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Biomedical subjects

M S Harbuz

Publications and source records attributed to M S Harbuz.

At least 37 records · Page 2Linked to original sources
PubMed2001

Nramp1 is expressed in neurons and is associated with behavioural and immune responses to stress.

The gene Nramp1 encoding the natural resistance-associated macrophage protein (Nramp1) influences susceptibility to intracellular infections and autoimmune diseases, and the humoral response to stress. Nramp1 functions as a proton/divalent cation antiporter in the membranes of late endosomes/lysosomes, regulating cytoplasmic iron levels in macrophages. The Drosophila homologue of Nramp1 is expressed in sensory neurons and macrophages, and influences taste behaviour directly through divalent cation transport. Here we demonstrate that murine Nramp1 is also expressed on neurons as well as microglial cells in the brain and influences the behavioural response to stress, hypothalamus-pituitary-adrenal (HPA) axis activation and mortality following Toxoplasma gondii infection in control and prestressed mice. We hypothesise that, although differences in HPA activation translate into differences in adrenal enlargement and basal circulating corticosterone levels, the primary influence of Nramp1 is at the level of the neuronal response to stress. These results provide new insight into the possible roles of divalent cation transporters of the Nramp gene family in regulating metal ion homeostasis in the brain and its pathological implications.

Adrenal Glands↗
PubMed2001

CRH in chronic inflammatory stress.

Corticotropin-releasing hormone (CRH) is an important regulator of inflammation at the central level through hypothalamo-pituitary-adrenal (HPA) axis control of glucocorticoid secretion. Integrity of the HPA axis during autoimmune disease is critical in controlling the severity of inflammation, but the evidence for an HPA axis defect in the etiology of autoimmune diseases is not compelling. CRH secreted from leukocytes and neuronal terminals in peripheral tissues also plays a role in mediating inflammation. Elucidating the pathways underlying the expression of CRH, both central and peripheral, and interactions of CRH with other inflammatory mediators such as substance P, confers great potential for the development of a new generation of anti-inflammatory agents.

Animals↗
PubMed2001

Central orexin-A activates hypothalamic-pituitary-adrenal axis and stimulates hypothalamic corticotropin releasing factor and arginine vasopressin neurones in conscious rats.

The effects of centrally injected orexin-A on plasma adrenocorticotropin (ACTH) and corticosterone levels and corticotropin releasing factor (CRF) and arginine vasopressin (AVP) mRNA in the parvocellular cells of the paraventricular nucleus (PVN) of the rat were investigated. In animals implanted previously with a lateral brain ventricle and femoral artery cannula, a single i.c.v. injection of orexin-A (10 microg/rat) resulted in a rapid, significant increase in plasma ACTH and corticosterone concentrations. Plasma ACTH reached a peak (12.5-fold greater than basal levels) at 30 min, which was maintained over 120 min before declining towards control levels by 240 min. Plasma corticosterone concentrations reached a peak (6.7-fold greater than basal levels) at 30 min. Orexin-A at a higher dose (30 microg/rat) also produced a rapid increase in plasma ACTH and corticosterone concentrations. The area under the curve for plasma levels of ACTH was similar for both doses of orexin-A. In a second study, orexin-A (10 microg/rat) was injected i.c.v. and brains and pituitaries were rapidly removed after 240 min. In situ hybridization histochemistry revealed that CRF and AVP mRNA levels were significantly increased in the parvocellular cells of the PVN. Pro-opiomelanocortin mRNA levels in the pituitary gland were not significantly elevated in response to orexin-A. These results suggest that orexin-A is able to act centrally to activate the hypothalamic-pituitary-adrenal axis involving stimulation of both CRF and AVP expression.

Adrenocorticotropic Hormone↗
PubMed2001

Increased corticosterone pulse frequency during adjuvant-induced arthritis and its relationship to alterations in stress responsiveness.

Frequent blood sampling from males rats was used to study hypothalamic-pituitary-adrenal (HPA) axis activation during arthritis and its association with diminished responses to acute psychological stress. In control rats, corticosterone release occurred in a series of 13 +/- 1 pulses per 24 h. Induction of arthritis by Mycobacterium-adjuvant injection initially increased the rate of hormone release within each pulse and, by day 14 postinjection, when hind-paw inflammation was established, caused a marked increase in pulse frequency to 22 +/- 1 per 24 h leading directly to elevated circulating corticosterone levels. In both control and adjuvant-treated rats, there was a marked response to a 10-min noise stress when the stimulus coincided with a rising or interpulse phase of the endogenous corticosterone rhythm. However, when the noise stress coincided with a falling phase of this rhythm, the response was greatly diminished. Since corticosterone pulse frequency was markedly increased and hence interpulse interval decreased by day 14, there was an increased probability of the noise stress occurring during the nonstress responsive falling phase of the corticosterone secretory cycle. As a result, the group mean response to noise stress was significantly smaller in the arthritic than the controls (70.2 +/- 9.2 versus 107.8 +/- 13.0 ng/ml, respectively). In contrast to the differential response to noise stress, all rats showed similar responses to the acute immunological challenge with i.v. lipopolysaccharide. Thus, altered basal pulse frequency is a major factor influencing HPA activation during acute psychological stress.

Animals↗
PubMed2001

The hypothalamo-pituitary-adrenal axis response to experimental traumatic brain injury.

Alterations in the hypothalamo-pituitary-adrenal (HPA) axis following traumatic brain injury have not been documented in detail. We used fluid percussion injury (FPI) to evaluate the early changes in components of the HPA axis following experimental traumatic brain injury. Wistar rats were sacrificed at 2 or 4 h following sham or FPI surgery. In situ hybridization histochemistry was used to determine the expression of mRNAs of corticotrophin releasing hormone (CRH) and arginine vasopressin (AVP) in the hypothalamus and pro-opiomelanocortin (POMC) in the pituitary. A group of animals undergoing no surgery were used as control. Repeated blood sampling from an indwelling catheter demonstrated that plasma corticosterone (CORT) levels peaked 30 min following surgery in sham and FPI animals but there was no significant difference in CORT concentration between these groups at any time. Pituitary POMC expression was increased following sham and FPI surgery (compared with control non-operated animals) but with no significant difference between the two groups undergoing surgery. Hypothalamic CRH mRNA expression was significantly higher in animals undergoing FPI compared with sham surgery. Hypothalamic AVP mRNA expression was not significantly increased when compared with control nonoperated animals. These data indicate that the anaesthesia and/or surgery associated with FPI or sham surgery induces a generalised activation of the HPA axis. The selective increase in CRH mRNA in animals undergoing FPI may be due to specific effects of traumatic brain injury rather than a general stress response and may suggest an additional neurotransmitter role for CRH following head injury. The absence of an AVP response suggests that the effects of FPI may be mediated through the CRH-alone-containing subpopulation of neurons.

Animals↗
PubMed2001

Endomorphins and activation of the hypothalamo-pituitary-adrenal axis.

Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides recently located in the central nervous system and immune tissues with high selectivity and affinity for the mu-opioid receptor. Intracerebroventricular (i.c.v.) administration of morphine stimulates the hypothalamo-pituitary-adrenal (HPA) axis. The present study investigated the effect of centrally administered EM-1 and EM-2 on HPA axis activation. Rats received a single i.c.v. injection of either EM-1 (0.1, 1.0, 10 microg), EM-2 (10 microg), morphine (10 microg), or vehicle (0.9% saline). Blood samples for plasma corticosterone determinations were taken immediately prior to i.c.v. administration and at various time points up to 4 h post-injection. Trunk blood, brains and pituitaries were collected at 4 h. Intracerebroventricular morphine increased plasma corticosterone levels within 30 min, whereas EM-1 and EM-2 were without effect. In addition, pre-treatment of i.c.v. EM-1 did not block the rise in corticosterone after morphine. Corticotrophin-releasing factor (CRF) mRNA and arginine vasopressin (AVP) mRNA in the paraventricular nucleus (PVN) and POMC mRNA in the anterior pituitary were found to be unaffected by either morphine or endomorphins. Since release of other opioids are elevated in response to acute stress, we exposed rats to a range of stressors to determine whether plasma EM-1 and EM-2 can be stimulated by HPA axis activation. Plasma corticosterone, ACTH and beta-endorphin were elevated following acute restraint stress, but concentrations of plasma EM-1-immunoreactivity (ir) and EM-2-ir did not change significantly. Corticosterone, ACTH and beta-endorphin were further elevated in adjuvant-induced arthritis (AA) rats by a single injection of lipopolysaccharide (LPS), but not by restraint stress. In conclusion, neither EM-1 or EM-2 appear to influence the regulation of the HPA axis. These data suggest that endomorphins may be acting on a different subset of the mu-opioid receptor than morphine. The failure to induce changes in plasma EM-ir in response to the chronic inflammatory stress of AA, the acute immunological stress of LPS, or the psychological stress of restraint, argues against an important role for endomorphins in mediating HPA axis activity.

Adrenocorticotropic Hormone↗
PubMed2001

Evidence that a single exposure to aversive stimuli triggers long-lasting effects in the hypothalamus-pituitary-adrenal axis that consolidate with time.

Because of its use as a negative reinforcer in animal studies and its potential pathological impact (e.g. post-traumatic stress disorder and depression), exposure to aversive stimuli is a relevant model for studying CNS plasticity. We present evidence that a single exposure to two predominantly emotional stressors [restraint in tubes and immobilization on wooden boards (IMO)] can modify the response of the hypothalamo-pituitary-adrenal (HPA) axis to a subsequent exposure to the same stressor days later in that a more rapid return to the baseline was observed in the poststress period. In addition, the effect was greater with IMO, the more severe stressor. Using IMO, we have further demonstrated that the effect of a previous single exposure to the stressor (i) increased with days elapsed between the two exposures; (ii) was specific for the previously experienced stressor; and (iii) was mediated via central-mediated effects [corticotropin-releasing factor (CRF) mRNA in the paraventricular nucleus of the hypothalamus]. These data suggest that animals retain memory about a single experience with stressors, resulting in an acceleration of the poststress recovery of the HPA axis that enhances progressively over a period of weeks. The extent to which the present data are relevant regarding post-traumatic stress disorders is unclear, but the study of the HPA response to severe stressors may be suitable for the study of the neurobiological basis of the progressive consolidation of learning over a long period of time (days to weeks).

Animals↗
PubMed2001

A pilot study into the therapeutic effects of music therapy at a cancer help center.

CONTEXT: Since the mid-1980s, music therapy has been a regular feature of the residential program at the internationally renowned Bristol Cancer Help Centre, United Kingdom. Music therapy complements other therapeutic interventions available to residents at the center. OBJECTIVE: To compare the therapeutic effects of listening to music in a relaxed state with the active involvement of music improvisation (the playing of tuned and untuned percussion instruments) in a music therapy group setting and to investigate the potential influence of music therapy on positive emotions and the immune system of cancer patients. DESIGN: A quantitative pre-posttest, psychological/physiological measures, and qualitative focus group design. SETTING: A cancer help center that offers a fully integrated range of complementary therapies, psychological support, spiritual healing, and nutritional and self-help techniques addressing the physical, mental, emotional, and spiritual needs of cancer patients and their supporters. PARTICIPANTS: Twenty-nine cancer patients, aged 21 to 68 years. INTERVENTION: Group music therapy interventions of listening to recorded/live music in a relaxed state and improvisation. MAIN OUTCOME MEASURES: Increased well-being and relaxation and less tension during the listening experience. Increased well-being and energy and less tension during improvisation. Increased levels of salivary immunoglobulin A and decreased levels of cortisol in both experiences. RESULTS: Psychological data showed increased well-being and relaxation as well as altered energy levels in both interventions. Physiological data showed increased salivary immunoglobulin A in the listening experience and a decrease in cortisol levels in both interventions over a 2-day period. Preliminary evidence of a link between positive emotions and the immune system of cancer patients was found. CONCLUSIONS: These findings, which link listening to music in a relaxed state and improvisation to alterations in psychological and physiological parameters, may provide a better understanding of the effectiveness of music therapy for cancer patients.

Adult↗
PubMed2000

Acute ethanol decreases NPY mRNA but not POMC mRNA in the arcuate nucleus.

The acute effects of ethanol and acetaldehyde on neuropeptide mRNA expression in the arcuate nucleus (ARC) was assessed. Acetaldehyde was increased in blood following ethanol with cyanamide (a potent inhibitor of aldehyde dehydrogenase) administration. Acetaldehyde is a toxin which can cause a variety of adverse effects following ethanol ingestion in some Oriental people with a genetic lower activity of aldehyde dehydrogenase. Neuropeptide Y (NPY) mRNA levels in ARC were significantly decreased in response to ethanol in the presence or absence of cyanamide compared to control. In contrast, proopiomelanocortin mRNA in ARC was not changed. These novel findings suggest that ethanol suppresses NPY gene expression in ARC and may play a role in ethanol-induced changes in neuronal function.

Acetaldehyde↗
PubMed2000

Glucocorticoids modulate BDNF mRNA expression in the rat hippocampus after traumatic brain injury.

Brain-derived neurotrophic factor (BDNF) expression in rat hippocampus is increased after experimental traumatic brain injury (TBI) and may be neuroprotective. Glucocorticoids are important regulators of brain neurotrophin levels and are often prescribed following TBI. The effect of adrenalectomy (ADX) on the expression of BDNF mRNA in the hippocampus after TBI has not been investigated to date. We used fluid percussion injury (FPI) and in situ hybridization to evaluate the expression of BDNF mRNA in the hippocampus 4 h after TBI in adrenal-intact or adrenalectomized rats (with or without corticosterone replacement). FPI and ADX independently increased expression of BDNF mRNA. In animals undergoing FPI, prior ADX caused further elevation of BDNF mRNA and this upregulation was prevented by corticosterone replacement in ADX rats. These findings suggest that glucocorticoids are involved in the modulation of the BDNF mRNA response to TBI.

Adrenalectomy↗
PubMed2000

Hypothalamo-pituitary-adrenal axis activation by administration of cyanamide: a potent inhibitor of aldehyde dehydrogenase.

In this report, we investigated the effects of cyanamide (a potent inhibitor of aldehyde dehydrogenase (ALDH: EC 1.2.1.3)) on hypothalamo-pituitary adrenal (HPA)-axis using in situ hybridization histochemistry and radioimmunoassay. Cyanamide administration resulted in a dose-dependent increase in plasma corticosterone concentrations, significant increases in not only corticotrophin releasing factor (CRF) mRNA, but also arginine vasopressin (AVP) mRNA in the paraventricular nucleus (PVN) and proopiomelanocortin (POMC) mRNA in the anterior pituitary. These results suggest that cyanamide is able to activate the HPA axis at all levels of the axis.

Aldehyde Dehydrogenase↗
PubMed2000

Antisense inhibition of pro-opiomelanocortin and proenkephalin A messenger RNA translation alters rat immune cell function in vitro.

Pro-opiomelanocortin (POMC) and proenkephalin A (PEA) antisense oligodeoxynucleotides respectively reduced and enhanced proliferation of rat splenocytes incubated with concanavalin A in vitro. Nonsense base sequences used as controls were without effect. Coincubation with the exogenous synthetic opioid peptides, ACTH, beta-endorphin, met-enkephalin or [D-ala,D-leu]-enkephalin did not significantly alter either the POMC or PEA antisense response, indicating potential differences in bioactivity of immunocyte opioid peptides compared with synthetic equivalents. Levels of the POMC opioid products, ACTH and beta-endorphin, were significantly reduced in splenocytes incubated with POMC antisense probes. These data provide evidence for functional effects of endogenous opioid peptides on rat splenocyte proliferation in vitro.

Adrenocorticotropic Hormone↗
PubMed2000

Novel opioid peptides endomorphin-1 and endomorphin-2 are present in mammalian immune tissues.

Endomorphin (EM)-1 and EM-2 are opioid tetrapeptides, reported within the central nervous system, which have very high specificity and affinity for the mu-opioid receptor. We have used newly developed and well-characterised radioimmunoassays (RIAs) in combination with reversed-phase high-performance liquid chromatography (HPLC) to detect EM-1 and EM-2 immunoreactivity (ir) in rat immune tissues. Endomorphins were detectable in extracts of rat spleen (total EM-1-ir/spleen: 440+/-73 pg, mean+/-SEM, a=group of eight rats; EM-2-ir: 150+/-12 pg) and thymus (EM-1-ir: 152+/-18 pg, mean+/-SEM n=8; EM-2-ir: 156+/-28 pg). EM-2-ir was detectable in extracts of human spleen (338+/-196 pg/g tissue, n=3). Multiple peaks of EM-1-ir and EM-2-ir were observed in rat spleen and thymus extracts, and multiple peaks of EM-2-ir were observed in extracts of human spleen, following reversed-phase HPLC and RIAs. This is the first report of endomorphin immunoreactivity in tissues of the rat and human immune systems.

Adult↗
PubMed2000

Early-life exposure to endotoxin alters hypothalamic-pituitary-adrenal function and predisposition to inflammation.

We have investigated whether exposure to Gram-negative bacterial endotoxin in early neonatal life can alter neuroendocrine and immune regulation in adult animals. Exposure of neonatal rats to a low dose of endotoxin resulted in long-term changes in hypothalamic-pituitary-adrenal (HPA) axis activity, with elevated mean plasma corticosterone concentrations that resulted from increased corticosterone pulse frequency and pulse amplitude. In addition to this marked effect on the development of the HPA axis, neonatal endotoxin exposure had long-lasting effects on immune regulation, including increased sensitivity of lymphocytes to stress-induced suppression of proliferation and a remarkable protection from adjuvant-induced arthritis. These findings demonstrate a potent and long-term effect of neonatal exposure to inflammatory stimuli that can program major changes in the development of both neuroendocrine and immunological regulatory mechanisms.

Animals↗
PubMed2000

Significance of pulsatility in the HPA axis.

A stress-free automated blood sampling system has been employed to demonstrate pulsatile hypothalamo-pituitary-adrenal (HPA) activity in the rat. In females, pulses of corticosterone secretion occur approximately once/hour throughout the 24 h cycle, with variation in pulse amplitude underlying a diurnal rhythm. Males show smaller pulses of secretion which become widely spaced during the early light phase nadir. Ageing does not affect the occurrence of pulses but the diurnal variation is lost. Analysis of the relationship between the HPA response to an acute noise stress and its coincidence with the various phases of the pulse, suggests that pulsatile activity arises from alternating periods of activation and suppression. Responses to i.v. corticotropin-releasing factor are not affected by pulse phase, indicating that this relationship is not generated at the pituitary-adrenal level. This phase relationship holds for all strains of rat except the hyperresponsive Fischer-344 in which an exaggerated stress response arises from a lack of phase-dependent suppression. Patterns of pulsatile activity are also modulated by neonatal programming or chronic HPA activation arising from adjuvant-induced arthritis, with consequent impact upon the response to acute stimuli. Thus, variations in the patterns of pulsatile activity are important determinants of both basal secretion and acute responses of the HPA axis.

Animals↗
PubMed2000

Cyanamide-induced activation of the hypothalamo-pituitary-adrenal axis.

The present study investigated the effects of acute administration of cyanamide (a potent inhibitor of aldehyde dehydrogenase used to treat alcoholics), on the hypothalamo-pituitary adrenal (HPA)-axis. Cyanamide resulted in a significant increase in arginine vasopressin mRNA and corticotrophin releasing factor (CRF) mRNA in the parvocellular cells of the paraventricular nucleus and pro-opiomelanocortin (POMC) mRNA in the anterior pituitary. Plasma corticosterone concentrations were elevated by a range of doses of cyanamide which were maintained in the high dose group at 4 h following administration. These results suggest that cyanamide is able to activate the HPA axis at all levels of the axis. Arginine vasopressin mRNA, in the parvocellular cells of the paraventricular nucleus is an important component of the stress response. Silver grain counting of emulsion dipped slides is commonly used for its evaluation following in-situ hybridization. This method is however, not entirely satisfactory and very time-consuming. We compared this method with a film autoradiographic method, and show that the film autoradiographic method is valid for the determination of arginine vasopressin mRNA in the parvocellular cells of the paraventricular nucleus.

Adrenal Glands↗
PubMed2000

Onset and severity of inflammation in rats exposed to the learned helplessness paradigm.

OBJECTIVE: To test the hypothesis that there is an association between susceptibility to inflammation and a hyporesponsive hypothalamo-pituitary-adrenal (HPA) axis. METHODS: Animals were separated on the basis of behaviour in the learned helplessness (LH) paradigm into groups of LH(+) (i.e. animals which did not escape footshock) and LH(-) animals. Adjuvant-induced arthritis (AA) was subsequently induced in the LH(+) and LH(-) animals. RESULTS: Plasma corticosterone was significantly increased in response to the LH test in the LH(-) compared with the LH(+) rats. We observed an earlier onset and increased inflammation in the LH(-) rats in spite of the greater corticosterone response to the acute stress. We noted lower levels of plasma testosterone in the LH(-) animals suggesting a possible influence for this protective factor in AA. CONCLUSION: These data suggest that increased onset and severity of inflammation in AA is not a simple consequence of an attenuated HPA axis response to stress as proposed in the Lewis rat. Indeed we have observed the converse. Together these data suggest that the balance of pro- and anti-inflammatory factors released in response to stress may influence the progress of AA.

Animals↗