Muscling in on salbutamol.
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Administration, Oral↗
Biomedical subjects
N J Rothwell
Publications and source records attributed to N J Rothwell.
Different receptor mechanisms mediate the pyrogenic and behavioral effects of interleukin 1.
Interleukin 1 (IL-1) is a cytokine released during immune activation that mediates the host's response to infection and inflammation. Peripheral and central injections of IL-1 induce fever and sickness behavior, including decreased food motivation and reduced interest in social activities. To determine the receptor mechanisms responsible for these effects, rats were injected with IL-1 receptor antagonist (IL-1ra), an endogenous cytokine that acts as a pure antagonist of IL-1 receptors. IL-1ra blocked the increased body temperature and oxygen consumption induced by injection of recombinant human IL-1 only when both cytokines were administered i.p. In contrast, i.p. or intracerebroventricular administration of IL-1ra blocked the depressive effect of IL-1 beta on food-motivated behavior and social exploration when this cytokine was administered by the same route as the antagonist. In addition, intracerebroventricular IL-1ra blocked the reduction in social exploration produced by i.p. IL-1 beta but had only partial antagonist effects on the decrease in food-motivated behavior induced by i.p. IL-1 beta. In each case, the dose of IL-1ra was 100- to 1000-fold in excess of the biologically active dose of IL-1. These results suggest that the receptor mechanisms that mediate the behavioral and pyrogenic effects of IL-1 are heterogeneous.
Animals↗
Lipocortin-1 inhibits NMDA receptor-mediated neuronal damage in the striatum of the rat.
Lipocortin-1 (annexin-1), an endogenous phospholipid and calcium binding protein, has been shown to significantly attenuate the damage produced by focal cerebral ischaemia in the rat. In the present study we have therefore investigated its effect on N-methyl-D-aspartate (NMDA) induced neuronal damage. Unilateral intrastriatal infusion of a potent and selective NMDA agonist, cis-2,4-methanoglutamate (MGlu), induced an extensive lesion of the striatum in the rat, which was inhibited (greater than 80%) by prior injection of MK801 (4 mg/kg, i.p.). Infusion of 1.2 micrograms of an active fragment of lipocortin-1 (N-terminal 1-188 aa) immediately after MGlu significantly reduced the extent of damage by 44.2 +/- 8.0%. In contrast, infusion of 3 microliters of neutralizing anti-lipocortin-1 antibody with MGlu increased lesion size by 158.9 +/- 22.0%. These findings indicate that the damage produced by intrastriatal infusion of MGlu is mediated by the NMDA receptor. Lipocortin-1 fragment markedly attenuated, and the neutralizing antibody increased, this NMDA mediated neuronal damage. These observations may explain the neuroprotective action of lipocortin following cerebral ischaemia.
Animals↗
Thermogenic actions of tryptophan in the rat are mediated independently of 5-HT.
Serotonin (5-HT) has been implicated in the central control of energy balance, via inhibition of food intake and stimulation of thermogenesis. Its rate of synthesis in brain is dependent on the availability of its precursor amino acid, tryptophan. The objective of the present study was therefore to investigate the thermogenic actions of tryptophan and to determine whether these actions are mediated by 5-HT. Central or peripheral injections of 5-HT (i.c.v.; 0.5-40 micrograms), 5-hydroxytryptophan (5-HTP) (i.c.v.; 20 micrograms) or tryptophan (i.p.; 20 mg/kg, i.c.v.; 12-60 micrograms) significantly increased resting oxygen consumption (VO2 by approximately 15-20%) in conscious rats, without apparent effects on physical activity. Small increases (5-7%) in VO2 were also observed following peripheral injections of aspartate or glycine (20 mg/kg) but not taurine, whilst central injections of tyrosine or leucine (15-18 micrograms) significantly increased VO2 by 15%. We have previously reported that the thermogenic and anorexic actions of 5-HT are mediated by corticotropin-releasing factor (CRF). In the present study, the thermogenic actions of 5-HTP, like those of 5-HT, were significantly reduced by pretreatment (5 min before) with the CRF antagonist alpha-helical CRF9-41 (25 micrograms, i.c.v.) or a polyclonal antibody to CRF. However, the thermogenic actions of tryptophan were not significantly modified by pretreatment with either the 5-HT antagonist, methysergide (20 micrograms, i.c.v.) or with the CRF antagonist or antibody and thus appear to act through different mechanisms to 5-HT.(ABSTRACT TRUNCATED AT 250 WORDS)
5-Hydroxytryptophan↗
Lipocortin-1 exhibits novel actions, providing clinical opportunities.
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Animals↗
Alzheimer's disease: pathology to potential treatments?
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Alzheimer Disease↗
Interleukin-1 receptor antagonist inhibits ischaemic and excitotoxic neuronal damage in the rat.
Interleukin-1 (IL-1) synthesis in the brain is stimulated by mechanical injury and IL-1 mimics some effects of injury, such as gliosis and neovascularization. We report that neuronal death resulting from focal cerebral ischaemia (middle cerebral artery occlusion, 24 h) is significantly inhibited (by 50%) in rats injected with a recombinant IL-1 receptor antagonist (IL-1ra, 10 micrograms, icv 30 min before and 10 min after ischaemia). Excitotoxic damage due to striatal infusion of an NMDA-receptor agonist (cis-2,4-methanoglutamate) was also markedly inhibited (71%) by injection of the IL-1ra. These data indicate that endogenous IL-1 is a mediator of ischaemic and excitotoxic brain damage, and that inhibitors of IL-1 action may be of therapeutic value in the treatment of acute or chronic neuronal death.
Animals↗
Eicosanoids, thermogenesis and thermoregulation.
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Adipose Tissue, Brown↗
Salbutamol, a beta 2-adrenoceptor agonist, increases skeletal muscle strength in young men.
1. beta 2-Adrenoceptor agonists have been shown to increase rapidly lean body mass and reverse muscle wasting in several animal models of human illness. However, no published information is available for humans. In the present study, we investigated the effects of a slow-release preparation of salbutamol or a placebo on skeletal muscle functional capacity in 12 healthy men. The strength of different muscle groups was measured on two occasions before and after 14 and 21 days of treatment. 2. No significant changes in muscle strength were observed with placebo during the trial. In contrast, the strength of both quadriceps muscles increased significantly (12 +/- 3%) after 14 days on salbutamol, and remained elevated at 21 days. Whereas the strength of the hamstring muscles of the dominant leg significantly increased after 21 days on salbutamol (22 +/- 6%), the strength of the non-dominant hamstring muscles returned to baseline values. 3. There was no significant change in the grip strength of either hand in these subjects during the trial. The maximal static inspiratory mouth pressure increased significantly (7 +/- 2%) after 14 days on salbutamol, and increased further after 21 days (15 +/- 4%); the expiratory mouth pressure remained constant. No significant changes in body weight, skinfold thickness, lean body mass or limb circumferences were measured in either group. 4. These data demonstrate that short-term administration of salbutamol increases voluntary muscle strength in man. However, the magnitude and duration of this effect vary between muscle groups. This study implies that the beta 2-adrenoceptor agonists may be of therapeutic potential in altering skeletal muscle function in humans.
Adult↗
Anabolic effects of clenbuterol on skeletal muscle are mediated by beta 2-adrenoceptor activation.
The potent anabolic effects of the beta 2-adrenoceptor agonist clenbuterol on skeletal muscle have been reported to be independent of actions on beta-adrenoceptors. In the present study clenbuterol, presented to rats in the diet (4 mg/kg), caused significant increases in gastrocnemius muscle mass, protein, and RNA content and a decrease in epididymal fat pad mass. These effects were not mimicked by oral administration of the beta 2-adrenoceptor agonist salbutamol even at high dose (52 mg/kg diet), and the effects of clenbuterol were not inhibited by addition of DL-propranolol (200 mg/kg diet). However, the selective beta 2-antagonist ICI-118,551 (200 mg/kg diet) reversed the anabolic effects of clenbuterol, and a high dose of DL-propranolol (1,000 mg/kg diet) also inhibited these actions of clenbuterol. Furthermore, continuous infusion of salbutamol (1.15 mg.kg body wt-1.day-1) via miniosmotic pumps did cause significant increases in muscle mass, protein, and RNA content. These results indicate that the anabolic effects of clenbuterol are dependent on interaction with the beta 2-adrenoceptor. However, a long duration of action appears to be required to induce the anabolic effects of beta 2-agonists.
Albuterol↗
Inhibition of central actions of cytokines on fever and thermogenesis by lipocortin-1 involves CRF.
In the present studies, the mechanisms underlying the inhibitory actions of lipocortin-1 on the pyrogenic and thermogenic properties of cytokines were investigated. Central (icv) injection of corticotropin-releasing factor (CRF, 4.7 micrograms) or the recombinant cytokines interleukin (IL)-1 alpha (50 ng), IL-1 beta (5 ng), IL-6 (20 ng), IL-8 (20 ng), or tumor necrosis factor-alpha (TNF-alpha, 1 microgram) in conscious rats produced significant increases in resting oxygen consumption (VO2, 13-26%) and colonic temperature (0.7-1.6 degrees C) within 2 h postinjection. Administration (icv) of a recombinant fragment (NH2-terminus, 1-188 amino acids) of human lipocortin-1 (1.2 micrograms) produced small increases in VO2 (< 5%) and body temperature (< 0.3 degrees C). Pretreatment (-5 min) with lipocortin-1 significantly attenuated the thermogenic and pyrogenic effects of centrally injected IL-1 beta (80% inhibition), IL-6 (60%), IL-8 (80%), or CRF (60%). However, pretreatment with lipocortin-1 failed to modify the actions of IL-1 alpha or TNF-alpha. We have previously demonstrated that the pyrogenic and thermogenic effects of IL-1 beta, IL-6, and IL-8 are dependent on the central actions of CRF, whereas IL-1 alpha and TNF-alpha act independently of CRF. Fever and thermogenesis induced by all of these cytokines (with the exception of IL-8) can also be prevented by administration of a cyclooxygenase inhibitor. The data presented here suggest that the potent antipyretic effects of lipocortin-1 may result from inhibition of the release or actions of CRF rather than modulation of eicosanoid synthesis.
Animals↗
Metabolic and febrile responses to typhoid vaccine in humans: effect of beta-adrenergic blockade.
Fever and activation of acute phase responses were induced in human volunteers by intramuscular injection of typhoid vaccine. Vaccine injection caused a rapid (within 1 h) and sustained rise in metabolic rate (peak response 16%, 6-8 h), followed by later increases in white blood cell count (3-4 h), skin temperature (4-5 h), oral temperature (5-6 h), heart rate (6-8 h), and plasma cortisol (5-8 h). A peak fever [1.2 +/- 0.2 degree C (SE) rise] was recorded 12 h after vaccine injection. The involvement of the sympathetic nervous system in the development of these responses was investigated by the oral administration of propranolol before (80 mg) and 3 h after (40 mg) vaccine injection. Propranolol prevented the increases in metabolic rate, heart rate, and skin temperature but did not inhibit the rise in oral temperature or white cell count after vaccine administration. These data indicate that the sympathetic nervous system is responsible for the rise in energy expenditure associated with fever in humans. However, the rise in body temperature can develop in the absence of this increase in metabolic rate possibly by changes in heat loss.
Acute-Phase Reaction↗
Thermogenesis, brown adipose tissue and dexfenfluramine in animal studies.
D-Fenfluramine is a potent stimulator of thermogenesis in the rat, an action which may contribute to its effects on body weight. The actions of D-fenfluramine appear to control release of endogenous 5-HT which subsequently induces release of eicosanoids and corticotrophin-releasing factor. Peripheral heat production results mainly from sympathetic activation of thermogenesis.
Adipose Tissue, Brown↗
Involvement of corticotrophin releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5-HT) and related compounds.
The present study investigated the involvement of corticotrophin-releasing factor (CRF) in the thermogenic and anorexic actions of serotonin (5-HT) in the rat. Serotonergic compounds and CRF antibody were injected directly into the third ventricle of conscious, male Sprague-Dawley rats. Thermogenesis was measured as changes in whole body oxygen consumption by indirect calorimetry. Central injections of 5-HT (0.5-50 micrograms, i.c.v.) significantly increased resting oxygen consumption (VO2; maximum 12.5% increase), without obvious effects on behaviour. Similar increases in VO2 (12-17%) were observed following central injections of the 5-HT precursors, tryptophan (14 micrograms, i.c.v.) or 5-hydroxytryptophan (5-HTP, 20 micrograms, i.c.v.), and peripheral (10 mg/kg, i.p.) or central (30 micrograms, i.c.v.) injections of the 5-HT reuptake inhibitor, DL-fenfluramine. Administration of a polyclonal CRF antibody (3 microliters, i.c.v.) 10 min prior to serotonergic compounds, significantly reduced (77-106%) the increases in VO2 observed in response to central injections of 5-HTP (20 micrograms), 5-HT (50 micrograms) or peripheral injections of fenfluramine, but not those observed in response to either 30 micrograms fenfluramine (i.c.v.) or 20 micrograms 5-HT. Voluntary food intake was measured for 6 h in rats following 16 h starvation. Six-hour food intake was significantly reduced (30-60%) in rats given central injections of 5-HT or 5-HTP, and central or peripheral injections of fenfluramine.(ABSTRACT TRUNCATED AT 250 WORDS)
5-Hydroxytryptophan↗
Lipocortin-1 is an endogenous inhibitor of ischemic damage in the rat brain.
Lipocortin-1 (annexin-1) is an endogenous peptide with antiinflammatory properties. We have previously demonstrated lipocortin immunoreactivity in certain glial cells and neurons in the rat brain (Strijbos, P.J.L.M., F.J.H. Tilders, F. Carey, R. Forder, and N.J. Rothwell. 1990. Brain Res. In press.), and have shown that an NH2-terminal fragment (1-188) of lipocortin-1 inhibits the central and peripheral actions of cytokines on fever and thermogenesis in the rat in vivo (Carey, F., R. Forder, M.D. Edge, A.R. Greene, M.A. Horan, P.J.L.M. Strijbos, and N.J. Rothwell. 1990. Am. J. Physiol. 259:R266; and Strijbos, P.J.L.M., J.L. Browning, M. Ward, R. Forder, F. Carey, M.A. Horan, and N.J. Rothwell. 1991. Br. J. Pharmacol. In press.). We now report that intracerebroventricular administration of lipocortin-1 fragment causes marked inhibition of infarct size (60%) and cerebral edema (46%) measured 2 h after cerebral ischemia (middle cerebral artery occlusion) in the rat in vivo. The lipocortin-1 fragment was effective when administered 10 min after induction of ischemia. Ischemia caused increased expression of lipocortin-1 around the area of infarction as demonstrated by immunocytochemistry. Intracerebroventricular injection of neutralizing antilipocortin-1 fragment antiserum increased the size of infarct (53%) and the development of edema (29%). These findings indicate that lipocortin-1 is an endogenous inhibitor of cerebral ischemia with considerable therapeutic potential.
Animals↗
Localization of immunoreactive lipocortin-1 in the brain and pituitary gland of the rat. Effects of adrenalectomy, dexamethasone and colchicine treatment.
The presence and localization of endogenous lipocortin-1 (LC-1, a protein which has been proposed to mediate the anti-inflammatory actions of the glucocorticoids) was studied by immunohistochemical techniques in rat brain and pituitary. A polyclonal antiserum specific for a fragment of lipocortin-1 (alpha alpha 1-188) was used to visualize immunoreactive LC-1 (iLC-1) in both neuronal and non-neuronal cell structures. Neuronal staining, which was independent of microtubular axonal transport mechanisms (in that it was not affected by blockade of axonal transport), was found in varicose nerve fibres in various regions of the brain. In addition, iLC-1 was found in the cytoplasm of neuronal cells throughout the brain. Of all brain regions which showed iLC-1, only the hippocampal neurons showed a reduced staining intensity after adrenalectomy. However, iLC-1 was not affected by dexamethasone treatment. Non-neuronal iLC-1 was found in ependymocytes lining the cerebral ventricles and aqueduct. In addition, iLC-1 was found in tanycytes in all circumventricular organs studied and in the ventral walls of the third ventricle, where some of the branching tail processes appeared to envelop local capillaries and neuronal cell bodies. A tancycyte-mediated release of LC-1 from varicose nerve fibres into the portal vasculature is proposed.
Adrenalectomy↗
Effects of central injection of glucose on thermogenesis in normal, VMH-lesioned and genetically obese rats.
Intra-cerebroventricular (i.c.v.) injection of glucose (0.1-1.0 mumol) caused dose-dependent increases in resting oxygen consumption (Vo2) of conscious rats (maximum increase of 15.4 +/- 2% at 0.5 mumol). These effects were significantly attenuated by peripheral (i.p.) pretreatment with the beta-adrenoceptor propranolol, indicating the importance of the sympathetic nervous system (SNS) in the response. Plasma glucose concentrations were elevated (11%) 30 min after central injection of glucose, but intravenous glucose (0.5 mumol) did not affect resting Vo2. Animals which had been fasted for 12 h prior to Vo2 measurement exhibited reduced basal Vo2 values, but the nutritional state of the animal did not affect the metabolic response to central injections of glucose (0.5 mumol). Rats exhibiting genetic (fa/fa Zucker rats) and hypothalamic (VMH-lesioned) obesity showed similar thermogenic responses to centrally administered glucose, to their lean counterparts. These data suggest a dual action of central glucose in the regulation of energy balance, involving stimulation of energy expenditure in addition to its reported inhibition of energy intake. The defective diet-induced thermogenesis associated with VMH and genetic obesities does not appear to result from an inability to respond to changes in intracerebroventricular glucose concentrations.
Animals↗
Central actions of CRF on thermogenesis are mediated by pro-opiomelanocortin products.
Corticotrophin-releasing factor (CRF) causes central activation of thermogenesis. The aim of this study was to investigate whether this action is mediated by ACTH or other peptides derived from the ACTH precursor pro-opiomelanocortin (POMC) within the CNS. Central (intracerebroventricular) injection of rat CRF caused dose-dependent increases in resting oxygen consumption (VO2) in conscious rats (maximal 26 +/- 5% at 2 nmol CRF). These responses were significantly attenuated by pretreatment (i.c.v.) with either a monoclonal antibody raised to gamma 1MSH or with naloxone which antagonises beta-endorphin (beta-EP) actions. The increases were not affected by pretreatment with monoclonal antibodies to ACTH or the N-terminal of POMC. Central injections of gamma 1-melanocyte-stimulating hormone (MSH) or beta-EP caused dose-dependent increases in VO2 (maximal at 0.5-1.5 pmol) and these were markedly inhibited by pretreatment with the anti-gamma 1-MSH antibody or naloxone respectively. Injection of ACTH or alpha MSH did not significantly affect VO2 at doses up to 2 nmol. These data indicate that the central actions of CRF on thermogenesis may be mediated, at least in part, by release of gamma MSH and/or beta-EP.
Animals↗