Early gender differences in the redox status of the brain mitochondria with age: effects of melatonin therapy

2013 ◽  
Vol 16 (2) ◽  
Author(s):  
Germaine Escames ◽  
María E. Díaz-Casado ◽  
Carolina Doerrier ◽  
Marta Luna-Sánchez ◽  
Luis C. López ◽  
...  
Keyword(s):  
Gender Differences ◽  
Mitochondrial Dysfunction ◽  
Nitrosative Stress ◽  
Brain Mitochondria ◽  
Male And Female ◽  
Atp Production ◽  
Female Mice ◽  
Stress Markers ◽  
Melatonin Administration ◽  
The Brain

AbstractMitochondrial dysfunction and oxidative/nitrosative stress are common features of senescence, and they explain some of the pathophysiological events during aging. In different animal models of aging, the existence of oxidative stress, inflammation, and mitochondrial dysfunction has been reported. There is no information, however, regarding the age when these symptoms begin and if they account for gender differences in aging. Here we analyzed oxidative/nitrosative stress markers and bioenergetics in the brain mitochondria of normal mice during the first 10 months of life, looking for early signs of senescence. Male and female mice were treated with vehicle or melatonin during the first 9 months of life, starting at weaning. Mice were sacrificed at 5 and 10 months of life, and pure brain mitochondria were prepared and assayed for respiratory chain activity, ATP production, and oxidative/nitrosative stress status. The results showed that the brain mitochondria from male mice have a better glutathione cycle than female mice, whereas female mice have higher electron transport chain activity and ATP production at 5 months old. Five months later, however, oxidative/nitrosative stress markers increased in both male and female mice, thus eliminating the differences between the genders. More importantly, these changes were prevented by chronic melatonin administration, which also restored the gender differences found in 5-month-old mice. Thus, melatonin administration as a single therapy can maintain the full function of the brain mitochondria during the early events of aging, a finding that has important consequences in the pathophysiology of brain senescence.

scholarly journals Gender differences in the response of CD-1 mouse bone to parathyroid hormone: potential role of IGF-I

2006 ◽  
Vol 189 (2) ◽  
pp. 279-287 ◽  
Author(s):  
Yongmei Wang ◽  
Takeshi Sakata ◽  
Hashem Z Elalieh ◽  
Scott J Munson ◽  
Andrew Burghardt ◽  
...  
Keyword(s):  
Gender Differences ◽  
Parathyroid Hormone ◽  
Cortical Bone ◽  
Mineral Apposition Rate ◽  
Mrna Levels ◽  
Male Mice ◽  
Bone Formation Rate ◽  
Male And Female ◽  
Female Mice ◽  
Igf I

Parathyroid hormone (PTH) exerts both catabolic and anabolic actions on bone. Studies on the skeletal effects of PTH have seldom considered the effects of gender. Our study was designed to determine whether the response of mouse bone to PTH differed according to sex. As a first step, we analyzed gender differences with respect to bone mass and structural properties of 4 month old PTH treated (80 μg/kg per day for 2 weeks) male and female CD-1 mice. PTH significantly increased fat free weight/body weight, periosteal bone formation rate, mineral apposition rate, and endosteal single labeling surface, while significantly decreasing medullary area in male mice compared with vehicle treated controls, but induced no significant changes in female mice. We then analyzed the gender differences in bone marrow stromal cells (BMSC) isolated from 4 month old male and female CD-1 mice following treatment with PTH (80 μg/kg per day for 2 weeks). PTH significantly increased the osteogenic colony number and the alkaline phosphatase (ALP) activity (ALP/cell) by day 14 in cultures of BMSCs from male and female mice. PTH also increased the mRNA level of receptor activator of nuclear factor κB ligand in the bone tissue (marrow removed) of both females and males. However, PTH increased the mRNA levels of IGF-I and IGF-IR only in the bones of male mice. Our results indicate that on balance a 2-weeks course of PTH is anabolic on cortical bone in this mouse strain. These effects are more evident in the male mouse. These differences between male and female mice may reflect the greater response to PTH of IGF-I and IGF-IR gene expression in males enhancing the anabolic effect on cortical bone.

scholarly journals Involvement of NMDA receptors containing the GluN2C subunit in the psychotomimetic and antidepressant-like effects of ketamine

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Mireia Tarrés-Gatius ◽  
Lluís Miquel-Rio ◽  
Leticia Campa ◽  
Francesc Artigas ◽  
Anna Castañé
Keyword(s):  
Motor Coordination ◽  
Sensory Information ◽  
Wild Type ◽  
Thalamic Nuclei ◽  
Treatment Resistant ◽  
Cortical Networks ◽  
Male And Female ◽  
Female Mice ◽  
Antidepressant Effects ◽  
The Brain

AbstractAcute ketamine administration evokes rapid and sustained antidepressant effects in treatment-resistant patients. However, ketamine also produces transient perceptual disturbances similarly to those evoked by other non-competitive NMDA-R antagonists like phencyclidine (PCP). Although the brain networks involved in both ketamine actions are not fully understood, PCP and ketamine activate thalamo-cortical networks after NMDA-R blockade in GABAergic neurons of the reticular thalamic nucleus (RtN). Given the involvement of thalamo-cortical networks in processing sensory information, these networks may underlie psychotomimetic action. Since the GluN2C subunit is densely expressed in the thalamus, including the RtN, we examined the dependence of psychotomimetic and antidepressant-like actions of ketamine on the presence of GluN2C subunits, using wild-type and GluN2C knockout (GluN2CKO) mice. Likewise, since few studies have investigated ketamine’s effects in females, we used mice of both sexes. GluN2C deletion dramatically reduced stereotyped (circling) behavior induced by ketamine in male and female mice, while the antidepressant-like effect was fully preserved in both genotypes and sexes. Despite ketamine appeared to induce similar effects in both sexes, some neurobiological differences were observed between male and female mice regarding c-fos expression in thalamic nuclei and cerebellum, and glutamate surge in prefrontal cortex. In conclusion, the GluN2C subunit may discriminate between antidepressant-like and psychotomimetic actions of ketamine. Further, the abundant presence of GluN2C subunits in the cerebellum and the improved motor coordination of GluN2CKO mice after ketamine treatment suggest the involvement of cerebellar NMDA-Rs in some behavioral actions of ketamine.

scholarly journals Cyclopamine and Rapamycin Synergistically Inhibit mTOR Signalling in Mouse Hepatocytes, Revealing an Interaction of Hedgehog and mTor Signalling in the Liver

Cells ◽  
2020 ◽  
Vol 9 (8) ◽  
pp. 1817
Author(s):  
Luise Spormann ◽  
Christiane Rennert ◽  
Erik Kolbe ◽  
Fritzi Ott ◽  
Carolin Lossius ◽  
...  
Keyword(s):  
Lipid Metabolism ◽  
Energy Homeostasis ◽  
In Vitro Studies ◽  
Primary Hepatocytes ◽  
Male And Female ◽  
Atp Production ◽  
Female Mice ◽  
Oxidative Respiration ◽  
Mtor Signalling

In the liver, energy homeostasis is mainly regulated by mechanistic target of rapamycin (mTOR) signalling, which influences relevant metabolic pathways, including lipid metabolism. However, the Hedgehog (Hh) pathway is one of the newly identified drivers of hepatic lipid metabolism. Although the link between mTOR and Hh signalling was previously demonstrated in cancer development and progression, knowledge of their molecular crosstalk in healthy liver is lacking. To close this information gap, we used a transgenic mouse model, which allows hepatocyte-specific deletion of the Hh pathway, and in vitro studies to reveal interactions between Hh and mTOR signalling. The study was conducted in male and female mice to investigate sexual differences in the crosstalk of these signalling pathways. Our results reveal that the conditional Hh knockout reduces mitochondrial adenosine triphosphate (ATP) production in primary hepatocytes from female mice and inhibits autophagy in hepatocytes from both sexes. Furthermore, in vitro studies show a synergistic effect of cyclopamine and rapamycin on the inhibition of mTor signalling and oxidative respiration in primary hepatocytes from male and female C57BL/6N mice. Overall, our results demonstrate that the impairment of Hh signalling influences mTOR signalling and therefore represses oxidative phosphorylation and autophagy.

scholarly journals Leptin pharmacokinetics in male mice

2017 ◽  
Vol 6 (1) ◽  
pp. 20-26 ◽  
Author(s):  
Robert A Hart ◽  
Robin C Dobos ◽  
Linda L Agnew ◽  
Neil A Smart ◽  
James R McFarlane
Keyword(s):  
Digestive Tract ◽  
Time Course ◽  
Normal Male ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Males And Females ◽  
High Degree ◽  
The Brain ◽  
Major Target

Pharmacokinetics of leptin in mammals has not been studied in detail and only one study has examined more than one time point in non-mutant mice and this was in a female mice. This is the first study to describe leptin distribution over a detailed time course in normal male mice. A physiologic dose (12 ng) of radiolabelled leptin was injected into adult male mice via the lateral tail vein and tissues were dissected out and measured for radioactivity over a time course of up to two hours. Major targets were the digestive tract, kidneys, skin and lungs. The brain was not a major target, and 0.15% of the total dose was recovered from the brain 5 min after administration. Major differences appear to exist in the distribution of leptin between the male and female mice, indicating a high degree of sexual dimorphism. Although the half-lives were similar between male and female mice, almost twice the proportion of leptin was recovered from the digestive tract of male mice in comparison to that reported previously for females. This would seem to indicate a major difference in leptin distribution and possibly function between males and females.

scholarly journals METABOLISM ANALYSIS IN MICE WITH REDUCED CITRATE SYNTHASE ACTIVITY

2017 ◽  
Vol 2 (105) ◽  
pp. 14-19
Author(s):  
Andrej Fokin ◽  
Petras Minderis ◽  
Rasa Žūkienė ◽  
Aivaras Ratkevičius
Keyword(s):  
Physical Activity ◽  
Gender Differences ◽  
Energy Expenditure ◽  
Citrate Synthase ◽  
Mouse Strains ◽  
Male Mice ◽  
Wild Type ◽  
Male And Female ◽  
Female Mice ◽  
Metabolism Analysis

Background.  Citrate  synthase  (CS)  plays  an  important  role  in  the  regulation  of  carbohydrate  oxidation. Variation in citrate synthase activity has an influence on metabolic changes. We tested the hypothesis that reduced mitochondrial CS activity could affect energy expenditure (EE) and respiratory quotient (RQ) in mouse model with an emphasizing on gender differences between tested strains. Methods. 16-week of age wild-type C57Bl/6J (B6) mouse strain, B6.A-(rs3676616-D10Utsw1)/Kjn (B6.A) and C57BL/6J-Chr 10A/J/NaJ (B6.A10) strains with reduced CS activity were studied in physiocage by the “Panlab” metabolism analysing equipment. The following parameters were calculated: EE (ml/min/kg^0.75), RQ, physical activity and rearing. Results. In female mice EE values were lower in B6.A10 strain compared to wild-type B6 strain. RQ values were similar in all tested mouse strains. In B6 mice EE was higher in females compared to males. Rearing was elevated in females of B6 mice compared to males. Conclusions. EE was lower in B6.A10 compared to B6 mice. Gender differences were noticed only in B6 mice: EE and rearing were significantly higher in female compared to male mice. Current study did not reveal any other association between reduced CS activity and EE or RQ variation in male and female mice.

scholarly journals Mitochondrial Respiration Is Impaired during Late-Stage Hamster Prion Infection

2017 ◽  
Vol 91 (18) ◽  
Author(s):  
Robert Faris ◽  
Roger A. Moore ◽  
Anne Ward ◽  
Dan E. Sturdevant ◽  
Suzette A. Priola
Keyword(s):  
Electron Transport ◽  
Transgenic Mice ◽  
Mitochondrial Dysfunction ◽  
Prion Protein ◽  
Prion Disease ◽  
Mitochondrial Respiration ◽  
Brain Mitochondria ◽  
Prion Strain ◽  
Prion Infection ◽  
The Brain

ABSTRACT Mitochondria are crucial to proper neuronal function and overall brain health. Mitochondrial dysfunction within the brain has been observed in many neurodegenerative diseases, including prion disease. Several markers of decreased mitochondrial activity during prion infection have been reported, yet the bioenergetic respiratory status of mitochondria from prion-infected animals is unknown. Here we show that clinically ill transgenic mice overexpressing hamster prion protein (Tg7) infected with the hamster prion strain 263K suffer from a severe deficit in mitochondrial oxygen consumption in response to the respiratory complex II substrate succinate. Characterization of the mitochondrial proteome of purified brain mitochondria from infected and uninfected Tg7 mice showed significant differences in the relative abundance of key mitochondrial electron transport proteins in 263K-infected animals relative to that in controls. Our results suggest that at clinical stages of prion infection, dysregulation of respiratory chain proteins may lead to impairment of mitochondrial respiration in the brain. IMPORTANCE Mitochondrial dysfunction is present in most major neurodegenerative diseases, and some studies have suggested that mitochondrial processes may be altered during prion disease. Here we show that hamster prion-infected transgenic mice overexpressing the hamster prion protein (Tg7 mice) suffer from mitochondrial respiratory deficits. Tg7 mice infected with the 263K hamster prion strain have little or no signs of mitochondrial dysfunction at the disease midpoint but suffer from a severe deficit in mitochondrial respiration at the clinical phase of disease. A proteomic analysis of the isolated brain mitochondria from clinically affected animals showed that several proteins involved in electron transport, mitochondrial dynamics, and mitochondrial protein synthesis were dysregulated. These results suggest that mitochondrial dysfunction, possibly exacerbated by prion protein overexpression, occurs at late stages during 263K prion disease and that this dysfunction may be the result of dysregulation of mitochondrial proteins.

Abstract P141: Gender Differences in the Development of Severe Pulmonary Hypertension and Right Ventricular Dysfunction in Apolipoprotein E--Deficient Mice Are Eliminated with Increasing Age

2011 ◽  
Vol 109 (suppl_1) ◽  
Author(s):  
Rod Partow-Navid ◽  
Soban Umar ◽  
Humann Matori ◽  
Andrea Iorga ◽  
Alan M Fogelman ◽  
...  
Keyword(s):  
Gender Differences ◽  
Pulmonary Hypertension ◽  
Right Ventricular ◽  
Apolipoprotein E ◽  
Young Male ◽  
Male Mice ◽  
Male And Female ◽  
Young Females ◽  
Female Mice ◽  
Deficient Mice

Apolipoprotein E (ApoE) is a multifunctional protein and its deficiency leads to the development of atherosclerosis in mice. Patients with pulmonary hypertension (PH) have reduced expression of ApoE in lung tissue. ApoE is known to inhibit endothelial and smooth muscle cell proliferation and has anti-inflammatory and anti-platelet aggregation properties. Young ApoE deficient mice have been shown to develop high fat diet-induced PH in a gender specific manner. Estrous cyclicity peaks at 7–8 months and declines by 9 months of age in mice. Here we investigated the effects of monocrotaline (MCT) on young and middle-aged ApoE deficient mice.Middle-Aged (MA) (11–12 month old) male (n=4) and female (n=4) and young (7–8 month old) male (n=5) and female (n=5) ApoE deficient mice were injected with a single intraperitoneal dose of MCT (60 mg/kg). Mice were closely monitored for ∼4 weeks with serial echocardiography for cardiopulmonary hemodynamic assessment. Direct cardiac catheterisation was performed terminally to record peak systolic right ventricular pressure (RVP). RV, LV, IVS and lung tissue was dissected and weighed. Trichrome staining and histochemical analyses were performed. At ∼4 weeks after MCT, MA male and female and young male mice developed severe PH (RVP: MA male=64±5 mmHg, MA female=71±4 mmHg, young male=60±5 mmHg, p=n.s between all the groups) whereas young females developed significantly less severe PH (RVP: 37±5 mmHg, P<0.05 vs. MA male and female, and young male). MA male and female and young male mice developed severe RV dysfunction (RV ejection fraction (RVEF): MA male=31±2%, MA female=28±4%, young male=36±1%, p=n.s between all the groups) whereas young females showed significantly better RV function (RVEF: 43±2%, P<0.05 vs. MA male and female, and young male). MA male and female mice also developed more severe RV hypertrophy (RV/LV+Septum, MA male=0.49, MA female=0.53, young female=0.39). MA male and female mice also manifested increased peripheral pulmonary artery muscularization and pulmonary fibrosis. Interestingly, the gender differences witnessed between young ApoE deficient male and female mice in the development of severe PH and RV dysfunction are abolished as the mice increase in age.

Stimulation of the brain serotonin receptor 7 rescues mitochondrial dysfunction in female mice from two models of Rett syndrome

2017 ◽  
Vol 121 ◽  
pp. 79-88 ◽  
Author(s):  
Daniela Valenti ◽  
Lidia de Bari ◽  
Daniele Vigli ◽  
Enza Lacivita ◽  
Marcello Leopoldo ◽  
...  
Keyword(s):  
Mitochondrial Dysfunction ◽  
Rett Syndrome ◽  
Serotonin Receptor ◽  
Brain Serotonin ◽  
Female Mice ◽  
The Brain ◽  
Stimulation Of

scholarly journals Iba1+ cell density and morphology classification at postnatal day 10 in four hippocampal subregions of female and male C57BL/6J mice

2021 ◽  
Author(s):  
Danielle Guez-Barber ◽  
Max Wragan ◽  
Dana Raphael ◽  
Haley M. Phillips ◽  
Kira Lu ◽  
...  
Keyword(s):  
Sex Differences ◽  
Cell Density ◽  
Female Rats ◽  
Male Rats ◽  
Lower Percentage ◽  
Male Mice ◽  
Male And Female ◽  
Female Mice ◽  
Mouse Hippocampus ◽  
The Brain

Microglia maintain normal brain function and support the brain′s response to disease and injury. The hippocampus is an area of focus for microglial study due to its central role in numerous behavioral and cognitive functions. Interestingly, microglia and related cells in the hippocampus and throughout the brain are distinct in male vs. female rodents, even in early life. Indeed, postnatal day (P)-dependent sex differences in number, density, and morphology of microglia-like cells have been reported in certain hippocampal subregions. For example, P3 female mice have more phagocytic microglia in dentate gyrus (DG) molecular layer (Mol) and CA1-3 stratum oriens (SO) regions vs. male mice, while P8 — but not P15 — male rats have more volume immunoreactive for markers of microglia-like cells (Iba1 and CD68) in the CA1 stratum radiatum (SR) vs. female rats. In the mouse, P10 is roughly equivalent to human term gestation, making it a common time point to study for many translationally-relevant neurobiological processes. However, sex differences in hippocampal microglia have not been examined in the P10 mouse hippocampus. In addition, key subregions of the hippocampus — CA3 SR, DG hilus — have not yet been assessed for sex differences in microglia. To address these knowledge gaps, we quantified Iba1+ cell densities and classified Iba1+ cell morphology in P10 male and female C57BL/6J mice. Four subregions in the bilateral anterior hippocampus were analyzed in 40-μm coronal sections: DG Mol (Mol), DG Hilus, CA1 SR and stratum lacunosum moleculare (CA1), and CA3 SR and stratum lucidum (CA3). Light microscope images (40x) were analyzed offline for Iba1+ cell density and morphology by an observer blind to sex. The morphology of each Iba1+ cell was used to place cells into one of four previously-published categories: Round or ameboid (round-ish soma, no processes), Stout (round-ish soma, short process), Thick (irregular soma with few, thick processes), or Thin (irregular soma with multiple thin processes). Analysis of Iba1+ cell density shows no difference between male and female mice in Mol, Hilus, CA3, or CA1 (male n=6, female n=7). However, morphology classification shows a sex-dependent difference in the Mol and Hilus, with female mice having a greater percentage of Thick Iba1+ cells vs. male mice (Mol, Hilus), and a lower percentage of Thin Iba1+ cells vs. male mice (Mol). With our analysis, it is unclear whether this greater percentage of thick and lower percentage of thin Iba1+ cells in the female vs. male hippocampus means Iba1+ microglia in female mice are ″younger″ or ″more active″ than those in male mice. However, these data are important as they reveal sex differences in Iba1+ microglia in the P10 mouse hippocampus. We discuss these results in the context of the large literature on sex differences in rodent microglia in the early postnatal period.

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