Developing Rat Pups Research Articles

N, N-dimethyltryptamine (DMT) in rodent brain: Concentrations, distribution, and recent pharmacological data.

Renewed interest in the clinical use of psychedelic drugs acknowledges their therapeutic effectiveness. It has also provided a changing frame of reference for older psychedelic drug study data, especially regarding concentrations of N, N-dimethyltryptamine (DMT) reported in rodent brains and recent discoveries in DMT receptor interactions in rat brain neurons and select brain areas. The mode of action of DMT in its newly defined role as a neuroplastogen, its effectiveness in treating neuropsychiatric disorders, and its binding to intracellular sigma-1 and 5HT2a receptors may define these possible roles. Recent data also show psychedelics promote neuroplasticity via activation of sigma-1 receptors associated with the endoplasmic reticulum and binding to 5-HT2a receptors predominantly related to the intracellular membrane of the Golgi apparatus in cortical neurons and the failure of DMT to occupy cell surface 5-HT2a receptors. While DMT has been proposed as the endogenous ligand for sigma-1, there is no identified ligand for intracellular 5-HT2a receptors, which serotonin cannot acquire. DMT is proposed to be the missing endogenous ligand. These data further suggest that DMT may be involved in brain development in rat pups. Brain levels of DMT have also been shown to be elevated by stress in the rat and appear to be under an inducible, adaptive, physiological regulatory system control. With DMT acting as the natural ligand for intracellular 5HT2a receptors in the Golgi, it may also explain the subjective effects observed from the administration of psychedelics in general and define some of the natural roles for DMT in particular.

Early-life prefrontal cortex inhibition and early-life stress lead to long-lasting behavioral, transcriptional, and physiological impairments.

Early-life stress has been linked to multiple neurodevelopmental and neuropsychiatric deficits. Our previous studies have linked maternal presence/absence from the nest in developing rat pups to changes in prefrontal cortex (PFC) activity. Furthermore, we have shown that these changes are modulated by serotonergic signaling. Here we test whether changes in PFC activity during early life affect the developing cortex leading to behavioral alterations in the adult. We show that inhibiting the PFC of mouse pups leads to cognitive deficits in the adult comparable to those seen following maternal separation. Moreover, we show that activating the PFC during maternal separation can prevent these behavioral deficits. To test how maternal separation affects the transcriptional profile of the PFC we performed single-nucleus RNA-sequencing. Maternal separation led to differential gene expression almost exclusively in inhibitory neurons. Among others, we found changes in GABAergic and serotonergic pathways in these interneurons. Interestingly, both maternal separation and early-life PFC inhibition led to changes in physiological responses in prefrontal activity to GABAergic and serotonergic antagonists that were similar to the responses of more immature brains. Prefrontal activation during maternal separation prevented these changes. These data point to a crucial role of PFC activity during early life in behavioral expression in adulthood.

Lactobacillus derived from breast milk facilitates intestinal development in IUGR rats.

The intestinal microbiota contributes to infant's intestine homeostasis. This study aimed to analyse how probiotics derived from breast milk promote infant intestinal development in rat pups. The effect of potential probiotics derived from breast milk on development of intrauterine growth retardation (IUGR) newborn rats' intestine was investigated. Limosilactobacillus oris ML-329 and Lacticaseibacillus paracasei ML-446 exhibited good hydrophobicity percentages (p < 0.05). ML-446 showed a significant effect on intestinal length and weight (p < 0.05). Meanwhile, the villus height of the IUGR newborn rats fed with ML-329 was significantly higher compared with those fed with Lacticaseibacillus rhamnosus GG (p < 0.05). Moreover, ML-329 and ML-446 both significantly stimulated the proliferation and differentiation of intestinal epithelial cells by increasing the number of ki67-positive cells, goblet cells, and lysozyme-positive Paneth cells (p < 0.05) through Wnt and Notch pathway. The proliferation and differentiation stimulating effects of ML-329 and ML-446 on IECs in the jejunum, ileum, and colon were mediated by activating the Wnt pathway with increased expression of wnt, lrp5, and β-catenin genes and accumulation of β-catenin, and by downregulating the Notch signalling pathway with decreased expression of the activated notch protein. Lactobacillus could facilitate IUGR rat pups' intestinal development and enhance the proliferation of Paneth cells and goblet cells. These findings provide further insights into promotion of the intestinal development by breast milk-derived beneficial microbes in early life of the IUGR newborn rats.

Teratogenic Effects of Bisphenol A Exposure During Maternal Pregnancy and Lactation on Developing Rat Pups Testes

Objective: To study the teratogenic effects of Bisphenol A exposure during maternal pregnancy and lactation on the testicular histology of developing rat pups.&#x0D; Design of Study: Laboratory-based experimental study.&#x0D; Place and Duration of Study: Department of Anatomy, Islamic International Medical College Rawalpindi in collaboration with the National Institute of Health (NIH) Islamabad Pakistan from Sep 2018 to Sep 2019.&#x0D; Methodology: Eight weeks old, ten pregnant female rats were divided into groups, each comprising five pregnant rats. Pups were born by spontaneous vaginal delivery. Control group A consisted of 15 male rat pups delivered from 5 pregnant rats, fed on a standard diet during pregnancy and lactation till the 21st day. Experimental group B consisted of 15 male rat pups delivered from 5 pregnant female rats who were administered subcutaneous Bisphenol A at a dose of during their pregnancy and lactation till the 21st day.&#x0D; Results: Significant deterioration of quantitative parameters in testes of the experimental group was seen. The seminiferous tubule diameter in group B was 81.99 ± 10.88 compared to group A which was 111.59 ± 8.36. The germinal epithelial height in group B was 10.47 ± 2.34 compared to 30.41 ± 2.43 in group A. The number of Leydig cells in group B was 17 ± 3.45 compared to 47 ± 4.44 in group A. The number of rounded spermatids in group B was 10 ± 3.74 compared to 38 ± 4.02 in group A.&#x0D; Conclusion: Bisphenol A has teratogenic effects on testicular histology of developing rats............

Prenatal cigarette smoke exposure slightly alters neurobehavioral development in neonatal rats: Implications for developmental origins of health and disease (DoHAD).

Numerous studies indicate that smoking during pregnancy exerts harmful effects on fetal brain development. The aim of this study was to determine the influence of maternal smoking during pregnancy on the early physical and neurobehavioral development of newborn rats. Wistar rats were subjected to whole-body smoke exposure for 2 × 40 min daily from the day of mating until day of delivery. For this treatment, a manual closed-chamber smoking system and 4 research cigarettes per occasion were used. After delivery the offspring were tested daily for somatic growth, maturation of facial characteristics and neurobehavioral development until three weeks of age. Motor coordination tests were performed at 3 and 4 weeks of age. We found that prenatal cigarette smoke exposure did not alter weight gain or motor coordination. Critical physical reflexes indicative of neurobehavioral development (eyelid reflex, ear unfolding) appeared significantly later in pups prenatally exposed to smoke as compared to the control group. Prenatal smoke exposure also resulted in a delayed appearance of reflexes indicating neural maturity, including hind limb grasping and forelimb placing reflexes. In conclusion, clinically relevant prenatal exposure to cigarette smoke results in slightly altered neurobehavioral development in rat pups. These findings suggest that chronic exposure of pregnant mothers to cigarette smoke (including passive smoking) results in persisting alterations in the developing brain, which may have long-lasting consequences supporting the concept of developmental origins of health and disease (DoHAD).

Protective Effect of Curcumin on Hippocampal and Behavior Changes in Rats Exposed to Fluoride During Pre- and Post-natal Period.

Introduction:Curcumin, a yellow-pigment, found in the popular Indian spice turmeric (Curcuma longa), poses pharmaceutical applications due to its anti-inflammatory, antioxidant, and chemoprotective properties. Excessive fluoride causes fluorosis leading to neurodegeneration and associated behavioral deficits, particularly in children. This study aimed at investigating the neuroprotective ability of curcumin on sodium fluoride (NaF)-related alterations of acetylcholine, catecholamines, histological changes in hippocampus and behavior of rats exposed to NaF during pre- and post-natal period.Methods:Pregnant albino Wistar rats were chosen and divided into four groups. The experimental period lasted 53 days (i.e. the gestational period of 23 days and post-gestational period of 30 days), at which the control group received normal tap water, the experimental group received NaF (20 ppm/kg bw) through drinking water, and the protective groups received curcumin (10 mg and 20mg/kg bw) by gavage and NaF (20 ppm/kg bw) through drinking water. Behavioral study (open field test) was done using postnatal pups aged 21 and 30 days. The brains of postnatal pups aged 1, 7, 14, 21, and 30 days were collected and used for biochemical analysis and those of pups aged 14, 21, and 30 days were used for histopathological analysis.Results:NaF-exposed rats showed a significant (P<0.05) decrease in body weight, brain weight, and behavioral activities, which were significantly reversed with curcumin treatment. The levels of epinephrine significantly (P<0.05) increased, whereas norepinephrine, dopamine and acetylcholine levels declined in NaF-treated group compared with the control group, which were significantly (P<0.05) reversed after treatment by curcumin (10 mg/kg bw and 20 mg/kg bw) along with NaF. The histological alterations, including shrinkage of neurons and nissal substances were observed in the hippocampus of NaF-treated pups that the control pups, whereas co-treatment with curcumin and NaF showed ameliorative effects and controlled the histological alterations.Conclusion:The results showed the neuroprotective effect of curcumin on behavior, neurotransmitter levels, and histological changes in the hippocampus against NaF-induced neurotoxicity in developing rat pups.

Regulatory Control of Microglial Phagocytosis by Estradiol and Prostaglandin E2 in the Developing Rat Cerebellum.

Microglia are essential to sculpting the developing brain, and they achieve this in part through the process of phagocytosis which is regulated by microenvironmental signals associated with cell death and synaptic connectivity. In the rat cerebellum, microglial phagocytosis reaches its highest activity during the third postnatal week of development but the factors regulating this activity are unknown. A signaling pathway, involving prostaglandin E2 (PGE2) stimulation of the estrogen synthetic enzyme aromatase, peaks during the 2nd postnatal week and is a critical regulator of Purkinje cell maturation. We explored the relationship between the PGE2-estradiol pathway and microglia in the maturing cerebellum. Toward that end, we treated developing rat pups with pharmacological inhibitors of estradiol and PGE2 synthesis and then stained microglia with the universal marker Iba1 and quantified microglia engaged in phagocytosis as well as phagocytic cups in the vermis and cerebellar hemispheres. Inhibition of aromatase reduced the number of phagocytic cups in the vermis, but not in the cerebellar hemisphere at postnatal day 17. Similar results were found after treatment with nimesulide and indomethacin, inhibitors of the PGE2-producing enzymes cyclooxygenase 1 and 2. In contrast, treatment with estradiol or PGE2 had little effect on microglial phagocytosis in the developing cerebellum. Thus, endogenous estrogens and prostaglandins upregulate the phagocytic activity of microglia during a select window of postnatal cerebellar development, but exogenous treatment with these same signaling molecules does not further increase the already high levels of phagocytosis. This may be due to an upper threshold or evidence of resistance to exogenous perturbation.

Impact of Gestational Chronic Intermittent Hypoxia and Hypertension on the Serotonergic System and Autoresuscitation in the Developmental Rat

Sudden infant death syndrome (SIDS) is characterized by the sudden death of a seemingly healthy infant during a sleep period under the age of 12 months. Abnormalities in the medullary serotonin (5HT) system, e.g. decreased tissue levels of 5HT and 5HTT, and increased immature 5HT neurons, have been identified in approximately 70% of infants that died of SIDS. Failed autoresuscitation (inability to recover breathing and heart rate following hypoxic apnea) is considered a possible mechanism of SIDS deaths, and animal studies have shown that 5HT neurons are critical for neonatal mice and rats to survive repeated episodes of severe hypoxia/asphyxia. Gestational chronic intermittent hypoxia (CIH) and preeclampsia both are risk factors for SIDS. In this study we asked whether the stressors, e.g. gestational/prenatal chronic intermittent hypoxia (CIH) and/or hypertension, would increase stress hormone levels, impair the maturity and integrity of medullary 5HT neurons and the ability to autoresuscitate from repetitive asphyxia in developing rat pups. The pregnant dams of normotensive Sprague Dawley (SD) rats and spontaneously hypertensive rats (SHR) were exposed to CIH or room air (RA) from gestation E4‐21, and then the serum corticosterone level (ELISA), the number and integrity of the medullary serotonin neurons (immunostainings), and in vivo autoresuscitation were assessed in the offspring pups at Postnatal (P) days 5–15.We found 1) SHR‐CIH pups have significantly higher serum corticosterone levels than SHR‐RA and SD‐RA pups at P7 (11,485 vs. 8078 &amp; 8970 pg/mL respectively, P&lt;0.05) and P10 (11,708 vs. 9040 &amp; 6,529 pg/mL respectively, P&lt;0.05). At P15 SD‐CIH, SHR‐CIH and SHR‐RA pups all have significantly higher corticosterone levels than SD‐RA pups; 2) Relative to the SD‐RA pups, SD‐CIH pups have a significantly higher total number of 5HT neurons and primarily due to increased number of Ki67/5HT‐ir positive neurons in the medulla. When compared to SD rats, we noticed that SHR pups appear to have more Ki67/5HT‐ir neurons which contribute to an increase in total number of 5HT neurons in the medulla than SD‐CIH &amp; SD‐RA (P&lt;0.01); and 3) the offspring pups of SHRs have the highest mortality rate during repetitive exposure of anoxia at all ages tested. Our data suggest that both gestational CIH and uncontrolled hypertension may lead to an impaired 5HT system in the offspring pups. The uncontrolled high blood pressure during pregnancy may cause placental insufficiency and contribute to failed autoresuscitation in response to repetitive anoxia in early postnatal life.Support or Funding InformationDartmouth UGAR, NIH HD036379, NIH HL28066

Labeling of neuronal morphology using custom diolistic techniques

BackgroundDiolistic labeling is increasingly utilized in neuroscience as an efficient, reproducible method for visualization of neuronal morphology. The use of lipophilic carbocyanine dyes, combined with particle-mediated biolistic delivery allows for non-toxic fluorescent labeling of multiple neurons in both living and fixed tissue. Since first described, this labeling method has been modified to fit a variety of research goals and laboratory settings. New methodDiolistic labeling has traditionally relied on commercially available devices for the propulsion of coated micro-particles into tissue sections. Recently, laboratory built biolistic devices have been developed which allow for increased availability and customization. Here, we discuss a custom biolistic device and provide a detailed protocol for its use. ResultsUsing custom diolistic labeling we have characterized alterations in neuronal morphology of the lateral/dentate nucleus of the rat cerebellum. Comparisons were made in developing rat pups exposed to abnormally high levels of 5-methyloxytryptamine (5-MT) pre-and postnatally. Using quantitative software; dendritic morphology, architecture, and synaptic connections, were analyzed. Comparison with existing method(s)The rapid nature of custom diolistics coupled with passive diffusion of dyes and compatibility with confocal microscopy, provides an unparalleled opportunity to examine features of neuronal cells at high spatial resolution in a three-dimensional tissue environment. ConclusionsWhile decreasing the associated costs, the laboratory-built device also overcomes many of the obstacles associated with traditional morphological labeling, to allow for reliable and reproducible neuronal labeling. The versatility of this method allows for its adaptation to a variety of laboratory settings and neuroscience related research goals.

Postnatal development of rat pups after maternal low-dose exposure to the neonicotinoid insecticide acetamiprid during gestation

Postnatal development of rat pups after maternal low-dose exposure to the neonicotinoid insecticide acetamiprid during gestation

Neurobehavioral assessment of maternal odor in developing rat pups: implications for social buffering

ABSTRACTSocial support can attenuate the behavioral and stress hormone response to threat, a phenomenon called social buffering. The mother’s social buffering of the infant is one of the more robust examples; yet we understand little about the neurobiology. Using a rodent model, we explore the neurobiology of social buffering by assessing neural processing of the maternal odor, a major cue controlling social buffering in rat pups. We used pups before (postnatal day (PN) 7) and after (PN14, PN23) the functional emergence of social buffering. Pups were injected with 14C 2-deoxyglucose (2-DG) and presented with the maternal odor, a control preferred odor incapable of social buffering (acetophenone), or no odor. Brains were removed, processed for autoradiography and brain areas identified as important in adult social buffering were assessed, including the amygdala basolateral complex (Basolateral Amygdala [BLA]), medial prefrontal cortex (mPFC), and anterior cingulate cortex (ACC). Results suggest dramatic changes in the processing of maternal odor. PN7 pups show mPFC and ACC activation, although PN14 pups showed no activation of the mPFC, ACC, or BLA. All brain areas assessed were recruited by PN23. Additional analysis suggests substantial changes in functional connectivity across development. Together, these results imply complex nonlinear transitions in the neurobiology of social buffering in early life that may provide insight into the changing role of the mother in supporting social buffering.

Effects of developmental hyperserotonemia on the morphology of rat dentate nuclear neurons

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder characterized by deficits in social cognition, disordered communication, restricted interests and repetitive behaviors. Furthermore, abnormalities in basic motor control, skilled motor gestures, and motor learning, are common in ASD. These characteristics have been attributed to a possible defect in the pre- and postnatal development of specific neural networks including the dentate-thalamo-cortical pathway, which is involved in motor learning, automaticity of movements, and higher cognitive functions.The current study utilized custom diolistic labeling and unbiased stereology to characterize morphological alterations in neurons of the dentate nucleus of the cerebellum in developing rat pups exposed to abnormally high levels of the serotonergic agonist 5-methyloxytryptamine (5-MT) pre-and postnatally. Occurring in as many as 30% of autistic subjects, developmental hyperserotonemia (DHS) is the most consistent neurochemical finding reported in autism and has been implicated in the pathophysiology of ASD. This exposure produced dramatic changes in dendritic architecture and synaptic features. We observed changes in the dendritic branching morphology which did not lead to significant differences (p>0.5) in total dendritic length. Instead, DHS groups presented with dendritic trees that display changes in arborescence, that appear to be short reaching with elaborately branched segments, presenting with significantly fewer (p>0.001) dendritic spines and a decrease in numeric density when compared to age-matched controls. These negative changes may be implicated in the neuropathological and functional/behavioral changes observed in ASD, such as delays in motor learning, difficulties in automaticity of movements, and deficits in higher cognitive functions.

Oxidative stress of brain and liver is increased by Wi-Fi (2.45 GHz) exposure of rats during pregnancy and the development of newborns

An excessive production of reactive oxygen substances (ROS) and reduced antioxidant defence systems resulting from electromagnetic radiation (EMR) exposure may lead to oxidative brain and liver damage and degradation of membranes during pregnancy and development of rat pups. We aimed to investigate the effects of Wi-Fi-induced EMR on the brain and liver antioxidant redox systems in the rat during pregnancy and development.Sixteen pregnant rats and their 48 newborns were equally divided into control and EMR groups. The EMR groups were exposed to 2.45GHz EMR (1h/day for 5 days/week) from pregnancy to 3 weeks of age. Brain cortex and liver samples were taken from the newborns between the first and third weeks. In the EMR groups, lipid peroxidation levels in the brain and liver were increased following EMR exposure; however, the glutathione peroxidase (GSH-Px) activity, and vitamin A, vitamin E and β-carotene concentrations were decreased in the brain and liver. Glutathione (GSH) and vitamin C concentrations in the brain were also lower in the EMR groups than in the controls; however, their concentrations did not change in the liver.In conclusion, Wi-Fi-induced oxidative stress in the brain and liver of developing rats was the result of reduced GSH-Px, GSH and antioxidant vitamin concentrations. Moreover, the brain seemed to be more sensitive to oxidative injury compared to the liver in the development of newborns.

Vitamin A deficiency: An oxidative stress marker in sodium fluoride (NaF) induced oxidative damage in developing rat brain

Fluoride induced oxidative stress through depletion in levels of various anti-oxidants such as glutathione, superoxide dismutase (SOD), fat soluble vitamins (D and E) with increased levels of lipid peroxidation (LPO) and fluoride aggravate the damage in rodents as well as in humans. Vitamins A, a fat soluble vitamin possess antioxidant property which plays a significant role in scavenging the free radicals species similar to vitamin D and E. Vitamin A is involved in neural tissue development and plasticity. The growing evidence about vitamin A being antioxidant in different biological reactions formed the basis to determine the effect of fluoride on its levels. The present study was conducted in Wistar rat pups. The pregnant wistar rats were dosed with 20ppm sodium fluoride (NaF) from day one of pregnancy till the pups were aged day30. The serum was collected from developing rat pups on regular intervals (14th, 21st, 30th day) and vitamin A levels were analyzed by High performance liquid chromatography (HPLC). Body weights, Behavioural studies and spectrophotometric estimation of SOD, LPO in brain lysates were also performed. The results showed significant decrease (p<0.001) in vitamin A in fluoride induced samples in comparison to the control samples suggesting that decreased levels of vitamin A can be used as another marker in fluoride induced toxicity studies.

Searsia chirindensis reverses the potentiating effect of prenatal stress on the development of febrile seizures and decreased plasma interleukin-1β levels

It is estimated that more than 80% of patients with epilepsy live in developing countries with 50–60% of them being children. This high prevalence is perpetuated by low socio-economic challenges, poor health care facilities and lack of drug affordability. Searsia chirindensis formerly known as rhus chirindensis and commonly known as ‘Red Current’ is a popular traditional medicinal plant, which has been used to treat a number of illnesses such as heart complaints and neurological disorders. The aim of this study is to investigate the effects of S. chirindensis on the development of febrile seizure in a prenatally stressed rat. Febrile seizures were induced by administering lipopolysaccharide to 14-day-old rat pups followed by kainic acid. A subset of the rats was treated with Searsia after induction of febrile seizures. Interleukin-1β (IL-1β) levels were measured in plasma. Lipid peroxidation was determined in liver tissue. Our data shows that treatment with Searsia reduced interleukin-1β levels in plasma of the febrile seizure rats and prevented lipid oxidation in the liver. Prenatal stress is dampened by the beneficial effects of Searsia on seizure development in rat pups. These results highlight the potentiating effects of Searsia in the reversal of febrile seizures and prenatal stress effects.

Sexual odor discrimination and physiological profiles in adult male rats after a neonatal, short term, reversible nasal obstruction.

The present study was designed to examine behavioral responses (interpreted as preferences) to olfactory cues (nest bedding odor and odors of estrous and anestrus females) in adult male rats after they had a short term reversible, bilateral, nasal obstruction (RbNO) as developing rat pups. These results were compared to behavior of control (untreated) and sham operated male littermates. Behavioral tests and physiological parameters were analyzed 90 days after recovery of nasal breathing. Experiments investigated the time spent in arms or the center of a maze of male rats in response to odors from the nest bedding or from adult females. There were no differences in responses between untreated, sham and RbNO adult male rats to fresh and nest bedding odors. RbNO males spent more time in the center of the maze when given a choice of estrus or anestrus female odors, or bedding odors from untreated or sham operated female rats. In contrast untreated and sham male rats preferred the odors of estrous females and of untreated or sham females. Plasma corticosterone levels in the males increased during the behavioral tests. Plasma testosterone levels were significantly lower in RbNO males compared to untreated males and did not increase during the behavioral tests compared to sham operated males. Males from all groups had similar preferences for the odor of bedding from adult RbNO females. Plasma levels of cholesterol and triglycerides were increased in RbNO adults. In conclusion, short term nasal obstruction in males while juvenile has long term consequences on hormones and behavioral preferences, thus potential partner selection when adult.

Caffeine alters sleep and breathing without an increase in brain serotonin in developing rat pups

In rat pups a reduction in serotonin (5HT) input to respiratory networks impairs anoxic auto‐resuscitation and impairs arousal during hypoxia. In contrast, blockade of adenosine receptors enhances auto‐resuscitation and attenuates the VE decline during the biphasic hypoxic ventilatory response. Caffeine (Caf), an adenosine receptor antagonist, used to treat apnea of prematurity in human infants, has well known effects on sleep and vigilance in adults and in some reports increases the levels of brain 5HT. We therefore examined the pharmacodynamics and the physiological effects of single IP injections of Caf (base) at 5 to 40 mg/kg in P9–P11 pups. Plasma Caf levels reached 10.9 and 76.3 mg/l for 5 and 40 mg/kg, respectively, at 60 min, and were stable until at least 90 min. Caf increased the % time awake at 10 and 40 mg/kg and at 40 mg/kg decreased the % time in active sleep. Caf did not change baseline heart or respiratory rate but the effect of Caf on VT and VE was dependent on state and dose. At 40 mg/kg, VT was increased during wake and quiet sleep whereas VE was increased only during wake. No increases in brainstem 5HT were found at either 10 or 40 mg/kg. In rat pups, a low dose of Caf alters sleep and at higher doses stimulates respiration. The effects of Caf on auto‐resuscitation and ventilation during hypoxia do not appear to be related to an increase in brainstem 5HT levels. NICHD 5‐PO1 HD036379 15

Neuroprotective and antiepileptogenic effects of combination of anti-inflammatory drugs in the immature brain

BackgroundInflammatory signaling elicited by prolonged seizures can be contributory to neuronal injury as well as adverse plasticity leading to the development of spontaneous recurrent seizures (epilepsy) and associated co-morbidities. In this study, developing rat pups were subjected to lithium-pilocarpine status epilepticus (SE) at 2 and 3 weeks of age to study the effect of anti-inflammatory drugs (AID) on SE-induced hippocampal injury and the development of spontaneous seizures.FindingsWe selected AIDs directed against interleukin-1 receptors (IL-1ra), a cyclooxygenase-2 (COX-2) inhibitor (CAY 10404), and an antagonist of microglia activation of caspase-1 (minocycline). Acute injury after SE was studied in the 2-week-old rats 24 h after SE. Development of recurrent spontaneous seizures was studied in 3-week-old rats subjected to SE 4 months after the initial insult.None of those AIDs were effective in attenuating CA1 injury in the 2-week-old pups or in limiting the development of spontaneous seizures in 3-week-old pups when administered individually. When empiric binary combinations of these drugs were tried, the combined targeting of IL-1r and COX-2 resulted in attenuation of acute CA1 injury, as determined 24 h after SE, in those animals. The same combination administered for 10 days following SE in 3-week-old rats, reduced the development of spontaneous recurrent seizures and limited the extent of mossy fiber sprouting.ConclusionsDeployment of an empirically designed ‘drug cocktail’ targeting multiple inflammatory signaling pathways for a limited duration after an initial insult like SE may provide a practical approach to neuroprotection and anti-epileptogenic therapy.

Neuropathies of spinal cord development in rat pups maternally fed with fried potato chips

Objective: Acrylamide is a neurotoxic material and recently elevated levels of acrylamide in varieties of foodstuffs were reported. The present study aimed to illustrate the demyelination of spinal cord of pups maternally fed a diet containing fried potato chips. Methods: Eighty fertile virgin female Wistar rats were made pregnant after mating with healthy male. Zero dates of gestation were determined and dams were arranged into three groups as control, acrylamide-treated (15 mg/kg body weight, p.o.) and 50% fried potato chips containing diet group. Treatments were carried every other day from 6th day of gestation until 3-week post-partum. The cervical spinal cord was separated and subjected for SDS-PAGE analysis and light and transmission electron microscopy. Results: Comparing with acrylamide-treatment, protein expression in spinal cord of pups maternally fed with fried potatoes was altered. Necrosis of motor neuronal cells within grey matter, hyperplasia of ependymal lining cells and fragility of white matter was detected. At ultrastructural level, the sensory and motor neuronal cells showed convoluted nuclear envelope and either chromatolysis or compacted chromatin material. Fragmentation of rough endoplasmic reticulum and damage of mitochondria become well evident in pups maternally fed with potato chips. The neuronal axons possessed vacuolation and demyelination associated with apparent damage of mitochondria. Conclusion: Supplementation of fried potato chips exerted neurotoxicity either directly through their content of acrylamide or via its metabolite glycidamide. Both components were reported to find their way across the placenta during gestation and breast milk during the lactation period, interfering with spinal cord differentiation and adversely affected demyelination.

137. Neuropathies of Spinal Cord Development of Rat Pups Maternally Fed on Fried Potato Chips

137. Neuropathies of Spinal Cord Development of Rat Pups Maternally Fed on Fried Potato Chips