Biomedical subjects

Fred Nyberg

Publications and source records attributed to Fred Nyberg.

At least 19 recordsLinked to original sources

PubMed2006

Altered extracellular levels of DOPAC and HVA in the rat nucleus accumbens shell in response to sub-chronic nandrolone administration and a subsequent amphetamine challenge.

Associated with acts of violence and polydrug use, abuse of anabolic androgenic steroids (AAS) is an increasing problem in society. The aim of the present study was to elucidate whether sub-chronic treatment with the AAS nandrolone decanoate affects dopamine release and dopamine metabolism in the rat nucleus accumbens shell, before and after an amphetamine challenge. Male Sprague-Dawley rats received daily i.m. injections of nandrolone decanoate (15 mg/kg) or vehicle for 14 days. On day 15, the animals were anaesthetized and a microdialysis probe was implanted into the nucleus accumbens shell. Extracellular fluid was collected 1h before and 3h after a single amphetamine injection (5 mg/kg). The samples were then analyzed regarding the content of dopamine, and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA), using HPLC with electrochemical detection. Two weeks of nandrolone decanoate administration caused a significant decrease of the basal DOPAC and HVA levels, which remained low during the first hour following the amphetamine challenge. Dopamine levels did not differ significantly between groups, neither after the nandrolone pre-treatment nor the amphetamine challenge. In conclusion, these novel findings indicate that AAS alter the metabolism of dopamine in a brain region involved in the development of drug dependence.

3,4-Dihydroxyphenylacetic Acid↗

PubMed2006

Design, synthesis, and incorporation of a beta-turn mimetic in angiotensin II forming novel pseudopeptides with affinity for AT1 and AT2 receptors.

A benzodiazepine-based beta-turn mimetic has been designed, synthesized, and incorporated into angiotensin II. Comparison of the mimetic with beta-turns in crystallized proteins showed that it most closely resembles a type II beta-turn. The compounds exhibited high to moderate binding affinity for the AT2 receptor, and one also displayed high affinity for the AT1 receptor. Molecular modeling showed that the high-affinity compounds could be incorporated into a previously derived model of AT2 receptor ligands.

Angiotensin II↗

PubMed2006

Short pseudopeptides containing turn scaffolds with high AT2 receptor affinity.

Two pentapeptides, Ac-Tyr-Ile-His-Pro-Phe/Ile, were synthesized and shown to have angiotensin II AT2 receptor affinity and agonistic activity. Based on these peptides, a new series of 13 pseudopeptides was synthesized via introduction of five different turn scaffolds replacing the Tyr-Ile amino acid residues. Pharmacological evaluation disclosed subnanomolar affinities for some of these compounds at the AT2 receptor. Substitution of Phe by Ile in this series of ligands enhanced the AT2 receptor affinity of all compounds. These results suggest that the C-terminal amino acid residues can be elaborated on to enhance the AT2 receptor affinity in truncated Ang II analogues.

Animals↗

PubMed2006

Growth hormone replacement in hypophysectomized rats affects spatial performance and hippocampal levels of NMDA receptor subunit and PSD-95 gene transcript levels.

Clinical studies have demonstrated that growth hormone (GH) promotes learning and memory processes in GH-deficient (GHD) patients. In animal studies, GH also influences the N-methyl-D-aspartate (NMDA) receptor system in the hippocampus, an essential component of long-term potentiation (LTP), which is highly involved in memory acquisition. This study was designed to examine the beneficial effects of recombinant human GH (rhGH) on cognitive function in male rats with multiple hormone deficiencies resulting from hypophysectomy (Hx). The performance of an rhGH-treated group and an untreated control group was appraised in the Morris water maze (MWM). The rhGH-treated group performed significantly better in the spatial memory task than the control animals on the second and third trial days. Further training eliminated this difference between the groups. Hippocampal mRNA expression of the NMDA subunits NR1, NR2A and NR2B, insulin-like growth factor type 1 receptor (IGF-1R), and postsynaptic density protein-95 (PSD-95) was then measured in the animals by Northern blot analysis. The results suggest that there may be a relationship between the NMDA receptor subunit mRNA expression levels and learning ability, and that learning is improved by rhGH in Hx rats. Furthermore, a link between MWM performance and PSD-95 was also suggested by this study.

Animals↗

PubMed2006

Influence of the anabolic-androgenic steroid nandrolone on cannabinoid dependence.

The identification of the possible factors that might enhance the risk of developing drug addiction and related motivational disorders is crucial to reduce the prevalence of these problems. Here, we examined in mice whether the exposure to the anabolic-androgenic steroid nandrolone would affect the pharmacological and motivational effects induced by Delta(9)-tetrahydrocannabinol (THC), the principal psychoactive component of Cannabis sativa. Mice received nandrolone using pre-exposure (during 14days before THC treatment) or co-administration (1h before each THC injection) procedures. Both nandrolone treatments did not modify the acute antinociceptive, hypothermic and hypolocomotor effects of THC or the development of tolerance after chronic THC administration. Nandrolone pre-exposure blocked THC- and food-induced conditioned place preference and increased the somatic manifestations of THC withdrawal precipitated by the CB1 cannabinoid antagonist rimonabant (SR141617A). The aversive effects of THC were not changed by nandrolone. Furthermore, nandrolone pre-exposure attenuated the anxiolytic-like effects of a low dose of THC without altering the anxiogenic-like effects of a high dose in the lit/dark box, open field and elevated plus-maze. Biochemical experiments showed that chronic nandrolone treatment did not modify CB1 receptor binding and GTP-binding protein activation in the caudate-putamen and cerebellum. Taken together, our results suggest that chronic nandrolone treatment alters behavioural responses related to cannabinoid addictive properties.

Anabolic Agents↗

PubMed2006

Modulation of peripheral inflammation by the substance P N-terminal metabolite substance P1-7.

The N-terminal metabolite of the undecapeptide substance P (SP), substance P1-7 (SP1-7), is known to modulate nociception in the central nervous system (CNS) and often has opposite effects from SP. This study investigated the ability of SP(1-7) to modulate the vasodilatation response to SP in anaesthetized rats under different injury conditions using a blister model of inflammation on the hind footpad. The results indicated that SP1-7 inhibited the vascular response to SP in a dose-dependent manner. The putative antagonists naloxone and D-Pro2-D-Phe7-SP1-7 (D-SP1-7) reversed the effect of SP1-7. D-SP1-7 improved the responsiveness to SP under chronic nerve injury, which suggests a role for endogenous SP1-7 in this model. SP1-7 did not inhibit the response to electrical stimulation of the sciatic nerve, which indicates that the heptapeptide interacts at a post-terminal binding site. The current results suggest that SP1-7 may have inhibitory properties in inflammation, analogous to its antinociceptive role in the central nervous system.

Animals↗

PubMed2006

Chromatographic characterization of substance P endopeptidase in the rat brain reveals affected enzyme activity following heat stress.

This paper describes a study of substance P endopeptidase (SPE)-like activity in various regions of the brain from male rats subjected to heat stress (HS). The enzyme activity was found to be affected in several brain areas including cerebellum, cerebral cortex, hippocampus, hypothalamus[sol ]thalamus and the spinal cord following HS. Significant increases in SPE activity were observed in, for example, hippocampus and the spinal cord. SPE-containing extracts from hippocampus were pooled and subsequently purified by size exclusion chromatography (using a Superdex 75 HR column) and by anion-exchange chromatography (using Resource Q column). The gel permeation chromatography separated the SPE-like activity into two fractions, one of which was suggested to be identical to neutral endopeptidase owing to its molecular size and inhibitory profile. The other active enzyme fraction behaved in conformity with SPE, previously identified in human cerebrospinal fluid. The activity of the purified fraction of these two enzymes was found to be increased (27%) in HS-treated animals.

Animals↗

PubMed2006

Brominated cyclodipeptides from the marine sponge Geodia barretti as selective 5-HT ligands.

The brominated cyclodipeptides barettin (cyclo[(6-bromo-8-entryptophan)arginine]) and 8,9-dihydrobarettin (cyclo[(6-bromotryptophan)arginine]) isolated from the marine sponge Geodia barretti have previously been shown to inhibit settlement of barnacle larvae in a dose-dependent manner in concentrations ranging from 0.5 to 25 microM. To further establish the molecular target and mode of action of these compounds, we investigated their affinity to human serotonin receptors. The tryptophan residue in the barettins resembles that of endogenous serotonin [5-hydroxytryptamine]. A selection of human serotonin receptors, including representatives from all subfamilies (1-7), were transfected into HEK-293 cells. Barettin selectively interacted with the serotonin receptors 5-HT2A, 5-HT2C, and 5-HT4 at concentrations close to that of endogenous serotonin, with the corresponding Ki values being 1.93, 0.34, and 1.91 microM, respectively. 8,9-Dihydrobarettin interacted exclusively with the 5-HT2C receptor with a Ki value of 4.63 microM; it failed to show affinity to 5-HT2A and 5-HT4, indicating that the double bond between the tryptophan and arginine residue plays an important role in the interaction with the receptor proteins.

Animals↗

PubMed2006

Identification of bikunin as an endogenous inhibitor of dynorphin convertase in human cerebrospinal fluid.

Dynorphin-converting enzymes constitute a group of peptidases capable of converting dynorphins to enkephalins. Through the action of these enzymes, the dynorphin-related peptides bind to delta-opioid instead of kappa-opioid receptors, leading to a change in the biological function of the neuropeptides. In this article, we describe the identification of the protein bikunin as an endogenous, competitive inhibitor of a dynorphin-converting enzyme in human cerebrospinal fluid. This protein is present together with its target enzyme in the same body fluids. The K(M) value of the convertase was found to be 9 microm, and the K(i) value of the inhibitor was 1.7 nm. The finding indicates that bikunin may play a significant role as a regulatory mechanism of neuropeptides, where one bioactive peptide is converted to a shorter sequence, which in turn, can affect the action of its longer form.

Alpha-Globulins↗

PubMed2006

Effect of high-calorie diet on the prevalence of diabetes mellitus in the one-humped camel (Camelus dromedarius).

The one-humped camel is a typical desert animal. It has the capability of withstanding the harsh climatic changes and the scarcity of food and water, in addition to the high-ambient temperature. The prevalence of diabetes mellitus in two different groups of the one-humped camel, group (A) control (n = 102) camels and group (B) high-calorie diet-fed camels (n = 103), in Al-Ain region (UAE) was studied using biochemical and radioimmunoassay techniques. In this article, 7% of the control camels have diabetes mellitus (blood glucose level: > or =140 mg/dL) compared to 21% of the high-calorie-fed camels. Plasma insulin level was significantly (P < 0.05) lower in group B compared to group A. The low insulin level in camels consuming high-caloric diet could be a sign of exhaustion of pancreatic beta cells. The hematological parameters were nearly similar in both groups and no significant differences were seen. Liver and kidney enzymes were normal in both groups. Iron and copper were significantly (P < 0.005) higher in the high-calorie-fed camels compared with the control. Our study indicates that high-caloric feed consumption in camels is associated with the development of disorders in glucose metabolism leading to diabetes mellitus.

Animals↗

PubMed2005

Nandrolone treatment decreases the alpha1B-adrenoceptor mRNA level in rat kidney, but not the density of alpha1B-adrenoceptors in cultured MDCK-D1 kidney cells.

We have previously shown that treatment of rats with the anabolic androgen steroid nandrolone decreased the density of alpha1B-adrenoceptors in the rat kidney [Uhlén, S., Lindblom, J., Kindlundh, A., Muhisha, P., Nyberg, F., (2003). Nandrolone treatment decreases the level of rat kidney alpha1B-adrenoceptors. Naunyn-Schmiedeberg's Arch. Pharmacol. 368, 91-98]. This effect may have been caused either by decreased de novo synthesis of alpha1B-adrenoceptors or by increased degradation of alpha1B-adrenoceptors [corrected] In the present study, we show that treatment of rats with nandrolone decreases the level of mRNA for the alpha1B-adrenoceptor in the kidneys, implying decreased synthesis of alpha1B-adrenoceptors. On the other hand, nandrolone did not decrease the density of alpha1B-adrenoceptors in Madin-Darby Canine Kidney (MDCK) cells, even though the sub-cell line tested, MDCK-D1, expresses both the androgen receptor and the alpha1B-adrenoceptor. It is concluded that the regulation of alpha1B-adrenoceptor expression by anabolic androgenic steroids is intricate and cell-type specific.

Adrenergic alpha-Antagonists↗

PubMed2005

Angiotensin II pseudopeptides containing 1,3,5-trisubstituted benzene scaffolds with high AT2 receptor affinity.

Two 1,3,5-trisubstituted aromatic scaffolds intended to serve as gamma-turn mimetics have been synthesized and incorporated in five pseudopeptide analogues of angiotensin II (Asp-Arg-Val-Tyr-Ile-His-Pro-Phe), replacing Val-Tyr-Ile, Val-Tyr, or Tyr-Ile. All the tested compounds exhibited nanomolar affinity for the AT2 receptor with the best compound (3) having a K(i) of 1.85 nM. Four pseudopeptides were AT2 selective, while one (5) also exhibited good affinity for the AT1 receptor (K(i) = 30.3 nM). This pseudopeptide exerted full agonistic activity in an AT2 receptor induced neurite outgrowth assay but displayed no agonistic effect in an AT1 receptor functional assay. Molecular modeling, using the program DISCOtech, showed that the high-affinity ligands could interact similarly with the AT2 receptor as other ligands with high affinity for this receptor. A tentative agonist model is proposed for AT2 receptor activation by angiotensin II analogues. We conclude that the 1,3,5-trisubstituted benzene rings can be conveniently prepared and are suitable as gamma-turn mimics.

Angiotensin II↗

PubMed2005

Endomorphin-1 and endomorphin-2 differentially interact with specific binding sites for substance P (SP) aminoterminal SP1-7 in the rat spinal cord.

Endomorphin-1 (EM-1) and endomorphin-2 (EM-2) represent two opioid active tetrapeptides with high affinity and selectivity for the mu-opioid (MOP) receptor. Both EM-1 and EM-2 exhibit strong inhibition of pain signals in the central nervous system (CNS). In contrast to these compounds, the undecapeptide substance P (SP) facilitates pain influx in the CNS. SP has been implicated in a number of functions in the central nervous system, including pain processing and reward. Its aminoterminal fragment SP1-7 has been shown to modulate several actions of SP in the CNS, the nociceptive effect included. Although the actions of SP1-7 have been known for long no specific receptor for the SP fragment has yet been cloned. In this study, we demonstrate the presence of specific binding sites for the heptapeptide in the rat spinal cord. The binding affinity for unlabeled SP1-7 to the specific sites for the labeled heptapeptide highly exceeded those of SP and other C- or N-terminal fragments thereof. The NK-1, NK-2 and NK-3 receptor ligands [Sar9, Met(O2)11]SP, R396 and senktide, respectively, showed no or negligible binding. Moreover, both EM-1 and EM-2 were found to interact with SP1-7 binding. However, a significant difference in binding affinity between the two opioid active tetrapeptides was observed. As recorded from replacement curves the affinity of EM-2 was 10 times weaker than that for SP1-7 but about 100 times higher than that of EM-1. Among other Tyr-Pro-containing peptides Tyr-MIF-1 but not Tyr-W-MIF-1 exhibited affinity of similar potency as EM-2. These results strengthen the previously observed differences between EM-1 and EM-2 in various functional studies. Moreover, using a cell line (C6) expressing the MOP receptor it was shown that the labeled SP1-7 did not interact with binding to this receptor and no functional response was seen for the SP heptapeptide on the MOP receptor by means of stimulation in the GTPgammaS assay. This suggests that the identified SP1-7 binding sites, with high affinity also for EM-2, are not identical to the MOP receptor and apparently not to any of the known tachykinin receptors.

Animals↗

PubMed2005

Administration of the anabolic androgenic steroid nandrolone decanoate affects substance P endopeptidase-like activity in the rat brain.

The effect of the anabolic androgenic steroid, nandrolone decanoate, on substance P endopeptidase-like activity was examined in adult male Sprague-Dawley rats. Nandrolone decanoate (15 mg/kg day) or oil vehicle (sterile arachidis oleum) were administered by intramuscular injections during 14 days. Substance P endopeptidase, a predominantly cytosolic enzyme, generates the bioactive N-terminal fragment substance P(1-7) from the enzyme substrate substance P. Nandrolone decanoate significantly reduced the substance P endopeptidase-like activity compared to control animals in hypothalamus (43% reduction), caudate putamen (44%), substantia nigra (32%) and the ventral tegmental area (27%). It was previously reported that both hypothalamus and caudate putamen contained significantly higher levels of substance P after nandrolone administration. The higher concentration of substance P in these regions could to an extent be attributed to the reduction in substance P endopeptidase-like activity. This result elucidates the important role of peptidase activity in the regulation of the substance P transmitter system. The present study provides additional support for the hypothesis that alterations in the substance P system in certain brain areas may contribute to some of the personality changes reported in connection with AAS abuse.

Amygdala↗

PubMed2005

Permeation of growth hormone across the blood-brain barrier.

Exogenous GH can affect central nervous system function when given peripherally to animals and as a supplemental therapy to humans. This study tested whether GH crosses the blood-brain barrier (BBB) by a specific transport system and found that both mice and rats have small but significant uptake of GH into the brain without a species difference. Determined by multiple-time regression analysis, the blood-to-brain influx transfer constants of 125I-labeled rat GH in mice (0.23+/-0.07 microl/g.min) and rats (0.32+/-0.04 microl/g.min) were comparable to those of some cytokines of similar size, with a half-time disappearance of 125I-GH of 3.8-7.6 min in blood. Intact 125I-GH was present in both serum and brain homogenate 20 min after iv injection. At this time, about 26.8% of GH in brain entered the parenchyma, whereas 10% was entrapped in endothelial cells. Neither excess GH nor insulin showed acute modulation of the influx, indicating lack of a saturable transport system for GH at the BBB. Binding and cellular uptake studies in cultured cerebral microvessel endothelial cells (RBE4) further ruled out the presence of high-capacity adsorptive endocytosis. The brain influx of GH by simple diffusion adds definitive value to the long-disputed question of whether and how GH crosses the BBB. The central nervous system effects of peripheral GH can be attributed to permeation of the BBB despite the absence of a specific transport system.

Animals↗

PubMed2005

New selective AT2 receptor ligands encompassing a gamma-turn mimetic replacing the amino acid residues 4-5 of angiotensin II act as agonists.

New benzodiazepine-based gamma-turn mimetics with one or two amino acid side chains were synthesized. The gamma-turn mimetics were incorporated into angiotensin II (Ang II) replacing the Val(3)-Tyr(4)-Ile(5) or Tyr(4)-Ile(5) peptide segments. All of the resulting pseudopeptides displayed high AT(2)/AT(1) receptor selectivity and exhibited AT(2) receptor affinity in the low nanomolar range. Molecular modeling was used to investigate whether the compounds binding to the AT(2) receptor could position important structural elements in common areas. A previously described benzodiazepine-based gamma-turn mimetic with high affinity for the AT(2) receptor was also included in the modeling. It was found that the molecules, although being structurally quite different, could adopt the same binding mode/interaction pattern in agreement with the model hypothesis. The pseudopeptides selected for agonist studies were shown to act as AT(2) receptor agonists being able to induce outgrowth of neurite cells, stimulate p42/p44(mapk), and suppress proliferation of PC12 cells.

Amino Acid Substitution↗

PubMed2005

Age-related effects of IGF-1 on the NMDA-, GH- and IGF-1-receptor mRNA transcripts in the rat hippocampus.

Insulin-like growth factor-1 (IGF-1) and growth hormone (GH) have been suggested to promote memory and cognitive capabilities. In a recent publication we observed that GH increase the proportion of the NR2B subunit mRNA transcript of the NMDA receptor in rat hippocampus. NR2B has been suggested to be essential for spatial learning and long-term potentiation (LTP). This effect of GH might be IGF-1-mediated or a result of a co-ordination with IGF-1. To test this hypothesis further, we examined the effects of 10 daily s.c. injections of IGF-1 on NMDA receptor subunits (NR1, NR2A, and NR2B), GH receptor (GHR), GH binding protein (GHBP) and type 1 IGF receptor (IGF-1R) gene transcripts in the hippocampus. The NR2B subunit mRNA increased in young (11 weeks) but not in older (14-16 months) rats and the expression of the NR2A mRNA was decreased in both groups. The ratio of NR2B to NR2A is suggested to mirror the potential for synaptic plasticity. In both age groups, IGF-1 treatment resulted in a significant increase of this ratio at transcription level. The GHR mRNA increased in young rats, mimicking the effect of GH, while the IGF-1R mRNA was decreased in the older group of rats after IGF-1 treatment. These results suggest that IGF-1 in many aspects may mediate the actions earlier shown for GH.

Age Factors↗

PubMed2005

The impact of chronic nandrolone decanoate administration on the NK1 receptor density in rat brain as determined by autoradiography.

Adult male Sprague-Dawley rats were treated with the anabolic androgenic steroid nandrolone decanoate (15 mg/kg day) or oil vehicle (sterile arachidis oleum) during 14 days. The effect on the densities of the neurokinin NK1 receptor in brain was examined with autoradiography. An overall tendency of attenuation of NK1 receptor density was observed after completed treatment with nandrolone decanoate. The density of the NK1 receptor was found to be significantly lower compared to control animals in the nucleus accumbens core (37% density reduction), in dentate gyrus (26%), in basolateral amygdaloid nucleus (23%), in ventromedial hypothalamic nucleus (36%), in dorsomedial hypothalamic nucleus (43%) and finally in the periaqueductal gray (PAG) (24%). In the cortex region, no structures exhibited any significant reduction of NK1 receptor density. This result provides additional support to the hypothesis that substance P and the NK1 receptor may be involved as important components that participate in mediating physiological responses including the adverse behaviors often associated with chronically administrated anabolic androgenic steroids in human.

Animals↗