Different SNP combinations in the GCH1 gene and use of labor analgesia

<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Results</p> <p>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.</p> <p>Conclusion</p> <p>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.</p

Growth Hormone and Anabolic Androgenic Steroids : Effects on Neurochemistry and Cognition

Growth hormone (GH) stimulates growth and metabolism but also displays profound effects on the central nervous system (CNS). GH affects neurogenesis and neuroprotection, and has been shown to counteract drug-induced apoptosis in the brain. Anabolic androgenic steroids (AAS), mainly abused for their anabolic and performance-enhancing properties, can cause several adverse effects, such as cardiovascular complications, sterility, depression, and aggression. GH and AAS are both believed to interact with several signaling systems in the CNS. The aim of this thesis was to further investigate the impact of GH and AAS on neurochemistry and cognitive functions. Recombinant human GH (rhGH) and the steroid nandrolone decanoate (ND) were administered, separately and in combination with each other, to male rats. The results demonstrated that administration of GH improved spatial memory, assessed in a water maze test. Furthermore, GH induced alterations of the GABAB receptor mRNA expression, density, and functionality in the brain, for example in regions associated with cognition. GH also altered the mu opioid peptide (MOP) receptor, but not the delta opioid peptide (DOP) receptor functionality in the brain. Thus, some of the GH effects on cognition may involve effects on the GABAB receptors and MOP receptors. ND, on the contrary, seemed to induce impairments of memory and also altered the GABAB receptor mRNA expression in the brain. Furthermore, ND lowered the IGF-1 plasma concentrations and attenuated the IGF-1, IGF-2, and GHR mRNA expression in the pituitary. In addition, significant effects of GH and ND were found on plasma steroid concentrations, organ weight, as well as body weight. In conclusion, this thesis contributes with further knowledge on the cognitive and neurochemical consequences of GH and ND use. The findings regarding ND are worrying considering the common use of AAS among adolescents. GH improves memory functions and affects signaling systems in the brain associated with cognition, hence the hypothesis that GH can reverse drug-induced impairments is further strengthened

Growth Hormone and Anabolic Androgenic Steroids : Effects on Neurochemistry and Cognition

Growth hormone (GH) stimulates growth and metabolism but also displays profound effects on the central nervous system (CNS). GH affects neurogenesis and neuroprotection, and has been shown to counteract drug-induced apoptosis in the brain. Anabolic androgenic steroids (AAS), mainly abused for their anabolic and performance-enhancing properties, can cause several adverse effects, such as cardiovascular complications, sterility, depression, and aggression. GH and AAS are both believed to interact with several signaling systems in the CNS. The aim of this thesis was to further investigate the impact of GH and AAS on neurochemistry and cognitive functions. Recombinant human GH (rhGH) and the steroid nandrolone decanoate (ND) were administered, separately and in combination with each other, to male rats. The results demonstrated that administration of GH improved spatial memory, assessed in a water maze test. Furthermore, GH induced alterations of the GABAB receptor mRNA expression, density, and functionality in the brain, for example in regions associated with cognition. GH also altered the mu opioid peptide (MOP) receptor, but not the delta opioid peptide (DOP) receptor functionality in the brain. Thus, some of the GH effects on cognition may involve effects on the GABAB receptors and MOP receptors. ND, on the contrary, seemed to induce impairments of memory and also altered the GABAB receptor mRNA expression in the brain. Furthermore, ND lowered the IGF-1 plasma concentrations and attenuated the IGF-1, IGF-2, and GHR mRNA expression in the pituitary. In addition, significant effects of GH and ND were found on plasma steroid concentrations, organ weight, as well as body weight. In conclusion, this thesis contributes with further knowledge on the cognitive and neurochemical consequences of GH and ND use. The findings regarding ND are worrying considering the common use of AAS among adolescents. GH improves memory functions and affects signaling systems in the brain associated with cognition, hence the hypothesis that GH can reverse drug-induced impairments is further strengthened

Toxic Impact of Anabolic Androgenic Steroids in Primary Rat Cortical Cell Cultures

The use of anabolic androgenic steroids (AASs) among non-athletes is a public health-problem, as abusers underestimate the negative effects associated with these drugs. The present study investigated the toxic effects of testosterone, nandrolone, stanozolol, and trenbolone, and aimed to understand how AAS abuse affects the brain. Mixed cortical cultures from embryonic rats were grown in vitro for 7 days and thereafter treated with increasing concentrations of AASs for 24 h (single-dose) or 3 days (repeated exposure). Cells were co-treated with the androgen-receptor (AR) antagonist flutamide, to determine whether the potential adverse effects observed were mediated by the AR. Cellular toxicity was determined by measuring mitochondrial activity, lactate dehydrogenase (LDH) release, and caspase-3/7 activity. Nandrolone, unlike the other AASs studied, indicated an effect on mitochondrial activity after 24 h. Furthermore, single-dose exposure with testosterone, nandrolone and trenbolone increased LDH release, while no effect was detected with stanozolol. However, all of the four steroids negatively affected mitochondrial function and resulted in LDH release after repeated exposure. Testosterone, nandrolone, and trenbolone caused their toxic effects by induction of apoptosis, unlike stanozolol that seemed to induce necrosis. Flutamide almost completely prevented AAS-induced toxicity by maintaining mitochondrial function, cellular integrity, and inhibition of apoptosis. Overall, we found that supra-physiological concentrations of AASs induce cell death in mixed primary cortical cultures, but to different extents, and possibly through various mechanisms. The data presented herein suggest that the molecular interactions of the AASs with the AR are primarily responsible for the toxic outcomes observed.Även finansierat av Kjell och Märta Beijers stiftelse</p

The Protective and Restorative Effects of Growth Hormone and Insulin-Like Growth Factor-1 on Methadone-Induced Toxicity In Vitro

Evidence to date suggests that opioids such as methadone may be associated with cognitive impairment. Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) are suggested to be neuroprotective and procognitive in the brain and may therefore counteract these effects. This study aims to explore the protective and restorative effects of GH and IGF-1 in methadone-treated cell cultures. Primary cortical cell cultures were harvested from rat fetuses and grown for seven days in vitro. To examine the protective effects, methadone was co-treated with or without GH or IGF-1 for three consecutive days. To examine the restorative effects, methadone was added for the first 24 h, washed, and later treated with GH or IGF-1 for 48 h. At the end of each experiment, mitochondrial function and membrane integrity were evaluated. The results revealed that GH had protective effects in the membrane integrity assay and that both GH and IGF-1 effectively recovered mitochondrial function and membrane integrity in cells pretreated with methadone. The overall conclusion of the present study is that GH, but not IGF-1, protects primary cortical cells against methadone-induced toxicity, and that both GH and IGF-1 have a restorative effect on cells pretreated with methadone.Även finansierat av Kjell och Märta Beijer stiftelsen.</p

Anabolic androgenic steroids exert a selective remodeling of the plasma lipidome that mirrors the decrease of the de novo lipogenesis in the liver

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)

GCH1-polymorphism and pain sensitivity among women with provoked vestibulodynia

Background: Provoked vestibulodynia (PVD) is a pain disorder localized in the vestibular mucosa. It is the most common cause of dyspareunia among young women and it is associated with general pain hypersensitivity and other chronic pain conditions. Polymorphism in the guanosine triphosphate cyclohydrolase (GCH1) gene has been found to influence general pain sensitivity and the risk of developing a longstanding pain condition. The aim of this study was to investigate GCH1-polymorphism in women with PVD and healthy controls, in correlation to pain sensitivity. Results: We found no correlation between the previously defined pain-protective GCH1-SNP combination and the diagnosis of PVD. Nor any correlation with pain sensitivity measured as pressure pain thresholds on the arm, leg and in the vestibule, coital pain scored on a visual analog scale and prevalence of other bodily pain conditions among women with PVD (n = 98) and healthy controls (n = 102). However, among patients with current treatment (n = 36), there was a significant interaction effect of GCH1-gene polymorphism and hormonal contraceptive (HC) therapy on coital pain (p = 0.04) as well as on pressure pain thresholds on the arm (p = 0.04). PVD patients carrying the specified SNP combination and using HCs had higher pain sensitivity compared to non-carriers. In non-HC-users, carriers had lower pain sensitivity. Conclusions: The results of this study gave no support to the hypothesis that polymorphism in the GCH1-gene contributes to the etiology of PVD. However, among patients currently receiving treatment an interaction effect of the defined SNP combination and use of hormonal contraceptives on pain sensitivity was found. This finding offers a possible explanation to the clinically known fact that some PVD patients improve after cessation of hormonal contraceptives, indicating that PVD patients carrying the defined SNP combination of GCH1 would benefit from this intervention

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

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

Structurally different anabolic androgenic steroids reduce neurite outgrowth and neuronal viability in primary rat cortical cell cultures

The illicit use of anabolic androgenic steroids (AAS) among adolescents and young adults is a major concern due to the unknown and unpredictable impact of AAS on the developing brain and the consequences of this on mental health, cognitive function and behaviour. The present study aimed to investigate the effects of supra-physiological doses of four structurally different AAS (testosterone, nandrolone, stanozolol and trenbolone) on neurite development and cell viability using an in vitro model of immature primary rat cortical cell cultures. A high-throughput screening image-based approach, measuring the neurite length and number of neurons, was used for the analysis of neurite outgrowth. In addition, cell viability and expression of the Tubb3 gene (encoding the protein beta-III tubulin) were investigated. Testosterone, nandrolone, and trenbolone elicited adverse effects on neurite outgrowth as deduced from an observed reduced neurite length per neuron. Trenbolone was the only AAS that reduced the cell viability as indicated by a decreased number of neurons and declined mitochondrial function. Moreover, trenbolone downregulated the Tubb3 mRNA expression. The adverse impact on neurite development was neither inhibited nor supressed by the selective androgen receptor (AR) antagonist, flutamide, suggesting that the observed effects result from another mechanism or mechanisms of action that are operating apart from AR activation. The results demonstrate a possible AAS-induced detrimental effect on neuronal development and regenerative functions. An impact on these events, that are essential mechanisms for maintaining normal brain function, could possibly contribute to behavioural alterations seen in AAS users