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N J Rothwell

Publications and source records attributed to N J Rothwell.

At least 91 records · Page 5Linked to original sources
PubMed1994

Lipocortin-1: cellular mechanisms and clinical relevance.

Lipocortin-1, a 37 kDa member of the annexin superfamily of proteins, originally evoked interest as one of the 'second messengers' of the anti-inflammatory actions of the glucocorticoids. Subsequent research has shown that the protein plays a major regulatory role in systems as diverse as cell-growth regulation and differentiation, neutrophil migration, CNS responses to cytokines, neuroendocrine secretion and neurodegeneration. The role of lipocortin-1 in mediating glucocorticoid-induced effects in these systems has been demonstrated using immunoneutralization strategies and by mimicking steroid actions with highly purified or recombinant lipocortin-1 or its biologically active peptide fragments. Originally the mode of action of lipocortin-1 seemed to be largely through inhibition of prostaglandin formation, but it is now clear that it can modify other aspects of cell function, perhaps pointing to a more fundamental mechanism than was originally envisaged. In this article Rod Flower and Nancy Rothwell review the nature, possible mechanisms and clinical relevance of these diverse actions of lipocortin-1.

Animals↗
PubMed1994

Mechanisms of activation of the pituitary-adrenal axis by tissue injury in the rat.

To characterize the mechanisms of the pituitary-adrenal (P-A) response to tissue injury, rats were injected intramuscularly (IM) with turpentine. This resulted in marked elevations in the plasma concentrations of ACTH and corticosterone within the first hour after injection, which were attenuated by either total deafferentation of the medial basal hypothalamus (MBH) or neonatal capsaicin pretreatment. The plasma concentrations of corticosterone remained elevated for 18 h in the turpentine-injected rats, despite a return of ACTH toward control values (by 2-4 h). Bioactive concentrations of interleukin-6 (IL-6) in plasma rose markedly after turpentine, and its concentrations were significantly correlated with plasma corticosterone concentrations 4-8 h after turpentine. Pretreatment with IL-1 receptor antagonist (IL-1ra) attenuated the release of IL-6 and had a marginal effect on the corticosterone response 6 h after turpentine. These results suggest that the early and late phase of the P-A response to tissue injury are mediated by different mechanisms.

Acute-Phase Reaction↗
PubMed1994

Tumor necrosis factor-alpha and fever after peripheral inflammation in the rat.

The involvement of endogenous tumor necrosis factor-alpha (TNF-alpha) in the pyrogenic [i.e., rise in colonic temperature (Tc)] and thermogenic [increase in oxygen consumption (VO2)] responses to inflammation was investigated in rats subjected to an intramuscular injection of turpentine. Turpentine administration caused a rise in Tc and VO2 within 2 h (0.9 +/- 0.1 degrees C, 27 +/- 2%, respectively). Eighteen to twenty hours after turpentine, the magnitude of these responses had increased (2.3 degrees C fever and a 28% increase in metabolic rate compared with control animals) and was associated with marked inflammation in the injected limb. A rapid (by 4 h) and sustained rise in the plasma concentration of the endogenous pyrogen IL-6, but not TNF-alpha, was also observed. Intravenous pretreatment with a TNF-alpha antiserum attenuated the rise in Tc observed 2, 8, and 18 h after turpentine injection and almost abolished the hypermetabolic response observed at 18 h. In addition, the TNF-alpha antiserum inhibited the peak rise (8 h) in plasma IL-6 by 76%. These findings indicate that endogenous TNF-alpha is involved in fever and hypermetabolism during inflammation and that it may exert these effects by inducing the release of IL-6 into circulation.

Animals↗
PubMed1994

CNS regulation of thermogenesis.

Thermogenesis (adaptive increases in heat production) can develop in response to low environmental temperature, alterations in the amount or composition of the diet, and pathogenic stimuli, such as infection, injury, and inflammation. Thermogenic responses to each of these stimuli appear to be mediated by activation of the sympathetic nervous system and, at least in experimental animals, by heat production in brown fat. Thermogenesis is under the direct control by the central nervous system (CNS), particularly by specific regions of the hypothalamus. Serotonergic pathways have been directly implicated in the central control of most forms of thermogenesis, and indirect evidence suggests involvement of adrenergic and cholinergic mechanisms. Numerous peptides have been shown to induce increases on metabolic rate when injected into the brains of experimental animals; of these, corticotrophin-releasing factor (CRF) has been the most extensively studied. CRF appears to mediate thermogenic responses to serotonergic agonists, injury, and cytokines, and may be involved in impaired thermogenic responses in certain genetically obese rodents. Cytokines, particularly interleukin-1 (IL-1) and IL-6, act as endogenous pyrogens in the brain and stimulate thermogenesis via synthesis of prostaglandins and CRF. Peptides such as lipocortin-1, arginine vasopressin, and alpha MSH potently inhibit central effects of cytokines. Pharmacological modification of thermogenesis may be clinically beneficial in treating conditions such as obesity, cachexia, and fever.

Animals↗
PubMed1993

Dexamethasone inhibits the pyrogenic activity of prostaglandin F2 alpha, but not prostaglandin E2.

The effect of dexamethasone on prostaglandin (PG) E2- and PGF2 alpha-induced fever was studied in rats. Intracerebroventricular injection of PGE2 and PGF2 alpha (500 ng) induced increases in body temperature (maximal temperature rises of 0.97 +/- 0.13 degrees C and 0.78 +/- 0.18 degrees C, respectively, vs. vehicle 0.12 +/- 0.09 degrees C) of unrestrained rats maintained within the thermoneutral zone. PGE2-induced fever peaked earlier and the defervescence was faster when compared to the response induced by PGF2 alpha. Subcutaneous pre-administration of dexamethasone (0.5 mg/kg) did not affect PGE2-induced fever (maximal temperature rise of 1.00 +/- 0.08 degrees C), but completely prevented the pyrogenic activity of PGF2 alpha (maximal temperature rise of 0.16 +/- 0.16 degrees C). Neither PGE2- nor PGF2 alpha-induced fever was significantly altered (maximal temperature rises of 0.90 +/- 0.11 degrees C and 0.64 +/- 0.14 degrees C, respectively) by intraperitoneal administration of indomethacin (2 mg/kg). These results demonstrate for the first time that glucocorticoids, in addition to inhibiting endotoxin- and cytokine-induced fever, can also modulate the pyrogenic activity of some prostaglandins, possibly via suppression of the synthesis of corticotropin-releasing factor, indicating that multiple mechanisms may be involved in the antipyretic activity of these steroids.

Animals↗
PubMed1993

Effect of dietary fish oil supplementation on fever and cytokine production in human volunteers.

The effect of dietary fish oil supplementation on acute phase responses to intramuscular injection of typhoid vaccine, and in vitro cytokine production, was investigated in human volunteers. Half of the subjects supplemented their normal diet with 4.5 g/day of fish oil for 6-8 weeks. Injection of typhoid vaccine in unsupplemented subjects caused an increase in white cell count, resting heart rate, metabolic rate, oxygen consumption, and oral temperature. Fish oil supplementation inhibited the tachycardia and attenuated the maximal increases in oral temperature and metabolic rate following typhoid vaccine. However, interpretation of these latter results were complicated by similarly attenuated responses in saline-injected subjects. The in vitro production of interleukin-1 and interleukin-6 from whole blood was suppressed by fish oil supplementation, however, production of tumor necrosis factor alpha was not significantly altered. Fish oil supplementation may therefore provide a non-pharmacological approach of attenuating several of the responses associated with injury and infection and this may be related to reduced cytokine (IL-1 and IL-6) production.

Journal Article↗
PubMed1993

Clenbuterol, a beta 2-adrenergic agonist, reverses muscle wasting due to scald injury in the rat.

The effects of clenbuterol, a beta 2-adrenergic agonist, on body weight, tissue masses, and protein and RNA contents were studied following scald injury (30 per cent TBSA) in the rat. While the masses of heart, liver and epididymal fat pads remained unaffected, significant reductions in gastrocnemius, plantaris and soleus muscle masses (approximately 11 per cent; P < 0.01) were observed following injury, none of which were mimicked by pair-feeding or could be attributed to dehydration. This muscle wasting was accompanied by significant reductions in protein and/or RNA content. Oral administration of clenbuterol (4 mg/kg diet) had no anabolic effects, either in the scalded animals or their pair-fed controls. While clenbuterol (12 mg/kg diet) did not affect the masses of heart and fat pads, increases in the wet weights (approximately 20 per cent), RNA (approximately 30 per cent) and protein content (approximately 20 per cent) of the gastrocnemius and plantaris muscles were observed in all animals; the magnitude of these effects was greater (P < 0.05) in the scalded animals than in their pair-fed controls. Clenbuterol had no effect on body weight but increased (P < 0.001) carcass water content. These data indicate that there is a selective mobilization of muscle protein and sparing of fat in the early phase following burn injury, and that beta 2-adrenergic agonists, such as clenbuterol, may be of therapeutic value in inhibiting or reversing muscle atrophy associated with thermal injury.

Animals↗
PubMed1993

Dietary N-3 fatty acids inhibit ischaemic and excitotoxic brain damage in the rat.

Arachidonic acid [20:4(N-6)] has been implicated in neurological damage induced by cerebral ischaemia. Membrane arachidonate concentrations can be reduced by changes in dietary fat intake. Therefore, in the present study, we have investigated the effects of N-3 fatty acid supplementation on neuronal damage induced by permanent focal cerebral ischaemia or pharmacological activation of striatal NMDA receptors. Weanling rats were fed either a control diet or an N-3 supplemented diet (1.75% by weight as N-3 fatty acids) for 6 weeks. N-3-supplemented animals reduced ischaemic damage following middle cerebral artery occlusion (36%, p < 0.05), and excitotoxic damage induced by infusion of the selective NMDA agonist (1-aminocyclobutane-cis-1,3-dicarboxylic acid, 43%, p < 0.001) compared to the control-fed group. These data are consistent with the proposed role of arachidonic acid in ischaemic and excitotoxic brain damage, and suggest that modest dietary supplementation with N-3 fatty acids may offer benefit to populations at high risk of stroke.

Amino Acids↗
PubMed1993

Inhibition of the thermogenic and pyrogenic responses to interleukin-1 beta in the rat by dietary N-3 fatty acid supplementation.

The thermogenic (increase in oxygen consumption, VO2) and pyrogenic (Tc) responses to the cytokine interleukin-1 beta (IL-1 beta) were studied in rats fed a n-3 fatty acid supplemented diet (8.75% n-3 fatty acids/kg diet). 4-6 weeks after commencing the diets, the n-3 supplemented rats exhibited reduced pyrogenic (0.5 +/- 0.1 degrees C versus 1.1 +/- 0.2 degrees C in control animals) and thermogenic (9 +/- 3% versus 22 +/- 6% in control animals) responses to intraperitoneal (i.p.) injection of IL-1 beta (1 micrograms/rat). However, responses to centrally administered IL-1 beta (5ng intracerebroventricular (i.c.v.)) were similar in both groups at this time. After 8-9 weeks of supplementation, n-3 supplemented animals exhibited attenuated responses to both ip IL-1 beta (VO2 responses reduced by 68% and Tc by 0.8 degrees C) and also i.c.v. IL-1 beta (VO2 responses reduced by 56% and Tc by 0.7 degrees C). N-3 supplementation did not, however, influence the thermogenic capacity of these animals since responses to noradrenaline were similar in control and n-3 fed animals (50% increase in VO2). These findings demonstrate that n-3 supplementation modifies the pyrogenic and thermogenic responses to IL-1 beta, probably via changes in eicosanoid metabolism. Modification of central responses to IL-1 are delayed compared to the effects of peripheral administration indicating separate mechanisms of IL-1 on fever and thermogenesis in the brain and the periphery.

Animals↗
PubMed1993

Involvement of cytokines in acute neurodegeneration in the CNS.

Cytokines, (particularly interleukins and growth factors) are synthesised in the brain, and induced by brain damage. Interleukin-I appears to directly mediate ischaemic and excitotoxic brain damage, whereas growth factors (e.g., bFGF, NGF), and the phospholipid binding protein lipocortin-1 exhibit neuroprotective actions. Central administration of recombinant interleukin-1 receptor antagonist markedly attenuates damage induced by focal cerebral ischaemia, or pharmacological activation of NMDA receptors in the rat brain. The mechanisms of action of these cytokines on neurodegeneration are unknown, but indirect evidence has implicated corticotropin releasing factor, arachidonic acid, and nitric oxide. In vitro effects of interleukin-1, growth factors, and lipocortin-1 have been reported on intracellular calcium homeostasis, which is critically important in neurodegeneration. Pharmacological modulation of the expression and/or actions of cytokines in the brain may be of considerable therapeutic benefit in the treatment of acute neurodegeneration.

Animals↗
PubMed1993

Chronic effects of interleukin-1 beta on fever, oxygen consumption and food intake in the rat.

Chronic subcutaneous infusion (from osmotic minipumps) of IL-1 beta (1 microgram/d) in male rats over seven days caused transient (1-3 d) increases in body temperature and reductions in body weight gain and food intake. By day 3, when colonic temperature was similar for vehicle and IL-1 infused groups, the acute responses (increases in temperature and VO2) to a maximal dose (1 microgram, sc) of IL-1 beta was almost identical in all animals. In a separate study intraperitoneal infusion of the same dose of IL-1 beta (1 microgram/d) increased the duration of changes in body temperature, weight and food intake, compared to subcutaneous infusion. In further groups of rats, pyrogenic responses to daily injections of IL-1 beta (1 microgram ip) were sustained for the entire 7 d period, but this treatment did not affect body weight. These data demonstrate that tolerance to infusion of IL-1 is not accompanied by reduced maximal responses to acute administration of IL-1, and indicate that more sustained effects of IL-1 are achieved by intraperitoneal rather than subcutaneous infusions, or by repetitive daily injections of the cytokine. These observations indicate that low levels of IL-1 release, maintained over periods of several days could be responsible for changes in body temperature and energy balance during chronic infections or inflammation.

Animals↗
PubMed1993

The neuropeptide CRF is involved in the modulation of the baroreflex during hindlimb ischaemia in the anaesthetized rat.

1. The effects of bilateral hindlimb ischaemia (BHLI), and of administration of the neuropeptide corticotrophin-releasing factor (CRF), were tested on cardiovascular variables in propofol-anaesthetized Sprague-Dawley rats. In addition, the effects of antagonizing endogenous CRF on the cardiovascular response to BHLI was investigated. 2. BHLI produced significant increases in mean arterial pressure and heart rate. Baroreflex sensitivity was reduced in all animals tested both 10 and 30 min after the induction of ischemia and this was accompanied by changes which are consistent with an underlying baroreflex resetting. 3. Intracerebroventricular (I.C.V.) administration of CRF (1.5 nmol) produced significant increases in heart rate but not mean arterial pressure. CRF also produced significant reductions in baroreflex sensitivity 10 and 30 min after administration, but there was no consistent evidence of baroreflex resetting. These effects of CRF could be prevented by pretreatment with the synthetic CRF antagonist, alpha-helical CRF(9-41) (alpha hCRF, 6.5 nmol, I.C.V.), which itself had no effect on these cardiovascular variables. 4. Pretreatment with alpha hCRF (6.5 nmol, I.C.V.) prevented the reduction in baroreflex sensitivity observed 10 min after the induction of BHLI, but had no consistent effect on the pressor or tachycardiac responses to BHLI and allowed a clear expression of BHLI-induced baroreflex resetting. alpha-Helical CRF(9-41) had no effect on the reduction in baroreflex sensitivity after 30 min of BHLI. 5. We conclude that corticotrophin-releasing factor mediates, at least in part, the early reduction in baroreflex sensitivity observed during hindlimb ischaemia in the rat.

Anesthesia↗
PubMed1993

Impaired febrile responses of aging mice are mediated by endogenous lipocortin-1 (annexin-1).

The mechanisms underlying age-related impairments in febrile responses were investigated in female C57Bl/lcrf-a(t) mice. Injection of norepinephrine, to assess total thermogenic capacity, significantly increased oxygen consumption (VO2) in all age groups, although the responses of the aged mice were significantly reduced. Injection of lipopolysaccharide or murine interleukin-1 beta (mIL-1 beta) significantly increased body temperature and VO2 in the young and adult mice but not in the aged mice. The impaired responses to mIL-1 beta in the aged mice were normalized by either injection of the glucocorticoid receptor antagonist RU-38486 or by injection of an antiserum to lipocortin-1 or its purified immunoglobulin G fraction. Injection of prostaglandin E2 significantly increased VO2 and body temperature in all age groups. Resting plasma corticosterone concentrations were significantly elevated in the aged and adult mice, whereas injection of mIL-1 beta significantly raised plasma corticosterone concentrations in all animals. These findings indicate that the impaired febrile response of aged female C57Bl/lcrf-a(t) mice may be caused by increased concentrations and/or sensitivity to endogenous glucocorticoids. The impaired febrile responses of aged mice appear to be mediated by endogenous lipocortin-1.

Aging↗
PubMed1993

Importance of brain IL-1 type II receptors in fever and thermogenesis in the rat.

Interleukin-1 (IL-1) acts centrally to induce fever and thermogenesis in rodents. The central actions of IL-1 alpha and IL-1 beta apparently involve different mechanisms, and the effects of IL-1 beta are not consistent with interaction with a type I (IL-1RI) 80-kDa receptor. In the present study the involvement of the type II IL-1 receptor (IL-1RII) was tested in the rat by examining the effects of central injection of a monoclonal antibody (ALVA-42), which blocks the IL-1RII. Pretreatment of rats with ALVA-42 (6 micrograms icv) inhibited the thermogenic and pyrogenic responses to intracerebroventricular injection of 5 ng (but not 50 ng) of IL-1 beta in conscious rats but did not significantly modify responses to IL-1 alpha. ALVA-42 also failed to modify the responses to peripherally administered IL-1 beta (1 microgram) but significantly attenuated the pyrogenic and thermogenic responses to peripheral (125 micrograms) or central (1 microgram) injection of endotoxin. These data indicate that IL-1RII mediates the central effects of a low dose of IL-1 beta, but not IL-1 alpha, on fever and thermogenesis in the rat. They also imply that responses to endotoxin are due, at least in part, to the activation of IL-1RII by IL-1 beta released within the brain and that effects of peripherally injected IL-1 beta involve different mechanisms, probably associated with IL-1RI.

Animals↗
PubMed1993

Fever and thermogenesis in response to bacterial endotoxin involve macrophage-dependent mechanisms in rats.

Increases in thermogenesis and body temperature (fever) frequently accompany infection or injury and are thought to be mediated by endogenous pyrogens (e.g. cytokines), which are released from activated immune cells such as macrophages. Therefore, we have investigated the effect of selective elimination of peripheral macrophages on the changes in oxygen consumption (VO2) and colonic temperature in response to bacterial lipopolysaccharide (LPS) in the rat. Peripheral macrophages were depleted by intravenous injection of liposomes containing the drug dichloromethylene diphosphonate (Cl2MDP). Resting oxygen consumption and colonic temperatures were not affected by macrophage elimination. In intact rats, peripheral injection of LPS (0.1-0.5 mg/kg) elicited an increase in colonic temperature and in oxygen consumption that declined at higher doses (2.5 mg/kg). The pyrogenic and thermogenic responses to LPS were significantly attenuated in rats in which peripheral macrophages were eliminated. Previously, we have reported that elimination of macrophages blunts the plasma interleukin-1 (IL-1) response to LPS. Here we show that elimination of macrophages does not affect the increase in plasma IL-6 concentrations in response to LPS. These data indicate that the pyrogenic and thermogenic responses to LPS are at least in part dependent on mechanisms involving peripheral macrophages, and that peripherally produced IL-1 rather than IL-6 may be an important mediator of the changes in oxygen consumption and colonic temperature in response to LPS.

Analysis of Variance↗
PubMed1993

Involvement of interleukin-1 and lipocortin-1 in ischaemic brain damage.

The cytokine interleukin-1 (IL-1) is synthesised within the brain and acts as a mediator of host defence responses to disease and injury. Several of these central actions of IL-1 are inhibited by an endogenous calcium and phospholipid binding protein, lipocortin-1. Synthesis of IL-1 and lipocortin-1 in the brain is markedly increased by neuronal damage, and inhibition of the actions of endogenous IL-1 by central injection of IL-1 receptor antagonist in the rat significantly inhibits ischaemic and excitotoxic brain damage. Lipocortin-1 appears to act as an endogenous neuroprotective agent that markedly attenuates ischaemic and excitotoxic damage. In contrast, inhibition of the actions of lipocortin-1 by injection of neutralising antiserum exacerbates both forms of neurodegeneration. The mechanisms underlying these effects of IL-1 and lipocortin-1 are largely unknown, but are probably independent of changes in body temperature. Actions of these molecules on corticotrophin releasing factor, arachidonic acid, excitatory amino acids, and nitric oxide, and the possible involvement of these factors in brain damage are discussed.

Animals↗