scholarly journals Developmental Changes of Leptin Receptors in Cerebral Microvessels: Unexpected Relation to Leptin Transport

Endocrinology ◽  
2007 ◽  
Vol 149 (3) ◽  
pp. 877-885 ◽  
Author(s):  
Weihong Pan ◽  
Hung Hsuchou ◽  
Hong Tu ◽  
Abba J. Kastin
Keyword(s):  
Leptin Receptor ◽  
Brain Perfusion ◽  
Developmental Changes ◽  
Pcr Analysis ◽  
Receptor Subtypes ◽  
Cerebral Microvessels ◽  
Leptin Receptors ◽  
Age Related ◽  
Significant Difference ◽  
Age Related Changes

The adipokine leptin participates not only in the regulation of feeding and obesity in adults but also in neonatal development. It crosses the blood-brain barrier (BBB) by receptor-mediated transport. Leptin concentrations in blood differ between neonates and adults. We determined the developmental changes of leptin receptor subtypes in the cerebral microvessels composing the BBB and examined their expected correlation with leptin transport across the BBB. Total RNA was extracted from enriched cerebral microvessels of mice 1, 7, 14, and 60 d of age for real-time RT-PCR analysis of leptin receptor subtypes. In cerebral microvessels from neonates, ObRa, ObRb, ObRc, and ObRe mRNA were all higher than in adults, but ObRd was not detectable. Hypothalamus showed similar age-related changes except for ObRb, which was higher in adults. The homologous receptor gp130 did not show significant age-related changes in either region. Despite the increase of leptin receptors, leptin permeation across the BBB after iv injection was less in the neonates. In situ brain perfusion with blood-free buffer showed no significant difference in the brain uptake of leptin between neonates and adults, indicating an antagonistic role of leptin-binding proteins in the circulation, especially the soluble receptor ObRe. The results are consistent with our previous finding that ObRe antagonizes leptin endocytosis in cultured endothelia and transport from blood to brain in mice. Overall, the developmental changes observed for leptin receptors unexpectedly failed to correlate with the entry of leptin into brain, and this may indicate different functions of the receptors in neonates and adults.

scholarly journals O20 Dose-linearity of the pharmacokinetics of an intravenous [14C]midazolam microdose in children

2019 ◽  
Vol 104 (6) ◽  
pp. e9.1-e9
Author(s):  
BD van Groen ◽  
WHJ Vaes ◽  
BK Park ◽  
EHJ Krekels ◽  
E van Duijn ◽  
...  
Keyword(s):  
Drug Disposition ◽  
Plasma Concentrations ◽  
Volume Of Distribution ◽  
Developmental Changes ◽  
Developmentally Regulated ◽  
Age Related ◽  
Dose Linearity ◽  
Significant Difference ◽  
Therapeutic Doses ◽  
Cyp3a Enzyme

BackgroundDrug disposition in children may vary from adults due to age-related variation in drug metabolism, but paediatric pharmacokinetic (PK) studies are challenging. Microdose studies present an innovation to study PK in paediatrics, and can only be used when the PK of a microdose are dose-linear to a therapeutic dose. We aimed to assess dose-linearity of [14C]midazolam (MDZ), a marker for the activity of the developmentally regulated CYP3A enzyme, by comparing the PK of an intravenous (IV) [14C]MDZ microtracer given simultaneously with therapeutic MDZ, with the PK of a single IV [14C]MDZ microdose.MethodsPreterm to 2-year-old infants admitted to the intensive care unit received [14C]MDZ IV either as a microtracer during therapeutic MDZ infusion or as an isolated microdose. Dense blood sampling was done up to 36 hours after dosing. Plasma concentrations of [14C]MDZ and [14C]1-OH-MDZ were determined by accelerator mass spectrometry. A population PK model was developed with NONMEM 7.4 to study whether there was a difference in the PK of the microtracer versus those of a microdose [14C]MDZ.ResultsOf fifteen children (median gestational age 39.4 [range 23.9–41.4] weeks, postnatal age 11.4 [0.6–49.1] weeks), nine received a microdose and six a microtracer [14C]MDZ (111 Bq/kg; 37.6 ng/kg). In a two-compartment PK model, bodyweight was the most significant covariate for volume of distribution. There was no statistically significant difference in any PK parameter between the [14C]MDZ microdose or microtracer, suggesting the PK of MDZ to be linear within the range of the therapeutic doses and microdoses.ConclusionOur data supports the dose-linearity of an IV [14C]MDZ microdose in children, thus a [14C]MDZ microdosing approach can be used to study developmental changes in hepatic CYP3A activity.Disclosure(s)This project was funded by the ZonMw ERA-NET PRIOMEDCHILD programme (projectnumber 113205022). * both authors contributed equally

scholarly journals Age-related positivity effect on behavioural responses of dogs to human vocalisations

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Iris Smit ◽  
Dora Szabo ◽  
Enikő Kubinyi
Keyword(s):  
Emotional Processing ◽  
Positive Emotions ◽  
Attention And Memory ◽  
Positivity Effect ◽  
Behavioural Responses ◽  
Fundamental Frequencies ◽  
Age Related ◽  
Significant Difference ◽  
The Brain ◽  
Age Related Changes

AbstractAge-related changes in the brain can alter how emotions are processed. In humans, valence specific changes in attention and memory were reported with increasing age, i.e. older people are less attentive toward and experience fewer negative emotions, while processing of positive emotions remains intact. Little is yet known about this “positivity effect” in non-human animals. We tested young (n = 21, 1–5 years) and old (n = 19, >10 years) family dogs with positive (laugh), negative (cry), and neutral (hiccup, cough) human vocalisations and investigated age-related differences in their behavioural reactions. Only dogs with intact hearing were analysed and the selected sound samples were balanced regarding mean and fundamental frequencies between valence categories. Compared to young dogs, old individuals reacted slower only to the negative sounds and there was no significant difference in the duration of the reactions between groups. The selective response of the aged dogs to the sound stimuli suggests that the results cannot be explained by general cognitive and/or perceptual decline. and supports the presence of an age-related positivity effect in dogs, too. Similarities in emotional processing between humans and dogs may imply analogous changes in subcortical emotional processing in the canine brain during ageing.

Age-related changes in the transcriptional profile of mouse RPE/choroid

2003 ◽  
Vol 15 (3) ◽  
pp. 258-262 ◽  
Author(s):  
Hisashi Ida ◽  
Sharon A. Boylan ◽  
Andrea L. Weigel ◽  
Leonard M. Hjelmeland
Keyword(s):  
Gene Expression ◽  
Expression Profiles ◽  
Cdna Probe ◽  
Gene Expression Profiles ◽  
Age Related Macular Degeneration ◽  
Pcr Analysis ◽  
Rt Pcr ◽  
Mouse Cdna ◽  
Age Related ◽  
Age Related Changes

To evaluate the age-related changes in gene expression occurring in the complex of retinal pigmented epithelium, Bruch’s membrane, and choroid (RPE/choroid), we examined the gene expression profiles of young adult (2 mo) and old (24 mo) male C57BL/6 mice. cDNA probe sets from individual animals were synthesized using total RNA isolated from the RPE/choroid of each animal. Probes were amplified using the Clontech SMART system, radioactively labeled, and hybridized to two different Clontech Atlas mouse cDNA arrays. From each age group, three independent triplicates were hybridized to the arrays. Statistical analyses were performed using the Significance Analysis of Microarrays program (SAM version 1.13; Stanford University). Selected array results were confirmed by semi-quantitative RT-PCR analysis. Of 2,340 genes represented on the arrays, ∼60% were expressed in young and/or old mouse RPE/choroid. A moderate fraction (12%) of all expressed genes exhibited a statistically significant change in expression with age. Of these 150 genes, all but two, HMG14 and carboxypeptidase E, were upregulated with age. Many of these upregulated genes can be grouped into several broad functional categories: immune response, proteases and protease inhibitors, stress response, and neovascularization. RT-PCR results from six of six genes examined confirmed the differential change in expression with age of these genes. Our study provides likely candidate genes to further study their role in the development of age-related macular degeneration and other aging diseases affecting the RPE/choroid.

P2-168 Age-related changes of brain perfusion by arterial spin labeled MRI

2004 ◽  
Vol 25 ◽  
pp. S274
Author(s):  
Norbert Schuff ◽  
Geon-Ho Jahng ◽  
Xiaoping Zhu ◽  
Ka-Lo Li ◽  
Michael W. Weiner
Keyword(s):  
Brain Perfusion ◽  
Age Related ◽  
Age Related Changes

scholarly journals Age-related changes in circadian responses to dark pulses

2000 ◽  
Vol 279 (2) ◽  
pp. R586-R590 ◽  
Author(s):  
Marilyn J. Duncan ◽  
Anthony W. Deveraux
Keyword(s):  
Wheel Running ◽  
Activity Rhythm ◽  
Circadian Pacemaker ◽  
Running Activity ◽  
Age Related ◽  
Wheel Running Activity ◽  
Significant Difference ◽  
Time Signals ◽  
Dark Pulse ◽  
Age Related Changes

Aging involves many alterations in circadian rhythms, including a loss of sensitivity to both photic and nonphotic time signals. This study investigated the sensitivity of young and old hamsters to the phase advancing effect of a 6-h dark pulse on the locomotor activity rhythm. Each hamster was tested four times during a period of ∼9 mo; periods of exposure to a 14-h photoperiod were alternated with the periods of exposure to constant light (20–80 lx), during which the dark pulses were administered. There was no significant difference in the phase shifts exhibited by the young (4–10 mo) and old hamsters (19–25 mo) or in the amount of wheel running activity displayed during each dark pulse. However, young hamsters had a significantly greater propensity to exhibit split rhythms immediately after the dark pulses. These results suggest that, although aging does not reduce the sensitivity of the circadian pacemaker to this nonphotic signal, it alters one property of the pacemaker, i.e., the flexibility of the coupling of its component oscillators.

Leptin receptors are expressed in coronary arteries, and hyperleptinemia causes significant coronary endothelial dysfunction

2005 ◽  
Vol 289 (1) ◽  
pp. H48-H56 ◽  
Author(s):  
Jarrod D. Knudson ◽  
Ü. Deniz Dincer ◽  
Cuihua Zhang ◽  
Albert N. Swafford ◽  
Ryoji Koshida ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Endothelial Dysfunction ◽  
Coronary Arteries ◽  
Leptin Receptor ◽  
Receptor Protein ◽  
Zucker Rats ◽  
Pcr Analysis ◽  
Leptin Receptors ◽  
Coronary Endothelium ◽  
Coronary Endothelial Dysfunction

Obesity is associated with marked increases in plasma leptin concentration, and hyperleptinemia is an independent risk factor for coronary artery disease. As a result, the purpose of this investigation was to test the following hypotheses: 1) leptin receptors are expressed in coronary endothelial cells; and 2) hyperleptinemia induces coronary endothelial dysfunction. RT-PCR analysis revealed that the leptin receptor gene is expressed in canine coronary arteries and human coronary endothelium. Furthermore, immunocytochemistry demonstrated that the long-form leptin receptor protein (ObRb) is present in human coronary endothelium. The functional effects of leptin were determined using pressurized coronary arterioles (<130 μm) isolated from Wistar rats, Zucker rats, and mongrel dogs. Leptin induced pharmacological vasodilation that was abolished by denudation and the nitric oxide synthase inhibitor Nω-nitro-l-arginine methyl ester and was absent in obese Zucker rats. Intracoronary leptin dose-response experiments were conducted in anesthetized dogs. Normal and obese concentrations of leptin (0.1–3.0 μg/min ic) did not significantly change coronary blood flow or myocardial oxygen consumption; however, obese concentrations of leptin significantly attenuated the dilation to graded intracoronary doses of acetylcholine (0.3–30.0 μg/min). Additional experiments were performed in canine coronary rings, and relaxation to acetylcholine (6.25 nmol/l-6.25 μmol/l) was significantly attenuated by obese concentrations of leptin (625 pmol/l) but not by physiological concentrations of leptin (250 pmol/l). The major findings of this investigation were as follows: 1) the ObRb is present in coronary arteries and coupled to pharmacological, nitric oxide-dependent vasodilation; and 2) hyperleptinemia produces significant coronary endothelial dysfunction.

Age-related changes in brain perfusion of normal subjects detected by 99m Tc-HMPAO SPECT

1998 ◽  
Vol 40 (7) ◽  
pp. 428-434 ◽  
Author(s):  
Y. Krausz ◽  
O. Bonne ◽  
M. Gorfine ◽  
H. Karger ◽  
B. Lerer ◽  
...  
Keyword(s):  
Brain Perfusion ◽  
Normal Subjects ◽  
Age Related ◽  
Hmpao Spect ◽  
Age Related Changes

Age-related changes in functional connectivity between young adulthood and late adulthood

2015 ◽  
Vol 7 (10) ◽  
pp. 4111-4122 ◽  
Author(s):  
Xin Xu ◽  
Qifan Kuang ◽  
Yongqing Zhang ◽  
Huijun Wang ◽  
Zhining Wen ◽  
...  
Keyword(s):  
Functional Connectivity ◽  
Young Adulthood ◽  
Brain Network ◽  
Late Adulthood ◽  
Functional Brain ◽  
Age Related ◽  
Functional Brain Network ◽  
Significant Difference ◽  
Network Metrics ◽  
Age Related Changes

The functional brain network in late adulthood has been found to show a significant difference from that in young adulthood using a variety of network metrics.

scholarly journals Astrocyte Leptin Receptor (ObR) and Leptin Transport in Adult-Onset Obese Mice

Endocrinology ◽  
2008 ◽  
Vol 149 (6) ◽  
pp. 2798-2806 ◽  
Author(s):  
Weihong Pan ◽  
Hung Hsuchou ◽  
Yi He ◽  
Amul Sakharkar ◽  
Courtney Cain ◽  
...  
Keyword(s):  
Leptin Receptor ◽  
Spontaneous Mutation ◽  
Brain Perfusion ◽  
Leptin Resistance ◽  
Immunofluorescent Staining ◽  
Adult Onset ◽  
Cerebral Microvessels ◽  
System Sensitivity ◽  
Perfusion Studies ◽  
Unknown Significance

The agouti viable yellow (Avy) spontaneous mutation generates an unusual mouse phenotype of agouti-colored coat and adult-onset obesity with metabolic syndrome. Persistent production of agouti signaling protein in Avy mice antagonizes melanocortin receptors in the hypothalamus. To determine how this disruption of neuroendocrine circuits affects leptin transport across the blood-brain barrier (BBB), we measured leptin influx in Avy and B6 control mice after the development of obesity, hyperleptinemia, and increased adiposity. After iv bolus injection, 125I-leptin crossed the BBB significantly faster in young (2 month old) B6 mice than in young Avy mice or in older (8 month old) mice of either strain. This difference was not observed by in situ brain perfusion studies, indicating the cause being circulating factors, such as elevated leptin levels or soluble receptors. Thus, Avy mice showed peripheral leptin resistance. ObRa, the main transporting receptor for leptin at the BBB, showed no change in mRNA expression in the cerebral microvessels between the age-matched (2 month old) Avy and B6 mice. Higher ObRb mRNA was seen in the Avy microvasculature with unknown significance. Immunofluorescent staining unexpectedly revealed that many of the ObR(+) cells were astrocytes and that the Avy mice showed significantly more ObR(+) astrocytes in the hypothalamus than the B6 mice. Although leptin permeation from the circulation was slower in the Avy mice, the increased ObR expression in astrocytes and increased ObRb mRNA in microvessels suggest the possibility of heightened central nervous system sensitivity to circulating leptin.

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