neonatal model of hypoxia-ischemia (HI). Seven day-old rats were subjected to permanent legation of the right common carotid artery followed to 2.5 hrs hypoxia 3 hrs later (HI). The neuroprotective effect of melatonin was evaluated 7 days after HI, or when rats reached adulthood, using behavioral and histological analyses. A beneficial effect was observed with 5 mg/kg melatonin administered before HI. The same dose repeated three times reduced further injury. A significant protective effect was found when 15 mg/kg melatonin was given 30 min before HI or when the same dose was given after HI and administration repeated after 24 and 48 hrs. The latter schedule of administration was used to assess the long-term protective effects. Melatonin did not affect growth rate and behavior at adulthood, but significantly improved the behavioral asymmetry and learning deficits induced by HI. Consistently, brain injury was significantly attenuated in the melatonin-treated ischemic group. The present study demonstrates that melatonin administration before or after HI in immature rats has an excellent and long-lasting benefit on ischemic outcomes suggesting that the drug could represent a potentially safe approach to perinatal brain damage in humans. [ABSTRACT FROM AUTHOR]

Abstract: We comprehensively re-analyzed the toxicity data for 18 industrial chemicals from repeated oral exposures in newborn and young rats, which were previously published. Two new toxicity endpoints specific to this comparative analysis were identified, the first, the presumed no observed adverse effect level (pNOAEL) was estimated based on results of both main and dose-finding studies, and the second, the presumed unequivocally toxic level (pUETL) was defined as a clear toxic dose giving similar severity in both newborn and young rats. Based on the analyses of both pNOAEL and pUETL ratios between the different ages, newborn rats demonstrated greater susceptibility (at most 8-fold) to nearly two thirds of these 18 chemicals (mostly phenolic substances), and less or nearly equal sensitivity to the other chemicals. Exceptionally one chemical only showed toxicity in newborn rats. In addition, Benchmark Dose Lower Bound (BMDL) estimates were calculated as an alternative endpoint. Most BMDLs were comparable to their corresponding pNOAELs and the overall correlation coefficient was 0.904. We discussed how our results can be incorporated into chemical risk assessment approaches to protect pediatric health from direct oral exposure to chemicals. [Copyright &y& Elsevier]

Abstract: This paper shows the toxicity of mercury (HgCl2 5mg/kg/day for 5 days, sc) applied at specific stages of development (1–5, 8–12 or 17–21 days old, 1st, 2nd and 3rd phases, respectively) on the performance of rats in three behavioral tasks and on cerebral mercury levels. The mercury exposure at the 1st and 2nd phases affected the performances of rats in the rim escape. Spontaneous alternation behavior was not altered by mercury exposure. In the open field task, habituation was absent when the rats were treated at the 1st phase, and the crossing response number was lower in rats exposed to mercury at the last period. In general, the brain accumulated large quantities of mercury. In short, the first days of postnatal life (1st phase) appeared to be more sensitive to mercury exposure than the other phases studied, since they presented behavioral deficits even at a time period somewhat after the exposure. [Copyright &y& Elsevier]