scholarly journals Androgenic Modulation of the Chloride Transporter NKCC1 Contributes to Age-dependent Isoflurane Neurotoxicity in Male Rats

2020 ◽  
Vol 133 (4) ◽  
pp. 852-866
Author(s):  
Gregory A. Chinn ◽  
Jennifer M. Sasaki Russell ◽  
Nicole A. Yabut ◽  
Deenu Maharjan ◽  
Jeffrey W. Sall
Keyword(s):  
Androgen Receptor ◽  
Recognition Memory ◽  
Spatial Memory ◽  
Probe Trial ◽  
Expression Patterns ◽  
Male Rats ◽  
Goal Time ◽  
Protein Levels ◽  
Androgen Receptor Antagonist ◽  
Memory Probe

Background Cognitive deficits after perinatal anesthetic exposure are well established outcomes in animal models. This vulnerability is sex-dependent and associated with expression levels of the chloride transporters NKCC1 and KCC2. The hypothesis was that androgen signaling, NKCC1 function, and the age of isoflurane exposure are critical for the manifestation of anesthetic neurotoxicity in male rats. Methods Flutamide, an androgen receptor antagonist, was administered to male rats on postnatal days 2, 4, and 6 before 6 h of isoflurane on postnatal day 7 (ntotal = 26). Spatial and recognition memory were subsequently tested in adulthood. NKCC1 and KCC2 protein levels were measured from cortical lysates by Western blot on postnatal day 7 (ntotal = 20). Bumetanide, an NKCC1 antagonist, was injected immediately before isoflurane exposure (postnatal day 7) to study the effect of NKCC1 inhibition (ntotal = 48). To determine whether male rats remain vulnerable to anesthetic neurotoxicity as juveniles, postnatal day 14 animals were exposed to isoflurane and assessed as adults (ntotal = 30). Results Flutamide-treated male rats exposed to isoflurane successfully navigated the spatial (Barnes maze probe trial F[1, 151] = 78; P < 0.001; mean goal exploration ± SD, 6.4 ± 3.9 s) and recognition memory tasks (mean discrimination index ± SD, 0.09 ± 0.14; P = 0.003), unlike isoflurane-exposed controls. Flutamide changed expression patterns of NKCC1 (mean density ± SD: control, 1.49 ± 0.69; flutamide, 0.47 ± 0.11; P < 0.001) and KCC2 (median density [25th percentile, 75th percentile]: control, 0.23 [0.13, 0.49]; flutamide, 1.47 [1.18,1.62]; P < 0.001). Inhibiting NKCC1 with bumetanide was protective for spatial memory (probe trial F[1, 162] = 6.6; P = 0.011; mean goal time, 4.6 [7.4] s). Delaying isoflurane exposure until postnatal day 14 in males preserved spatial memory (probe trial F[1, 140] = 28; P < 0.001; mean goal time, 6.1 [7.0] s). Conclusions Vulnerability to isoflurane neurotoxicity is abolished by blocking the androgen receptor, disrupting the function of NKCC1, or delaying the time of exposure to at least 2 weeks of age in male rats. These results support a dynamic role for androgens and chloride transporter proteins in perinatal anesthetic neurotoxicity. Editor’s Perspective What We Already Know about This Topic What This Article Tells Us That Is New

scholarly journals Development of progressive albuminuria in male Munich Wistar Frömter rats is androgen dependent

2015 ◽  
Vol 47 (7) ◽  
pp. 281-289
Author(s):  
Laura Herlan ◽  
Johannes Unland ◽  
Sebastian Langer ◽  
Leonard Schulte ◽  
Sabrina Schütten ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Urinary Albumin Excretion ◽  
Urinary Albumin ◽  
Male Rats ◽  
Significant Suppression ◽  
Tubular Injury ◽  
Main Study ◽  
Androgen Receptor Antagonist ◽  
Renal Tubular ◽  
Nephron Deficit

Munich Wistar Frömter (MWF) rats develop spontaneous albuminuria that is linked to autosomal genetic loci and inherit a nephron deficit in both female and male animals, respectively. However, albuminuria and kidney damage are clearly more pronounced in males. Here we tested whether androgens and the androgen receptor influence albuminuria in male MWF. We first demonstrated in a pilot study that orchiectomy (Ox) of male MWF led to a significant suppression of urinary albumin excretion (UAE), while continuous testosterone supplementation in MWF Ox led to UAE levels similar to sham-operated (Sham) MWF rats. Subsequently, we performed a comparative main study between male MWF and normal Wistar rats to evaluate the effect of the androgen receptor on UAE development in adult animals up to the age of 18 wk. MWF Sham developed a marked increase in UAE compared with Wistar Sham (48.30 ± 6.16 vs. 0.42 ± 0.08 mg/24 h, P < 0.0001). UAE was significantly lower in MWF Ox compared with MWF Sham (−55%, P < 0.0001). In MWF Ox animals supplemented with testosterone and treated with the androgen receptor antagonist flutamide (OxTF) UAE at 18 wk was even lower compared with MWF Ox (−71%, P < 0.01) and similar to age-matched female MWF. The mRNA expression of renal tubular injury markers Kim1 and NGAL was increased in MWF Sham compared with Wistar Sham ( P < 0.0008, respectively) and expression decreased significantly in MWF OxTF ( P < 0.0004, respectively). Thus, the sexual dimorphism in albuminuria development in MWF can be attributed to testosterone and the androgen receptor in male rats.

The effect of anastrozol on spatial memory in adult rats

2009 ◽  
Vol 4 (2) ◽  
pp. 186-189 ◽  
Author(s):  
Július Hodosy ◽  
Peter Celec ◽  
Daniela Ostatníková ◽  
Marieta Cagánová ◽  
Zdeněk Putz ◽  
...  
Keyword(s):  
Androgen Receptor ◽  
Spatial Memory ◽  
Estrogen Receptors ◽  
Molecular Mechanisms ◽  
Male Rats ◽  
Radial Arm Maze ◽  
Adult Rats ◽  
Pharmacological Blockade ◽  
Level Of Significance ◽  
And Control

AbstractAndrogens are known to affect cognitive functions via organizational and activational effects. It is unknown whether the effects are mediated via the androgen receptor or after conversion to estradiol with aromatase via estrogen receptors. The aim of our study was to find out whether testosterone affects spatial memory directly or through its metabolite estradiol. Rats were treated with testosterone; with testosterone and the aromatase blocker anastrozole or saline. An 8 radial arm maze was used for testing spatial memory twice daily for 4 days. Each arm was baited with food, and the ability of animals to learn the location of food was assessed. Testosterone treated rats and control rats achieved comparable coefficients of spatial memory, although the plasma levels of testosterone differed markedly. Anastrozole treatment resulted in the worst performance in the maze. The differences between groups did not reach the level of significance. It can be concluded that aromatase and, thus, the conversion of testosterone to estradiol may play a role in spatial memory, as pharmacological blockade of aromatase led to a decrease in maze performace of adult male rats. Detailed molecular mechanisms should be the focus of further studies.

scholarly journals Contextual Fear Memory Formation and Destabilization Induce Hippocampal RyR2 Calcium Channel Upregulation

2018 ◽  
Vol 2018 ◽  
pp. 1-11
Author(s):  
Jamileth More ◽  
María Mercedes Casas ◽  
Gina Sánchez ◽  
Cecilia Hidalgo ◽  
Paola Haeger
Keyword(s):  
Spatial Memory ◽  
Fear Memory ◽  
Contextual Fear Conditioning ◽  
Male Rats ◽  
Endoplasmic Reticulum Membrane ◽  
Memory Retention ◽  
Contextual Fear ◽  
Memory Processes ◽  
Contextual Fear Memory ◽  
Protein Levels

Hippocampus-dependent spatial and aversive memory processes entail Ca2+ signals generated by ryanodine receptor (RyR) Ca2+ channels residing in the endoplasmic reticulum membrane. Rodents exposed to different spatial memory tasks exhibit significant hippocampal RyR upregulation. Contextual fear conditioning generates robust hippocampal memories through an associative learning process, but the effects of contextual fear memory acquisition, consolidation, or extinction on hippocampal RyR protein levels remain unreported. Accordingly, here we investigated if exposure of male rats to contextual fear protocols, or subsequent exposure to memory destabilization protocols, modified the hippocampal content of type-2 RyR (RyR2) channels, the predominant hippocampal RyR isoforms that hold key roles in synaptic plasticity and spatial memory processes. We found that contextual memory retention caused a transient increase in hippocampal RyR2 protein levels, determined 5 h after exposure to the conditioning protocol; this increase vanished 29 h after training. Context reexposure 24 h after training, for 3, 15, or 30 min without the aversive stimulus, decreased fear memory and increased RyR2 protein levels, determined 5 h after reexposure. We propose that both fear consolidation and extinction memories induce RyR2 protein upregulation in order to generate the intracellular Ca2+ signals required for these distinct memory processes.

scholarly journals Changes in Hippocampal Androgen Receptor Density and Behavior in Sprague-Dawley Male Rats Exposed to a Low-Pressure Blast Wave

2020 ◽  
Vol 5 (2) ◽  
pp. 135-145
Author(s):  
Jay R. Hoffman ◽  
Amitai Zuckerman ◽  
Omri Ram ◽  
Oren Sadot ◽  
Hagit Cohen
Keyword(s):  
Androgen Receptor ◽  
Spatial Memory ◽  
Blast Wave ◽  
Low Pressure ◽  
Male Rats ◽  
Morris Water Maze Test ◽  
Control Group ◽  
Sprague Dawley ◽  
Post Exposure ◽  
Anxiety Index

Objective: The purpose of this study was to examine the effect of exposure of a low-intensity blast wave on androgen receptor (AR) density in the hippocampus and the potential influence on behavioral and cognitive responses. Methods: Sprague-Dawley rats were randomly assigned to either a blast exposed group (n = 27) or an unexposed (control) group (n = 10). Animals were treated identically, except that rats within the control group were not exposed to any of the characteristics of the blast wave. Behavior measures were conducted on day seven post-exposure. The rats were initially assessed in the elevated plus maze followed by the acoustic startle response paradigm. Spatial memory performance using the Morris water-maze test was assessed at 8-days post-exposure, for seven consecutive days. Following all behavioral tests AR immunofluorescence staining was performed in different hippocampal subregions. Results: A significant elevation in anxiety index (p < 0.001) and impaired learning (p < 0.015) and spatial memory (p < 0.0015) were noted in exposed rats. In addition, a significant attenuation of the AR was noted in the CA1 (p = 0.006) and dentate gyrus (p = 0.031) subregions of the hippocampus in blast exposed animals. Correlational analyses revealed significant associations between AR and both anxiety index (r = –.36, p = 0.031) and memory (r = –0.38, p = 0.019). Conclusions: The results of this study demonstrate that exposure to a low-pressure blast wave resulted in a decrease in AR density, which was associated with significant behavioral and cognitive changes.

Computational and Functional Analysis of the Androgen Receptor Antagonist Atraric Acid and Its Derivatives

2013 ◽  
Vol 13 (5) ◽  
pp. 801-810 ◽  
Author(s):  
Maria Papaioannou ◽  
Annu A. Soderholm ◽  
Wei Hong ◽  
Yifan Dai ◽  
Julia Roediger ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Androgen Receptor ◽  
Receptor Antagonist ◽  
Androgen Receptor Antagonist

scholarly journals CK2 Pro-Survival Role in Prostate Cancer Is Mediated via Maintenance and Promotion of Androgen Receptor and NFκB p65 Expression

2019 ◽  
Vol 12 (2) ◽  
pp. 89
Author(s):  
Janeen H. Trembley ◽  
Betsy T. Kren ◽  
Md. J. Abedin ◽  
Daniel P. Shaughnessy ◽  
Yingming Li ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Inhibitory Effect ◽  
Strongly Correlated ◽  
Protein Levels ◽  
Small Molecule Inhibition ◽  
Prostate Cells ◽  
Cell Death Response ◽  
Stress Signals ◽  
Castrate Resistant

The prosurvival protein kinase CK2, androgen receptor (AR), and nuclear factor kappa B (NFκB) interact in the function of prostate cells, and there is evidence of crosstalk between these signals in the pathobiology of prostate cancer (PCa). As CK2 is elevated in PCa, and AR and NFκB are involved in the development and progression of prostate cancer, we investigated their interaction in benign and malignant prostate cells in the presence of altered CK2 expression. Our results show that elevation of CK2 levels caused increased levels of AR and NFκB p65 in prostate cells of different phenotypes. Analysis of TCGA PCa data indicated that AR and CK2α RNA expression are strongly correlated. Small molecule inhibition or molecular down-regulation of CK2 caused reduction in AR mRNA expression and protein levels in PCa cells and in orthotopic xenograft tumors by various pathways. Among these, regulation of AR protein stability plays a unifying role in CK2 maintenance of AR protein levels. Our results show induction of various endoplasmic reticulum stress signals after CK2 inhibition, which may play a role in the PCa cell death response. Of note, CK2 inhibition caused loss of cell viability in both parental and enzalutamide-resistant castrate-resistant PCa cells. The present work elucidates the specific link of CK2 to the pathogenesis of PCa in association with AR and NFκB expression; further, the observation that inhibition of CK2 can exert a growth inhibitory effect on therapy-resistant PCa cells emphasizes the potential utility of CK2 inhibition in patients who are on enzalutamide treatment for advanced cancer.

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