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Biomedical subjects

I M Jackson

Publications and source records attributed to I M Jackson.

At least 73 records · Page 4Linked to original sources
PubMed1989

Beta-endorphin mediates clonidine stimulated growth hormone release.

The role of beta-endorphin in the stimulation of growth hormone secretion elicited by administration of clonidine (Clon), an alpha2-adrenergic agonist, was investigated in awake, freely moving male rats. Animals were infused slowly with either 1 ml of normal rabbit serum (NRS), beta-endorphin antiserum (beta-end-AS) or ACTH antiserum (ACTH-AS) 2 h before the administration of Clon (100 microgram/kg body weight, intravenously). In addition, naloxone (Nal) (2.5 mg/kg body weight, intravenously) was given 15 min prior to Clon in some experiments. Blood samples were taken at 15-min intervals prior to and following Clon administration. Clon caused plasma GH levels to rise 15-fold to peak levels of 177 +/- 38 ng/ml (p less than 0.01) at 30 min. Pretreatment of both Nal or beta-end-AS significantly reduced Clon-stimulated GH secretion to 72 +/- 19 ng/ml (p less than 0.05) and 87 +/- 30 ng/ml (p less than 0.05) respectively. In contrast, the infusion of ACTH antiserum did not affect Clon-stimulated GH release. Our data suggest that beta-endorphin or a related opioid peptide is an important mediator of GH secretion induced by alpha2-adrenergic stimulation. Since blockade of opioid receptors blunted Clon-induced GH release only partially (approximately 50%), other mediators are most likely activated following alpha 2-adrenergic stimulation.

Adrenergic alpha-Agonists↗
PubMed1988

Immunological blockade of endogenous thyrotropin-releasing hormone impairs recovery from hyperglycemia in mice.

Administration of antiserum to thyrotropin-releasing hormone (TRH) into the lateral cerebral ventricle of mice significantly attenuated recovery from hyperglycemia induced by treatment with 2-deoxyglucose but had no effect on the plasma glucose of saline-treated mice. TRH, injected centrally together with the anti-TRH antibody, reversed the effect of the antiserum and blocked the development of hyperglycemia. These findings suggest that activation of TRH neurons in the central nervous system may be a physiological event influencing recovery from hyperglycemia.

Animals↗
PubMed1988

Neurons containing a N-terminal sequence of the TRH-prohormone (preproTRH53-74) are present in a unique location of the midbrain periaqueductal gray of the rat.

Using an antiserum (no. 373) raised against a tyrosinated analog of preproTRH53-74 [( Tyr1]preproTRH53-74 or pYT 22), we have demonstrated the presence of a discrete population of immunoreactive neurons in the midbrain periaqueductal gray (PAG). Relative to the distribution of serotonin, somatostatin, peptide histidine isoleucine (PHI), methionine enkephalin, substance P and neurotensin-containing neuronal perikarya in the PAG, neurons containing immunoreactive pYT 22 occupied a unique location in the ventrolateral PAG. In contrast, terminal fields containing these neuroactive substances with the exception of PHI, were seen in abundance in the region of the ventrolateral PAG neurons. These studies indicate that a non-TRH sequence contained within the N-terminal portion of the TRH prohormone are expressed in a distinct group of neurons in the ventrolateral PAG. The location of these neurons in the PAG in a region richly innervated by nerve terminals containing analgesia-mediating substances, suggests a possible role for proTRH-derived peptides in the modulation of nociception.

Animals↗
PubMed1988

Post-translational processing of thyrotropin-releasing hormone precursor in rat brain: identification of 3 novel peptides derived from proTRH.

The sequence of rat hypothalamic pro-thyrotropin releasing hormone, deduced by sequencing of cDNA, in addition to 5 TRH progenitor sequences contains leader, trailer and 4 intervening sequences separated by paired basic amino acid sequences. We have developed radioimmunoassays to synthetic peptides corresponding to portions of these cryptic proTRH sequences and have used these assays to identify and partially characterize proTRH peptides, distinct from TRH, in extracts of rat brain. Two of these peptides correspond closely in size to one intervening sequence and the carboxy-terminal sequence of proTRH. Three other peptides correspond to the intact amino-terminal leader sequence and two peptides formed by a further cleavage of the leader sequence at an internal paired basic amino acid sequence.

Animals↗
PubMed1988

Biosynthesis of thyrotropin-releasing hormone by a rat medullary thyroid carcinoma cell line.

Prepro-thyrotropin-releasing hormone (TRH) messenger RNA was detected in the rat medullary thyroid carcinoma cell line CA77. The RNA of 1.6 kilobases comigrated with that found in rat hypothalamus. Using three radioimmunoassays specific for pro-TRH-derived peptides, we demonstrated that CA77 cells synthesize high levels of immunoreactive TRH and all of the other pro-TRH-derived peptides identified in hypothalamic tissue. The relative levels of the pro-TRH-derived peptides also indicate that CA77 cells process the TRH precursor in a manner similar to hypothalamic tissue. CA77 cells provide a promising model system for further studies of prepro-TRH gene regulation and post-translational maturation.

Animals↗
PubMed1988

Identification, characterization and localization of thyrotropin-releasing hormone precursor peptides in perinatal rat pancreas.

The sequence of rat hypothalamic prepro TRH, deduced from its complementary DNA, contains five TRH progenitor sequences and six cryptic sequences separated by paired basic amino acid residues. We have utilised antisera against two synthetic peptides corresponding to sequences within proTRH, [Tyr53] preproTRH (53-74), part of the amino terminal leader sequence of proTRH and [Cys 74,83] preproTRH-(75-82), representing a TRH progenitor sequence flanked by cysteine residues (pCC10) in radioimmunoassays (RIA) to identify and chromatographically characterize proTRH derived peptides in extracts of rat perinatal pancreas and to localize these peptides immunohistochemically. Two forms of immunoreactive pYT22 (ipYT22) were observed, similar in size to ipYT22 seen in extracts of adult rat brain. By RIA immunoreactive pCC10 was detectable in neonatal but not fetal pancreas. However, immunohistochemical double staining of both fetal and neonatal rat pancreas colocalized both ipYT22 and ipCC10 with immunoreactive insulin in the B-cell of the developing Islets of Langerhans. These findings indicate that the B-cell of the perinatal pancreas synthesizes TRH from a prohormone encoded by a mRNA similar to that present in adult rat hypothalamus.

Amino Acid Sequence↗
PubMed1988

Molecular biology and regulation of the hypothalamic hormones.

Over the past twenty years, each of the five major hypothalamic releasing or release-inhibiting hormones has been sequenced and its gene structure determined. With the use of molecular biological techniques, such as in situ hybridization, Northern blot analysis or gene constructs for in vitro or in vivo transfection studies--together with 'traditional' neuroendocrinological techniques, such as immunocytochemistry, radio-immunoassay and portal vessel cannulation--investigators have been able to address major issues in neuroendocrine regulation. Several common themes have emerged: messenger RNA expression is uniformly present in neurons that are immunopositive for the specific hypothalamic hormone. Steady state RNA levels within the hypophysiotropic neuron groups are either increased or reduced by changes in specific target hormones that conform to predictions based on previous physiological data. Regulation by the requisite peripheral hormone is exquisitely anatomically specific and is not evident in extrahypophysiotropic regions. Determining the receptor or genetic basis of this specificity is a major focus of current research. Clarifying the apparently lesser role of afferent neural pathways to the hypothalamus in regulating releasing hormone mRNA levels is also an important challenge. Clinically, the measurement of levels of releasing hormones in the peripheral circulation appears to be of limited usefulness, except in rare cases of ectopic GRH or CRH secretion. For diagnostic purposes, each of the releasing hormones has specific utility in amplifying the release and measurement of pituitary hormones, both to clarify the overall physiological activity of the hypothalamic-pituitary-target hormone axis and to further define the anatomic locus of any underlying disturbance. The usefulness of somatostatin as a diagnostic tool is presently limited, but the development of SS receptor antagonists might have significant impact in future clinical investigation. The molecular mechanisms of action of the hypothalamic hormones have been separated into those whose receptor-effector function is mediated by the cAMP-adenylate cyclase pathway(s), GRH and CRH, and those working through the phosphoinositide-protein kinase C cascade, GnRH and TRH. Each of the hormone receptors is coupled to intermediary G proteins, somatostatin uniquely to the inhibitory subclass. The mechanisms responsible for sensitization (priming) or desensitization are not fully understood but are presumably related to receptor down regulation and protein phosphorylation.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1988

The relationship between histological grade, oestrogen receptor status, events and survival at 8 years in the NATO ('Nolvadex') trial.

A pathological review was carried out on 600 patients with breast carcinoma entered into the 'Nolvadex' Adjuvant Trial Organisation (NATO) study. The tumours were graded histologically and these results were compared with the oestrogen receptor (ER) status of the tumours, the numbers of recurrences and the length of survival of the patients. It was found that histological grading was predictive both in terms of events and survival, and correlates significantly with oestrogen receptor status; within histological grades I and II, patients receiving 'Nolvadex' had fewer events and deaths compared with patients in the control group. For patients with grade III tumours qualitatively it was in the same direction as the benefit obtained in patients with grade I and II tumours.

Breast Neoplasms↗
PubMed1988

Multiple compression and plasto-elastic behaviour of paracetamol and microcrystalline cellulose mixtures.

Radial tensile strength, friability, ER/PC (elastic recovery/plastic compression) ratio and energy ratio analyses were evaluated for various mixtures of paracetamol and microcrystalline cellulose (Avicel). A good correlation occurred between the energy ratio and the other variables. Linear relationships were found between log tensile strength and percentage energy ratio and also between radial tensile strength and stress relaxation energy. Capping occurred when the percentage energy ratio was greater than 15% and the ER/PC ratio greater than 1.5. To produce tablets with acceptable tensile strength and friability, the percentage energy ratio for Avicel/paracetamol should be greater than 10%. The optimal mixture of the two powders, as far as the tensile strength, friability and absence of capping were concerned, was found to be 50% w/w Avicel, 50% w/w paracetamol.

Acetaminophen↗
PubMed1988

Molecular forms of gonadotropin-releasing hormone associated peptide (GAP): changes within the rat hypothalamus and release from hypothalamic cells in vitro.

We have developed RIAs using antisera directed against the cryptic peptide of the GnRH precursor (termed GnRH-associated peptide, GAP) and have used these together with a GnRH assay to characterize proGnRH-derived peptides in rat hypothalamic extracts. On Sephadex chromatography we have identified three molecular forms of GAP-like immunoreactivity (GAP-LI), in addition to the GnRH decapeptide. The largest of these forms is an 8.0-kilodalton (kD) GAP-LI which appears to be the complete proGnRH peptide. The second is a 6.5-kD GAP-LI, and is similar to the complete cryptic peptide (i.e. proGnRH14-69 or GAP1.56). The third peptide is a 2.5 kD C-terminal fragment of the cryptic peptide, representing a processed form of GAP. In whole hypothalamic extracts from normal rats the 8.0-kD form was the major form, comprising 60-70% of the total GAP-LI. All three forms were present in three distinct areas of the rat hypothalamus, namely median eminence (ME), anterior and mid-hypothalamus. However in the ME the proportion of 8.0-kD GAP-LI was significantly reduced and the proportion of 6.5-kD GAP-LI significantly increased compared to anterior and mid-hypothalamic samples (p less than 0.05). In whole hypothalamic extracts from pregnant and lactating rats the total content of proGnRH-derived peptides was reduced but the relative proportions of these peptides were not significantly changed from normal female rats. However, in postlactating rats, 2 weeks after removal of pups, the total levels of GAP-LI were unchanged compared to normals, but the percentage of 8.0-kD GAP-LI was significantly decreased and the percentage of 2.5-kD GAP-LI significantly increased compared to normals (p less than 0.05), suggesting that proGnRH may undergo additional processing dependent on physiological condition. In fetal and neonatal rats the proportion of the 6.5-kD peptide was increased and that of the 8.0-kD peptide decreased compared to adults, and this change became less significant with increasing age. In ovariectomized rats the proportion of 6.5-kD GAP-LI was increased and that of 8.0-kD GAP-LI decreased; this change was partially reversed with steroid treatment. Both the 6.5 and 2.5-kD forms were released by high K+ stimulation of neonatal hypothalamic cells in culture. These results indicate that there is differential processing of the proGnRH precursor within the hypothalamus and in altered physiological states.

Aging↗
PubMed1988

Triiodothyronine exerts direct cell-specific regulation of thyrotropin-releasing hormone gene expression in the hypothalamic paraventricular nucleus.

Thyroid hormone administered systemically exerts negative feedback control of biosynthesis of the TRH pro-hormone in the hypothalamic paraventricular nucleus (PVN), the origin of neurons that regulate anterior pituitary TSH secretion, but not in any other group of TRH-synthesizing neurons in the brain. To determine whether this response is mediated by direct effects on PVN neurons, we studied the effect of unilateral stereotaxic implants of L-T3 into the anterior hypothalamus on the concentration of pro-TRH mRNA and pro-TRH in the PVN of hypothyroid rats. Because hypothalamic-pituitary-thyroid function is also regulated by central catecholamines, we also determined the effect of unilateral ablation of ascending catecholaminergic fibers to one side of the PVN by stereotaxic injection of 6-hydroxydopamine or transection of ascending catecholaminergic pathways. T3-implanted hypothyroid animals showed a marked reduction in pro-TRH mRNA and immunoreactive pro-TRH in medial parvocellular neurons of the PVN on the same side as the implant, but not in contralateral PVN neurons or TRH-synthesizing neurons in other hypothalamic regions. In contrast, hypothyroid animals implanted with pellets of hormonally inactive 3,5-diiodo-L-thyronine showed intense symmetric hybridization and immunoreaction product in both wings of the PVN. Despite marked unilateral reduction in the catecholamine innervation to the PVN, no reduction in pro-TRH mRNA or immunoreactive pro-TRH was observed in the PVN on the affected side compared to that on the unaffected side. These studies demonstrate that negative feedback regulation of thyroid hormone occurs directly on TRH neurons and is restricted only to those in the PVN tuberoinfundibular system.

Animals↗
PubMed1988

Spinal cord TRH deficiency is associated with incomplete recovery of denervated muscle in the rat.

The raphe-spinal pathway, which contains co-localized serotonin (5-HT), thyrotropin-releasing hormone (TRH), and several TRH-prohormone-derived non-TRH peptides, projects to the ventral horn of the spinal cord. Pharmacologic ablation of this pathway with the 5-HT neurotoxin, 5,7-dihydroxytryptamine, in neonatal rats resulted in deficient recovery of plantar foot muscles, functionally denervated with botulinum toxin type A. Failure of reinnervation was suggested by slower and incomplete recovery of the plantar foot compound muscle action potential amplitude and by a reduced mean diameter of plantar foot muscle fibers in ablated rats. These findings indicate that deprivation of alpha motor neurons from descending raphe-spinal input interferes with their ability to respond to muscle-derived signals for reinnervation.

5,7-Dihydroxytryptamine↗
PubMed1987

Characterization of LH-RH immunoreactivity in mammalian pituitary neural lobe by HPLC.

High performance liquid chromatography was used to characterize luteinizing hormone-releasing hormone (LH-RH) immunoreactivity that was previously identified immunocytochemically in the pituitary neural lobes of bats, ferrets and humans. Extracts of bat posterior lobe and hypothalamus, ferret posterior lobe and hypothalamus and human neurohypophysis were partially purified with C-18 Bond-Elut cartridges. Samples were chromatographed using a C-18 reverse phase HPLC column, and LH-RH-immunoreactive moieties were separated by gradient elution (TFA/acetonitrile solvent system). For bats and ferrets, the major peak of neural lobe LH-RH immunoreactivity eluted with a retention time identical to that of hypothalamic LH-RH. Synthetic mammalian standard added to bat and ferret hypothalamic extracts coeluted as a single peak with the predominant form of LH-RH immunoreactivity present in those tissues. In humans, the peak of LH-RH immunoreactivity in neural lobe extracts coeluted with synthetic standard. These results provide strong evidence that the LH-RH-immunoreactive fibers which terminate within the neural lobe contain authentic LH-RH. Additional minor peaks of LH-RH immunoreactivity were observed in posterior lobe and hypothalamic extracts of both bats and ferrets. Comparisons of posterior lobe content of LH-RH immunoreactivity across species verify that the neural lobe projection is a major component of the LH-RH system in bats, whereas it is represented only minimally in the laboratory rat.

Adult↗
PubMed1987

GRF immunoreactive neurons in the paraventricular nucleus of the rat: an immunohistochemical study with monoclonal and polyclonal antibodies.

Our study demonstrates a complex GRF neuronal system within the rat hypothalamus. Using both high affinity polyclonal and high specificity monoclonal antibodies to rat (r) GRF, we have substantiated evidence for immunoreactive GRF (GRF-i) perikarya in the parvocellular portion of the paraventricular nucleus. Other hypothalamic areas containing rGRF-positive perikarya include the lateral arcuate nucleus, lateral hypothalamus, perifornical area and dorsomedial nucleus. GRF-i neuronal terminals were seen in the external zone of the median eminence, more rostrally in the periventricular nucleus, and near the suprachiasmatic nucleus and more caudally in the dorsomedial nucleus and ventral premammillary nucleus.

Animals↗
PubMed1987

Thyroid hormone regulates TRH biosynthesis in the paraventricular nucleus of the rat hypothalamus.

Thyroid hormone is important in the regulation of synthesis and secretion of thyroid-stimulating hormone (TSH) in the anterior pituitary, but its role in the control of hypothalamic thyrotropin-releasing hormone (TRH) is controversial. To determine whether thyroid hormone regulates the function of TRH in the hypothalamic tuberoinfundibular system, a study was made of the effect of hypothyroidism on thyrotropin-releasing hormone messenger RNA (proTRH mRNA) and TRH prohormone in the rat paraventricular nucleus. Extracts of rat hypothalamic paraventricular nucleus were examined by quantitative Northern blot analysis, and coronal sections of rat brain were examined by in situ hybridization histochemistry and immunocytochemistry. A nearly twofold increase in proTRH mRNA was observed in hypothyroid animals; this increase could be obliterated by levothyroxine treatment, suggesting an inverse relation between circulating thyroid hormone and proTRH mRNA. In situ hybridization showed that this response occurred exclusively in medial parvocellular neurons of the paraventricular nucleus. A simultaneous increase in proTRH mRNA and immunoreactive TRH prohormone in this region suggests that hypothyroidism induces both transcription and translation of the TRH prohormone in the paraventricular nucleus.

Animals↗