| 1. |
- Balgoma, David, et al.
(författare)
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Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver
- 2020
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Ingår i: Metabolomics. - : SPRINGER. - 1573-3882 .- 1573-3890. ; 16:1
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: The abuse of anabolic androgenic steroids (AASs) is a source of public concern because of their adverse effects. Supratherapeutic doses of AASs are known to be hepatotoxic and regulate the lipoproteins in plasma by modifying the metabolism of lipids in the liver, which is associated with metabolic diseases. However, the effect of AASs on the profile of lipids in plasma is unknown.Objectives: To describe the changes in the plasma lipidome exerted by AASs and to discuss these changes in the light of previous research about AASs and de novo lipogenesis in the liver.Methods: We treated male Wistar rats with supratherapeutic doses of nandrolone decanoate and testosterone undecanoate. Subsequently, we isolated the blood plasma and performed lipidomics analysis by liquid chromatography-high resolution mass spectrometry.Results: Lipid profiling revealed a decrease of sphingolipids and glycerolipids with palmitic, palmitoleic, stearic, and oleic acids. In addition, lipid profiling revealed an increase in free fatty acids and glycerophospholipids with odd-numbered chain fatty acids and/or arachidonic acid.Conclusion: The lipid profile presented herein reports the imprint of AASs on the plasma lipidome, which mirrors the downregulation of de novo lipogenesis in the liver. In a broader perspective, this profile will help to understand the influence of androgens on the lipid metabolism in future studies of diseases with dysregulated lipogenesis (e.g. type 2 diabetes, fatty liver disease, and hepatocellular carcinoma).
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| 2. |
- Brolin, Erika, et al.
(författare)
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Chronic administration of morphine using mini-osmotic pumps affects spatial memory in the male rat
- 2018
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Ingår i: Pharmacology, Biochemistry and Behavior. - : Elsevier BV. - 0091-3057 .- 1873-5177. ; 167, s. 1-8
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Tidskriftsartikel (refereegranskat)abstract
- The use of opioid analgesics to treat non-cancer pain has increased over the years. Many chronic pain patients suffer from numerous adverse effects, such as reduced quality of life, development of dependence, and cognitive impairments. Cognitive processes are regulated by several systems, one of which involves growth hormone (GH) and its secondary mediator insulin-like growth factor-1 (IGF-1), but also glutamatergic transmission, including receptors such as the N-methyl-D-aspartate (NMDA)-receptor complex. In the laboratory, repeated injections are commonly used to establish animal models of long-term or chronic drug exposure. However, in the present study, we aimed to mimic a more human dose regimen using constant drug delivery provided by mini-osmotic pumps implanted subcutaneously in male Sprague Dawley rats. After developing opioid tolerance the cognitive function of rats was studied. Spatial learning and memory capabilities were evaluated using the rat Morris water maze (MWM). Moreover, gene expression related to the GH/IGF-1-axis and the NMDA-receptor system was analyzed using quantitative PCR (qPCR) and plasma levels of IGF-1 were assessed using the ELISA technique. Our results demonstrate that rats exposed to morphine for 27 days display memory impairments in the MWM probe trial. However, the behavioral effects of chronic morphine treatment were not accompanied by any significant differences in terms of mRNA expression or IGF-1 plasma concentration. The animal model used in this study provides a simple and suitable way to investigate the behavioral and neurochemical effects of chronic opioid treatment similar to the exposure seen in human pain patients.
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| 3. |
- Brolin, Erika, 1984-
(författare)
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Growth hormone in the brain : Focus on cognitive function
- 2017
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Cognitive impairments are an increasing health problem worldwide. In the developed countries, the average life expectancy has dramatically increased over the last decades, and with an elderly population more cases of cognitive impairments appear. Age, genetics, and different medical conditions such as diabetes mellitus, and substance use disorders may all contribute to declined cognitive ability. Physiological functions also decrease with increasing age, as does the activity of the growth hormone (GH)/insulin-like growth factor-1 (IGF-1) axis. Interestingly, both GH and IGF-1 are recognized for their neuroprotective effects and cognitive enhancement. The overall aim of this thesis was to investigate the impact of the somatotrophic axis (i.e. GH/IGF-1 axis) in rodents with cognitive deficiencies induced by diabetes or long-term drug exposure. For the first time cognitive impairments were characterized in diabetic mice using a spatial learning and memory task called the Barnes maze (BM). In diabetic mice, impaired learning in the BM was associated with decreased expression of the GH receptor (GHR) in the frontal cortex, a region important for e.g. working memory. Treatment with GH reversed certain cognitive impairments seen in diabetic animals. In rats treated with gamma-hydroxybutyrate (GHB), a significant decrease of Igf1 mRNA expression in the frontal cortex was observed. This observation may explain the impaired cognitive function previously seen following GHB administration. Furthermore, rats exposed to chronic morphine delivered in mini-osmotic pumps displayed memory impairments in the Morris water maze (MWM), an effect that seems to be associated with the composition of the N-methyl-d-aspartate (NMDA) receptor complex in the frontal cortex. In conclusion, the result strengthens the evidence for GH being a cognitive enhancer. Moreover, the result within this thesis identifies the frontal cortex as an important brain region, where gene expression related to the somatotrophic system is affected in rodents with cognitive impairments. The thesis especially emphasizes the importance of the local somatotrophic system in the brain with regard to cognitive function.
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| 4. |
- Brolin, Erika, et al.
(författare)
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The mRNA expression of insulin-like growth factor-1 (Igf1) is decreased in the rat frontal cortex following gamma-hydroxybutyrate (GHB) administration
- 2017
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 646, s. 15-20
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Tidskriftsartikel (refereegranskat)abstract
- In recent years, growth hormone (GH), together with its secondary mediators insulin-like growth factor-1 (IGF-1) and insulin-like growth factor-2 (IGF-2), have been highlighted for their beneficial effects in the central nervous system (CNS), in particular as cognitive enhancers. Cognitive processes, such as learning and memory, are known to be impaired in individuals suffering from substance abuse. In the present study, we investigated the effect of gamma-hydroxybuturate (GHB), an illicit drug used for its sedating and euphoric properties, on genes associated with the somatotrophic axis in regions of the brain important for cognitive function. Sprague Dawley rats (n =36) were divided into three groups and administered either saline, GHB 50 mg/kg or GHB 300 mg/kg orally for seven days. The levels of Ghr, Igf1 and Igf2 gene transcripts were analyzed using qPCR in brain regions involved in cognition and dependence. The levels of IGF-1 in blood plasma were also determined using ELISA. The results demonstrated a significant down-regulation of Igf1 mRNA expression in the frontal cortex in high-dose treated rats. Moreover, a significant correlation between Igf1 and Ghr mRNA expression was found in the hippocampus, the frontal cortex, and the caudate putamen, indicating local regulation of the GH/IGF-1 axis. To summarize, the current study concludes that chronic GHB treatment influences gene expression of Ghr and Igf1 in brain regions involved in cognitive function.
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| 5. |
- Dabo, Fatimah, et al.
(författare)
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Different SNP combinations in the GCH1 gene and use of labor analgesia
- 2010
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Ingår i: Molecular Pain. - : SAGE Publications. - 1744-8069. ; 6, s. 41-
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Tidskriftsartikel (refereegranskat)abstract
- Background: The aim of this study was to investigate if there is an association between different SNP combinations in the guanosine triphosphate cyclohydrolase (GCH1) gene and a number of pain behavior related outcomes during labor. A population-based sample of pregnant women (n = 814) was recruited at gestational week 18. A plasma sample was collected from each subject. Genotyping was performed and three single nucleotide polymorphisms (SNP) previously defined as a pain-protective SNP combination of GCH1 were used. Results: Homozygous carriers of the pain-protective SNP combination of GCH1 arrived to the delivery ward with a more advanced stage of cervical dilation compared to heterozygous carriers and non-carriers. However, homozygous carriers more often used second line labor analgesia compared to the others. Conclusion: The pain-protective SNP combination of GCH1 may be of importance in the limited number of homozygous carriers during the initial dilation of cervix but upon arrival at the delivery unit these women are more inclined to use second line labor analgesia.
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| 6. |
- Diwakarla, Shanti, et al.
(författare)
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Aryl Sulfonamide Inhibitors of Insulin-Regulated Aminopeptidase Enhance Spine Density in Primary Hippocampal Neuron Cultures
- 2016
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Ingår i: ACS Chemical Neuroscience. - : American Chemical Society (ACS). - 1948-7193. ; 7:10, s. 1383-1392
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Tidskriftsartikel (refereegranskat)abstract
- The zinc metallopeptidase insulin regulated aminopeptidase (IRAP), which is highly expressed in the hippocampus and other brain regions associated with cognitive function, has been identified as a high-affinity binding site of the hexapeptide angiotensin IV (Ang IV). This hexapeptide is thought to facilitate learning and memory by binding to the catalytic site of IRAP to inhibit its enzymatic activity. In support of this hypothesis, low molecular weight, nonpeptide specific inhibitors of TRAP have been shown to enhance memory in rodent models. Recently, it was demonstrated that linear and macrocyclic Ang IV-derived peptides can alter the shape and increase the number of dendritic spines in hippocampal cultures, properties associated with enhanced cognitive performance. After screening a library of 10 500 drug like substances for their ability to inhibit IRAP, we identified a series of low molecular weight aryl sulfonamides, which exhibit no structural similarity to Ang IV, as moderately potent IRAP inhibitors:A structural and biological characterization of three of these aryl sulfonamides was performed. Their binding modes to human IRAP were explored by docking calculations combined with molecular dynamics simulations and binding affinity estimations using the linear interaction energy method. Two alternative binding modes emerged from this analysis, both of which correctly rank the ligands according to their experimental binding affinities for this series of compounds. Finally, we show that two of these drug-like IRAP inhibitors can alter dendritic spine morphology and increase spine density in primary cultures of hippocampal neurons.
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| 7. |
- Diwakarla, Shanti, et al.
(författare)
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Binding to and Inhibition of Insulin-Regulated Aminopeptidase (IRAP) by Macrocyclic Disulfides Enhances Spine Density
- 2016
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Ingår i: Molecular Pharmacology. - : American Society for Pharmacology & Experimental Therapeutics (ASPET). - 0026-895X .- 1521-0111. ; 89:4, s. 413-424
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Tidskriftsartikel (refereegranskat)abstract
- Angiotensin IV (Ang IV) and related peptide analogues, as well as non-peptide inhibitors of insulin-regulated aminopeptidase (IRAP), have previously been shown to enhance memory and cognition in animal models. Furthermore, the endogenous IRAP substrates oxytocin and vasopressin are known to facilitate learning and memory. In this study, the two recently synthesized 13-membered macrocylic competitive IRAP inhibitors HA08 and HA09, which were designed to mimic the N-terminal of oxytocin and vasopressin, were assessed and compared based on their ability to bind to the IRAP active site, and alter dendritic spine density in rat hippocampal primary cultures. The binding modes of the IRAP inhibitors HA08, HA09 and of Ang IV in either the extended or γ-turn conformation at the C-terminal to human IRAP were predicted by docking and molecular dynamics (MD) simulations. The binding free energies calculated with the linear interaction energy (LIE) method, which are in excellent agreement with experimental data and simulations, have been used to explain the differences in activities of the IRAP inhibitors, both of which are structurally very similar, but differ only with regard to one stereogenic center. In addition, we show that HA08, which is 100-fold more potent than the epimer HA09, can enhance dendritic spine number and alter morphology, a process associated with memory facilitation. Therefore, HA08, one of the most potent IRAP inhibitors known today, may serve as a suitable starting point for medicinal chemistry programs aided by MD simulations aimed at discovering more drug-like cognitive enhancers acting via augmenting synaptic plasticity.
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| 8. |
- Enhamre, Erika, et al.
(författare)
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The expression of growth hormone receptor gene transcript in the prefrontal cortex is affected in male mice with diabetes-induced learning impairments
- 2012
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Ingår i: Neuroscience Letters. - : Elsevier BV. - 0304-3940 .- 1872-7972. ; 523:1, s. 82-86
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Tidskriftsartikel (refereegranskat)abstract
- Previous studies have indicated that both growth hormone (GH) deficiency and diabetes are conditions associated with impairments in learning and memory processes. In this study, we investigated the effect of streptozotocin-induced diabetes on spatial learning in mice using the Barnes maze (BM). The expression of the GH receptor (GHR) gene transcript in areas of the brain associated with learning and memory were examined. The results indicated that the GHR gene transcript is up-regulated in the prefrontal cortex (PFC) of diabetic mice compared to controls. In addition, there was a significant correlation between the expression of GHR mRNA and performance in the BM during the acquisition phase in diabetic but not control mice. These results suggest that diabetes induces an imbalance in the GH/IGF-1 system leading to altered activity in the PFC and associated cognitive deficiencies.
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| 9. |
- Florén Lind, Sara, et al.
(författare)
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Acute caffeine differently affects risk-taking and the expression of BDNF and of adenosine and opioid receptors in rats with high or low anxiety-like behavior
- 2023
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Ingår i: Pharmacology, Biochemistry and Behavior. - 0091-3057 .- 1873-5177. ; 227-228
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Tidskriftsartikel (refereegranskat)abstract
- Anxiety disorders are common psychiatric conditions with a partially elucidated neurobiology. Caffeine, an unspecific adenosine receptor antagonist, is a common psychostimulant with anxiogenic effects in sensitive individuals. High doses of caffeine produce anxiety-like behavior in rats but it is not known if this is specific for rats with high baseline anxiety-like behavior. Thus, the aim of this study was to investigate general behavior, risk-taking, and anxiety-like behavior, as well as mRNA expression (adenosine A2A and A1, dopamine D2, and, μ, κ, δ opioid, receptors, BDNF, c-fos, IGF-1) in amygdala, caudate putamen, frontal cortex, hippocampus, hypothalamus, after an acute dose of caffeine. Untreated rats were screened using the elevated plus maze (EPM), giving each rat a score on anxiety-like behavior based on their time spent in the open arms, and categorized into a high or low anxiety-like behavior group accordingly. Three weeks after categorization, the rats were treated with 50 mg/kg caffeine and their behavior profile was studied in the multivariate concentric square field (MCSF) test, and one week later in the EPM. qPCR was performed on selected genes and corticosterone plasma levels were measured using ELISA. The results demonstrated that the high anxiety-like behavior rats treated with caffeine spent less time in risk areas of the MCSF and resituated towards the sheltered areas, a behavior accompanied by lower mRNA expression of adenosine A2A receptors in caudate putamen and increased BDNF expression in hippocampus. These results support the hypothesis that caffeine affects individuals differently depending on their baseline anxiety-like behavior, possibly involving adenosine receptors. This highlights the importance of adenosine receptors as a possible drug target for anxiety disorders, although further research is needed to fully elucidate the neurobiological mechanisms of caffeine on anxiety disorders.
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| 10. |
- Florén Lind, Sara, et al.
(författare)
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Acute low dose caffeine affects behavior profile and activity, an examination of male rats with high or low anxiety-like behavior
- 2023
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Ingår i: Behavioural Brain Research. - : Elsevier. - 0166-4328 .- 1872-7549. ; 455
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Tidskriftsartikel (refereegranskat)abstract
- Anxiety disorders affect up to one third of the population. Caffeine, an adenosine receptor antagonist, is thought to have a dose-dependent effect on anxiety. We recently showed that a high dose of caffeine (50 mg/kg) differentially affected anxiety-like behavior in rats with high or low baseline anxiety-like behavior, replicating findings using relatively high doses in human patient samples. It is not known if low doses of caffeine have similar effects. The elevated plus maze (EPM) was used to categorize male Wistar rats (13 weeks of age) into groups of high or low anxiety-like behavior. Behavior was evaluated using the multivariate concentric square field (MCSF) test and the EPM after a low 10 mg/kg dose of caffeine. Multivariate data analysis demonstrated that caffeine decreased the differences between the high and low anxiety group, whereas the separation remained for the high and low control groups. For the caffeine treated rats, univariate statistics showed an increase in parameters regarding activity in the EPM and duration in the slope of the MCSF. Regarding risk-taking, shelter-seeking, and exploratory behavior, caffeine did not affect the groups differently. In conclusion, these results demonstrate increased activity in the caffeine-treated rats, together with a potentially anxiolytic effect and increased impulsivity that did not differ between the baseline anxiety groups. In contrast to high caffeine doses, a low dose does not generally affect rats with high anxiety at baseline differently than rats with low anxiety-like behavior. Further studies are warranted to fully elucidate the effects of caffeine in anxiety.
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