Fred Nyberg

Calcitonin gene-related peptide is a potent inhibitor of substance P degradation

Calcitonin gene-related peptide (CGRP) was found to potently inhibit a substance P endopeptidase isolated from human CSF. CGRP potentiated substance P irritant actions; a possible mechanism is interaction for a common metabolic step. Somatostatin is another peptide capable of competing with substance P endopeptidase.

Mephedrone, compared with MDMA (ecstasy) and amphetamine, rapidly increases both dopamine and 5-HT levels in nucleus accumbens of awake rats

BACKGROUND AND PURPOSE The designer drug 1‐(4‐methylphenyl)‐2‐methylaminopropan‐1‐one (4‐methylmethcathinone, mephedrone) is reported to possess psychostimulant, entactogenic and hallucinogenic effects. The purpose of this study was to examine the effects of acute administration of mephedrone on extracellular levels of dopamine (DA) and 5‐HT in the nucleus accumbens of awake rats and compare these effects with those induced by 3,4‐methylenedioxymethamphetamine (MDMA, ecstasy) and amphetamine.

Growth Hormone in the Brain: Characteristics of Specific Brain Targets for the Hormone and Their Functional Significance☆

During the past decade studies have shown that growth hormone (GH) may exert profound effects on the central nervous system (CNS). For instance, GH replacement therapy was found to improve the psychological capabilities in adult GH deficient (GHD) patients. Furthermore, beneficial effects of the hormone on certain functions, including memory, mental alertness, motivation, and working capacity, have been reported. Likewise, GH treatment of GHD children has been observed to produce significant improvement in many behavioral problems seen in these individuals. Studies also indicated that GH therapy affects the cerebrospinal fluid levels of various hormones and neurotransmitters. Further support that the CNS is a target for GH emerges from observations indicating that the hormone may cross the blood-brain barrier (BBB) and from studies confirming the presence of GH receptors in the brain. It was previously shown that specific binding sites for GH are present in discrete areas in the CNS of both humans and rats. Among these regions are the choroid plexus, hippocampus, hypothalamus, and spinal cord. The density of GH binding in the various brain regions was found to decline with increasing age. More recently, we were able to clone and determine the structure of several GH receptors in the rat and human brain. Although the brain receptor proteins for the hormone were shown to differ in molecular size compared to those present in peripheral tissues the corresponding transcripts did not seem to differ from their peripheral congeners. GH receptors in the hypothalamus are likely to be involved in the regulatory mechanism for hormone secretion and those located in the choroid plexus have been suggested to have a role in the receptor-mediated transport of GH across the BBB. The functions mediated by the GH receptors identified in the hippocampus are not yet known but recently it was speculated that they may be involved in the hormones action on memory and cognitive functions.

Characterization of putative growth hormone receptors in human choroid plexus

The ability to bind iodine-labelled human growth hormone ([125I]hGH) was measured in different parts of the human brain. The choroid plexus contained the highest amount of binding sites (receptors) and was therefore selected for further studies. The binding between [125I]hGH and the receptor was saturable, of high affinity (Ka = 0.63 nM-1) and pH- as well as time-dependent. After solubilization with Triton X-100 the receptors retained their hormone-binding properties and eluted in the high molecular weight range (greater than 500,000) upon molecular sieve chromatography. Analysis by an affinity cross-linking technique indicated a hormone-binding unit of molecular weight 51,000. The molecular characteristics of the identified binding sites are discussed in comparison to those of growth hormone receptors of human and animal origin.

Growth Hormone and Its Receptors in the Central Nervous System – Location and Functional Significance

During the past few years, there has been increasing interest in functions that growth hormone (GH) may play in the central nervous system. Accumulating evidence that the hormone may pass the blood-brain barrier and the psychological improvements seen in adults following GH therapy have received particular attention. This paper will review our recent studies on GH receptors in the human and rat brain. A recent study on the effects of GH treatment in adult growth hormone-deficient patients on quality of life and cerebrospinal fluid levels of various hormones and neurotransmitters is also included.

Age-related reduction of human growth hormone-binding sites in the human brain

Previous studies have shown that alterations in various neuroendocrine functions occur with increasing age. We here report a study of growth hormone (GH)-binding sites in different areas of post-mortem human brains collected from individual males and females of different age. The results indicate that there exists a significant negative correlation between the density of GH-binding sites and increasing age. This phenomenon was observed in both sexes in brain areas such as choroid plexus, hippocampus, hypothalamus, pituitary and putamen but not in e.g. thalamus. In all tissues (except for choroid plexus), the GH binding was significantly higher in those originating from females than those from males. This discrepancy was found likely to be associated with the affinity of GH to lactogenic rather than to somatogenic sites as no pronounced sex difference in binding was observed in the presence of excessive amounts of human prolactin. Data also indicate that the putative GH receptors in the various brain regions differ with regard to binding constants and to the estimated molecular size of the hormone-binding units. The loss of GH receptors in brain of elderly people may have consequences in several physiological courses. The decrease in GH binding at hypothalamic and pituitary levels may be of importance for the mechanisms behind the release or secretion of the hormone.

Pathophysiology of brain edema and cell changes following hyperthermic brain injury

Publisher Summary This chapter focuses on brain edema formation in heat stress and its contribution to cell injury. In addition, the basic concepts of brain edema formation, including various biomechanical and biophysical factors, and chemical mediators involved in this mechanism are reviewed. Based on the experimental observations, a new pharmacological approach to reduce edema formation and cell injury by modifying the breakdown of the blood–brain barrier in heat stress is discussed. Brain edema is a serious complication of various neurological diseases following traumatic, ischemic, or hypoxic injuries to the central nervous system. The early clinical symptoms of brain edema comprise signs of headache, nausea, vomiting, disturbances of consciousness, and occasionally coma. Progression of edema leads to brain herniation and vascular infarction that are common causes of death. The effects of hyperthermia on brain dysfunction is reduced by advancing age, anaesthesia, or prior heat experience indicating that the age and physiological states of the animals before heat exposure are important determining factors for the outcome of thermal brain damage.

Characterization of substance P(1-7) and (1-8) generating enzyme in human cerebrospinal fluid

A substance P-hydrolyzing endopeptidase has been purified from a large quantity of human cerebrospinal fluid by ion exchange chromatography (DEAE-Sepharose CL-6B) and molecular sieving (Sephadex G-100 and Sephacryl S-200). The purification was monitored by measuring the conversion of synthetic substance P using a radioimmunoassay specific for its (1-7) fragment. The enzyme has an apparent molecular weight of 43,000. It cleaves predominantly at the Phe7-Phe8 and Phe8-Gly9 bonds but gives no or negligible conversion of the other tachykinins, neuromedin K and L (substance K).

Growth hormone induces age-dependent alteration in the expression of hippocampal growth hormone receptor and N-methyl-D-aspartate receptor subunits gene transcripts in male rats

Studies were conducted to evaluate the effects of s.c. injected recombinant human growth hormone (GH) on the expression of the gene transcript of N-methyl-D-aspartate receptor subunits type 1 (NR1), type 2A (NR2A), and type 2B (NR2B) in the male rat hippocampus. The GH-induced effects on the expression of hippocampal gene transcripts of GH receptor (GHR) and GH-binding protein were also examined. Male Sprague–Dawley rats, kept in four groups of two different ages, was treated with the hormone or saline during 10 days before decapitation and tissue dissection. Brain tissues collected were analyzed for mRNA content by using the Northern blot technique. The results indicated that in adult young rats (11 weeks of age) the hormone elicited a decrease in the mRNA expression of NR1 but an increase in that of the NR2B subunit. In elderly adult rats (57–67 weeks of age) GH induced an increase in the expression of the hippocampal message for NR1 and NR2A. Meanwhile, the hormone induced a significant up-regulation of the GHR transcript in hippocampus of adult young rats but not in elderly adult rats. It was further found that a significant positive correlation exists between the level of GHR mRNA and the expression of the NR2B subunit transcript in adult young rats. The GH-induced increase in the expression of hippocampal mRNA for the NR2B subunit is compatible with a previously observed memory promoting effect seen for the hormone, because overexpression of this N-methyl-D-aspartate receptor subunit is shown to enhance cognitive capabilities.

Prodynorphin CpG-SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics

The genetic, epigenetic and environmental factors may influence the risk for neuropsychiatric disease through their effects on gene transcription. Mechanistically, these effects may be integrated through regulation of methylation of CpG dinucleotides overlapping with single‐nucleotide polymorphisms (SNPs) associated with a disorder. We addressed this hypothesis by analyzing methylation of prodynorphin (PDYN) CpG‐SNPs associated with alcohol dependence, in human alcoholics. Postmortem specimens of the dorsolateral prefrontal cortex (dl‐PFC) involved in cognitive control of addictive behavior were obtained from 14 alcohol‐dependent and 14 control subjects. Methylation was measured by pyrosequencing after bisulfite treatment of DNA. DNA binding proteins were analyzed by electromobility shift assay. Three PDYN CpG‐SNPs associated with alcoholism were found to be differently methylated in the human brain. In the dl‐PFC of alcoholics, methylation levels of the C, non‐risk variant of 3′‐untranslated region (3′‐UTR) SNP (rs2235749; C > T) were increased, and positively correlated with dynorphins. A DNA‐binding factor that differentially targeted the T, risk allele and methylated and unmethylated C allele of this SNP was identified in the brain. The findings suggest a causal link between alcoholism‐associated PDYN 3′‐UTR CpG‐SNP methylation, activation of PDYN transcription and vulnerability of individuals with the C, non‐risk allele(s) to develop alcohol dependence.