scholarly journals Autism-Like Behavior in the Offspring of CYP11A1-Overexpressing Pregnant Rats

2021 ◽  
Vol 15 ◽  
Author(s):  
Tianying Pan ◽  
Chuan Jiang ◽  
Juan Cheng ◽  
Jiang Xie ◽  
Xinghui Liu ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Repetitive Behavior ◽  
Autism Spectrum ◽  
Receptor Expression ◽  
Gamma Aminobutyric Acid ◽  
Primary Microglia ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Necrosis Factor Alpha ◽  
Sd Rats

Autism spectrum disorders (ASD) represent a complex group of neurodevelopmental disorders that are characterized by impaired social behavior and communication as well as repetitive behavior and restricted interests. Prenatal exposure to high levels of testosterone and preeclampsia are thought to be risk factors of ASD. We had previously reported that overexpression of the mitochondrial cholesterol side-chain cleavage enzyme (CYP11A1) could lead to both preeclampsia-like symptoms and increased testosterone levels in pregnant rats. In this study, we investigated the association between high CYP11A1 levels in pregnant rats and autism-like behavior in their offspring. Timed-pregnant Sprague-Dawley (SD) rats were injected with CYP11A1 gene-carrying adenoviruses on gestational day 8.5, and their offspring were then compared with those from timed-pregnant control SD rats. Compared with their control counterparts, the offspring of the CYP11A1-ovexpressing dams displayed more symptoms of anxiety and spent less time in social interactions and more time in self-grooming and rearing, all indicators of autism-like behavior. Sequencing of the transcriptome in primary microglia from the offspring of CYP11A1-overexpressing dams revealed that immune pathways were highly activated, and the gamma-aminobutyric acid type A (GABAA) receptor genes were among the top differentially expressed genes. Using primary microglia cultures generated from neonatal rats, tumor necrosis factor-alpha expression was found to be elevated in the cells transfected with CYP11A1-carrying adenoviruses. Additionally, the offspring of CYP11A1-overexpressing dams displayed dysregulated GABAA receptor expression. Taken together, these results suggest that abnormal CYP11A1 gene expression in pregnant rats could lead to microglial immune activation and dysregulated GABAA receptor expression in their offspring and thereby anxiety and autism-related behavior. Our study suggests that the pathways regulated by CYP11A1 could be promising preventative and therapeutic targets for ASD.

Role of nitric oxide in the natriuretic and diuretic responses in pregnant rats

2003 ◽  
Vol 285 (5) ◽  
pp. F938-F944 ◽  
Author(s):  
Ali A. Khraibi ◽  
Tianzheng Yu ◽  
Daiyi Tang
Keyword(s):  
Nitric Oxide ◽  
Control Period ◽  
Fractional Excretion ◽  
Normal Pregnancy ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Sd Rats ◽  
Fractional Excretion Of Sodium ◽  
Lower Ability

Normal pregnancy is characterized by sodium conservation and increase in plasma volume, yet the natriuretic response to acute saline volume expansion (VE) is intact in pregnant rats. Nitric oxide (NO) has been suggested to play a role in renal and cardiovascular adaptations to normal pregnancy. The objective of this study was to determine the role of NO in the natriuretic and diuretic responses to VE during pregnancy. Infusion of NG-monomethyl-l-arginine (l-NMMA) was used to inhibit NO synthesis. Nine groups of Sprague-Dawley (SD) rats were studied: nonpregnant (NP-VE, n = 7), midterm pregnant (MP-VE, n = 8), and late-term pregnant (LP-VE, n = 7) SD groups that underwent VE alone after a control period; NP-l-NMMA ( n = 7), MP-l-NMMA ( n = 8), and LP-l-NMMA ( n = 7) SD groups that were infused with l-NMMA after a control period; and another three groups of SD rats (NP-VE-l-NMMA, n = 8; MP-VE-l-NMMA, n = 7; and LP-VE-l-NMMA, n = 12) that underwent simultaneous VE and l-NMMA infusion after a control period. The change in fractional excretion of sodium was 7.22 ± 1.03% for NPVE, 9.89 ± 1.85% for NP-l-NMMA, and 17.66 ± 1.85% for NP-VE-l-NMMA ( P < 0.05 vs. NP-VE and NP-l-NMMA); 6.61 ± 1.07% for MP-VE, 7.99 ± 1.92% for MP-l-NMMA, and 10.24 ± 1.91% for MP-VE-l-NMMA [not significant (NS) vs. MP-VE and MP-l-NMMA]; 8.20 ± 1.92% for LP-VE, 8.09 ± 0.70% for LP-l-NMMA, and 7.57 ± 1.11% for LP-VE-l-NMMA (both NS vs. LP-VE and LP-l-NMMA). The increase in renal interstitial hydrostatic pressure was significantly greater in all NP compared with pregnant groups with similar experimental intervention (i.e., VE, l-NMMA, or VE-l-NMMA). In conclusion, the natriuretic and diuretic responses to VE and l-NMMA infusion were additive in NP but not in pregnant rats, indicating a possible lower ability of pregnant rats to respond to combined significant natriuretic and diuretic stimuli.

scholarly journals Secreted Monocyte miR-27a, via Mesenteric Arterial Mas Receptor-eNOS Pathway, Causes Hypertension

2019 ◽  
Author(s):  
Xue Zou ◽  
Jialiang Wang ◽  
Caiyu Chen ◽  
Xiaorong Tan ◽  
Yu Huang ◽  
...  
Keyword(s):  
Plasma Concentrations ◽  
Receptor Expression ◽  
Mesenteric Arteries ◽  
Sprague Dawley ◽  
Hek 293 ◽  
Mas Receptor ◽  
Sd Rats ◽  
293 Cells ◽  
Enos Phosphorylation ◽  
Endothelial Nitric Oxide

Abstract BACKGROUND Essential hypertension is associated with increased plasma concentrations of extracellular vesicles (EVs). We aimed to determine the role of monocyte miR-27a in EVs on arterial Mas receptor expression, and its involvement in the pathogenesis of hypertension. METHODS THP-1 cells were transfected with miR-27a mimic and miR-27a inhibitor, and EVs were collected. Mas receptor expression and endothelial nitric oxide synthase (eNOS) phosphorylation were determined by immunoblotting. Sprague–Dawley (SD) rats received EVs via tail-vein injection. Blood pressure (BP) was measured with the tail-cuff method. The vasodilatory response of mesenteric arteries was measured using a small vessel myograph. RESULTS EVs from THP-1 cells increased rat BP by impairing Ang-(1–7)-mediated vasodilation in mesenteric arteries, which was further exaggerated by EVs from lipopolysaccharides-treated THP-1 cells. As the receptor and key signaling of Ang-(1–7), next experiments found that Mas receptor expression and eNOS phosphorylation were decreased in mesenteric arteries from EVs-treated SD rats. Screening studies found miR-27a in EVs may be involved in this process. Through transfection with miR-27a inhibitor or miR-27a mimic, we found that miR-27a downregulates Mas receptor expression in endothelial cells. Injection of EVs from miR-27a-transfected HEK-293 cells decreased Mas receptor and eNOS phosphorylation in mesenteric arteries, impaired Ang-(1–7)-mediated vasodilation and increased BP. Earlier effects were reversed using cells with downregulation of miR-27 in EVs. CONCLUSIONS Monocyte miR-27a in EVs decreases Mas receptor expression and eNOS phosphorylation in endothelium, impairs Ang-(1–7)-mediated vasodilation, and causes hypertension. Understanding the contributions of EVs in the pathogenesis of hypertension may facilitate their use as a diagnostic biomarker.

scholarly journals Significance of GABAA Receptor for Cognitive Function and Hippocampal Pathology

2021 ◽  
Vol 22 (22) ◽  
pp. 12456
Author(s):  
Yuya Sakimoto ◽  
Paw Min-Thein Oo ◽  
Makoto Goshima ◽  
Itsuki Kanehisa ◽  
Yutaro Tsukada ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Gabaa Receptor ◽  
Neuronal Excitability ◽  
Autism Spectrum ◽  
Contextual Learning ◽  
Learning Performance ◽  
Inhibitory Synapses ◽  
Gamma Aminobutyric Acid ◽  
Contextual Memory ◽  
Spatiotemporal Information

The hippocampus is a primary area for contextual memory, known to process spatiotemporal information within a specific episode. Long-term strengthening of glutamatergic transmission is a mechanism of contextual learning in the dorsal cornu ammonis 1 (CA1) area of the hippocampus. CA1-specific immobilization or blockade of α-amino-3-hydroxyl-5-methyl-4-isoxazole-propionate (AMPA) receptor delivery can impair learning performance, indicating a causal relationship between learning and receptor delivery into the synapse. Moreover, contextual learning also strengthens GABAA (gamma-aminobutyric acid) receptor-mediated inhibitory synapses onto CA1 neurons. Recently we revealed that strengthening of GABAA receptor-mediated inhibitory synapses preceded excitatory synaptic plasticity after contextual learning, resulting in a reduced synaptic excitatory/inhibitory (E/I) input balance that returned to pretraining levels within 10 min. The faster plasticity at inhibitory synapses may allow encoding a contextual memory and prevent cognitive dysfunction in various hippocampal pathologies. In this review, we focus on the dynamic changes of GABAA receptor mediated-synaptic currents after contextual learning and the intracellular mechanism underlying rapid inhibitory synaptic plasticity. In addition, we discuss that several pathologies, such as Alzheimer’s disease, autism spectrum disorders and epilepsy are characterized by alterations in GABAA receptor trafficking, synaptic E/I imbalance and neuronal excitability.

Hormone profiles for progesterone, oestradiol, prolactin, plasma renin activity, aldosterone and corticosterone during pregnancy and pseudopregnancy in two strains of rat: correlation with renal studies

1987 ◽  
Vol 113 (3) ◽  
pp. 435-444 ◽  
Author(s):  
H. O. Garland ◽  
J. C. Atherton ◽  
C. Baylis ◽  
M. R. A. Morgan ◽  
C. M. Milne
Keyword(s):  
Plasma Renin Activity ◽  
Plasma Renin ◽  
Renin Activity ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Corticosterone Concentration ◽  
Hormone Profile ◽  
Sd Rats ◽  
Renal Changes ◽  
Low Levels

ABSTRACT Plasma samples were obtained throughout pregnancy and pseudopregnancy from Sprague–Dawley (SD) rats and during pregnancy from rats of the Munich Wistar (MW) strain. The concentrations of progesterone, oestradiol, prolactin, plasma renin activity (PRA), aldosterone and corticosterone were measured by radioimmunoassay to establish hormonal profiles in the two strains of rat. Circulating progesterone concentrations in both strains of rat were significantly higher during pregnancy than in virgin controls, except at term in the SD group. The hormonal pattern for pseudopregnancy was similar to that of the first half of pregnancy. Oestradiol concentrations were similar to, or lower than, those in virgin controls throughout pseudopregnancy and for the first 2 weeks of pregnancy in both strains of rat. Increased concentrations of steroid were seen only in the pregnant groups towards term. In SD rats, highest prolactin concentrations were apparent during the first half of pregnancy and pseudopregnancy, and at term in the pregnant group. Pregnant MW rats showed a different profile for this hormone, with low levels throughout pregnancy except at term. In all groups PRA rose to a peak at day 9 and decreased to day 16. Pregnant SD rats also showed a significant increase at term. Aldosterone concentrations were significantly increased at several stages of pregnancy in both strains of rat, particularly during the second half of gestation. Pseudopregnant animals showed a different hormone profile, with no significant changes until day 16 when lower concentrations were recorded. There was little variation in the circulating corticosterone concentration except in pregnant rats at term when levels fell. These findings are discussed in relation to the known renal changes of pregnancy and pseudopregnancy. J. Endocr. (1987) 113, 435–444

Electroacupuncture alleviates the transition from acute to chronic pain through the p38 MAPK/TNF-α signalling pathway in the spinal dorsal horn

2021 ◽  
pp. 096452842110207
Author(s):  
Ying Jin ◽  
Jie Zhou ◽  
Fangfang Xu ◽  
Zeqin Ren ◽  
Jun Hu ◽  
...  
Keyword(s):  
Chronic Pain ◽  
Dorsal Horn ◽  
P38 Mapk ◽  
Spinal Dorsal Horn ◽  
Mitogen Activated Protein Kinase ◽  
Sprague Dawley ◽  
Necrosis Factor Alpha ◽  
Spinal Dorsal ◽  
Sd Rats ◽  
Tnf Α

Background: Hyperalgesic priming (HP) is a model of the transition from acute to chronic pain. Electroacupuncture (EA) could inhibit pain development through the peripheral dorsal root ganglia; however, it is unclear whether it can mitigate the transition from acute to chronic pain by attenuating protein expression in the p38 MAPK (mitogen-activated protein kinase)/tumour necrosis factor alpha (TNF-α) pathway in the spinal dorsal horn. Aims: We aimed to determine whether EA could prevent the transition from acute to chronic pain by affecting the p38 MAPK/TNF-α pathway in the spinal dorsal horn in a rat model established using HP. Methods: We first randomly subdivided 30 male Sprague-Dawley (SD) rats into 5 groups ( n = 6 per group): control (N), sham HP (Sham-HP), HP, HP + SB203580p38 MAPK (HP+SB203580), and HP + Lenalidomide (CC-5013) (HP+Lenalidomide). We then randomly subdivided a further 30 male SD rats into 5 groups ( n = 6 per group): Sham-HP, HP, sham EA (Sham EA), EA (EA), and EA + U-46619 p38 MAPK agonist (EA+U-46619). We assessed the effects of EA on the mechanical paw withdrawal threshold and p38 MAPK/TNF-α expression in the spinal dorsal horn of rats subjected to chronic inflammatory pain. Results: Rats in the EA group had reduced p38 MAPK and TNF-α expression and had significantly reduced mechanical hyperalgesia compared with rats in the other groups. Conclusion: Our findings indicate that EA could increase the mechanical pain threshold in rats and inhibit the transition from acute pain to chronic pain. This mechanism could involve reduced p38 MAPK/TNF-α expression in the spinal dorsal horn.

scholarly journals Binding effects of Alpinia galanga oil and its nanoemulsion 1 to GABAA receptors in rat cortical membranes

2021 ◽  
Author(s):  
Nattakanwadee Khumpirapang ◽  
Krit Suknuntha ◽  
Songyot Anuchapreeda ◽  
Petrine Wellendorph ◽  
Anette Müllertz ◽  
...  
Keyword(s):  
Gabaa Receptor ◽  
Methyl Eugenol ◽  
Anesthetic Activity ◽  
Gamma Aminobutyric Acid ◽  
Sprague Dawley ◽  
Promising Alternative ◽  
Alpinia Galanga ◽  
Receptor Modulation ◽  
Cortical Membranes ◽  
Muscimol Binding

Abstract Anesthetic activity of Alpinia galanga oil (AGO) has been reported however the mechanism of action in mammals has not been clear. In the present study, the binding effects of AGO and its three active components to gamma-aminobutyric acid type A (GABAA) receptor in cortical membranes of Sprague-Dawley rats were firstly investigated using a [3H]muscimol binding assay. Dimethyl sulfoxide (DMSO) was used to deliver these test samples. The results showed that only AGO and methyl eugenol displayed positive modulation at the highest concentration whereas 1,8-cineole and 4-allylphenyl acetate were inactive. An oil-in-water nanoemulsion containing 20%w/w AGO (NE-AGO) was formulated to deliver AGO instead of DMSO. This NE-AGO significantly enhanced a specific [3H]muscimol binding to 179% of the control with EC50 of 391 µg/mL. The result correlates well to the amount of methyl eugenol in AGO. This result confirms that the anesthetic activity of AGO and methyl eugenol is associated with GABAA receptor modulation, while that of 1,8-cineole and 4-allylphenyl acetate is not and may instead be related to other mechanisms. AGO showed well-tolerated by human cells. Therefore, the formulated NE-AGO might be a promising alternative anesthetic product for humans.

scholarly journals Exacerbated LPS/GalN-Induced Liver Injury in the Stress-Sensitive Wistar Kyoto Rat Is Associated with Changes in the Endocannabinoid System

Molecules ◽  
2020 ◽  
Vol 25 (17) ◽  
pp. 3834
Author(s):  
Marykate Killilea ◽  
Daniel M. Kerr ◽  
Beth M. Mallard ◽  
Michelle Roche ◽  
Antony M. Wheatley
Keyword(s):  
Liver Injury ◽  
Acute Liver Injury ◽  
Endocannabinoid System ◽  
Hepatic Function ◽  
Receptor Expression ◽  
Sprague Dawley ◽  
Wky Rats ◽  
Sd Rats ◽  
Rat Strain ◽  
Wistar Kyoto

Acute liver injury (ALI) is a highly destructive and potentially life-threatening condition, exacerbated by physical and psychological stress. The endocannabinoid system plays a key role in modulating stress and hepatic function. The aim of this study was to examine the development of acute liver injury in the genetically susceptible stress-sensitive Wistar-Kyoto (WKY) rat compared with normo-stress-sensitive Sprague Dawley (SD) rats, and associated changes in the endocannabinoid system. Administration of the hepatotoxin lipopolysaccharide/D-Galactosamine (LPS/GalN) resulted in marked liver injury in WKY, but not SD rats, with increased alanine aminotransferase (ALT), aspartate aminotransferase (AST) and glutamate dehydrogenase (GLDH) plasma levels, significant histopathological changes, increased hepatic pro-inflammatory cytokine expression and caspase-3 activity and expression and reduced Glutathione (GSH) activity. Furthermore, compared to SD controls, WKY rats display increased anandamide and 2-Arachidonoylglycerol levels concurrent with decreased expression of their metabolic enzymes and a decrease in cannabinoid (CB)1 receptor expression following LPS/GalN. CB1 antagonism with AM6545 or CB2 agonism with JWH133 did not alter LPS/GalN-induced liver injury in SD or WKY rats. These findings demonstrate exacerbation of acute liver injury induced by LPS/GalN in a stress-sensitive rat strain, with effects associated with alterations in the hepatic endocannabinoid system. Further studies are required to determine if the endocannabinoid system mediates or modulates the exacerbation of liver injury in this stress-sensitive rat strain.

scholarly journals Prenatal Exposure to Lamotrigine: Effects on Postnatal Development and Behaviour in Rat Offspring

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sekar Sathiya ◽  
Murugan Ganesh ◽  
Periyathambi Kalaivani ◽  
Vijayan Ranju ◽  
Srinivasan Janani ◽  
...  
Keyword(s):  
Postnatal Development ◽  
Prenatal Exposure ◽  
Clinical Signs ◽  
Female Offspring ◽  
Receptor Expression ◽  
Female Rats ◽  
Sprague Dawley ◽  
Pregnant Rats ◽  
Male And Female ◽  
Male And Female Rats

Use of antiepileptic drugs (AEDs) in pregnancy warrants various side effects and also deleterious effects on fetal development. The present study was carried out to assess the effects of prenatal exposure to lamotrigine (LTG) on postnatal development and behavioural alterations of offspring. Adult male and female Sprague Dawley rats weighing 150–180 g b. wt. were allowed to copulate and pregnancy was confirmed by vaginal cytology. Pregnant rats were treated with LTG (11.5, 23, and 46 mg/kg, p.o) from gestational day 3 (GND 3) and this treatment continued till postnatal day 11 (PND 11). Offspring were separated from their dam on day 21 following parturition. LTG, at 46 mg/kg, p.o, produced severe clinical signs of toxicity leading to death of dam between GND 15 and 17. LTG, at 11.5 and 23 mg/kg, p.o, showed significant alterations in offspring’s incisors eruption and vaginal opening when compared to age matched controls. LTG (23 mg/kg, p.o) exposed female offspring expressed hyperactive behaviour and decreased GABA-A receptor expression when compared to control rats. These results reveal that prenatal exposure to LTG may impart differential postnatal behavioural alterations between male and female rats which paves way for further investigations.

Abstract P344: Increased Expression and Function of Endothelin Receptors in Aorta of (mRen2)27 Hypertensive Rats

Hypertension ◽  
2016 ◽  
Vol 68 (suppl_1) ◽  
Author(s):  
Victor M Pulgar ◽  
Oludamilola T Ademoyero ◽  
Serguei S Sidach ◽  
Azeez A Aileru
Keyword(s):  
Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Muscle Cells ◽  
Receptor Expression ◽  
Maximal Response ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Sd Rats ◽  
Increased Sensitivity ◽  
And Function

Endothelin-1 (ET-1) contributes to various cardiovascular diseases including hypertension. ET-1 is produced in the endothelium and acts via ET A receptors, located in smooth muscle cells, and via ET B receptors, located in both endothelium and smooth muscle cells. Activation of ET A produces vasoconstriction, whereas endothelial ET B activation mediates vasodilation, with previous studies showing that ET-1-mediated vasoconstriction is enhanced in hypertension. We hypothesized that increased ETA-mediated function is present in vasculature of the (mRen2)27 hypertensive rat. Western blotting of total protein extracts from thoracic aorta was used to determine expression of ET A and ET B from Sprague-Dawley (SD n=4) and (mRen2)27 hypertensive (n=5) rats. Specificity of western blot signals for ET A and ET B was assessed by using pre-absorption of primary antibody with the corresponding antigenic peptide and intensity of signals was measured by densitometry (NIH-J Image). Contractile responses to ET-1 (10 -11 -10 -7 M) in intact and denuded aorta were determined by wire myography (Multi Myograph, DMT-USA) in the presence of the ET A blocker BQ123 (10 -6 M) or the ET B blocker BQ788 (10 -6 M). Contraction to ET-1 was expressed as maximal response (ET MAX as %K MAX ) and sensitivity (pD 2 =-Log [EC 50 ]). In aortae from (mRen2)27 rats ET A and ET B receptor expression (48 and 31 kDa bands) was greater relative to aortae of SD rats (p<0.05). ET-1 contraction showed increased sensitivity in (mRen2)27 vs SD aortae (pD 2 , 8.17±0.15 vs 7.76±0.12, p<0.05) with similar ET MAX (157±16 vs 145±6 %K MAX , p>0.05). In intact arteries, blockade of ET B increased ET-1 sensitivity (pD 2 8.4±0.3, p<0.05) in SD without effect on intact arteries from (mRen2)27 rats. In denuded arteries, ETB blockade increased ET MAX only in aortae from (mRen2)27 (205±12 vs 152±5, p<0.05). Thus, increased ET A expression mediates greater ET-1-dependent contraction in vasculature of (mRen2)27 rats. In (mRen2)27 rats, loss of endothelial ET B receptor function in intact arteries may contribute to enhanced constrictor responses to ET-1, whereas increased ET B receptors in smooth muscle cells provide a counterbalancing vasodilation to offset maximal contractile effects of ET-1 in this model of hypertension.

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