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Biomedical subjects

N J Rothwell

Publications and source records attributed to N J Rothwell.

At least 127 records · Page 7Linked to original sources
PubMed1991

Functions and mechanisms of interleukin 1 in the brain.

Interleukin 1 (IL-1), a cytokine with diverse actions, has been proposed as a mediator of both beneficial and detrimental responses to inflammation and injury. Many of the actions of IL-1, such as those on behaviour, neuroendocrine function, sleep, fever and metabolism, are mediated by the CNS, as described here by Nancy Rothwell. IL-1 can be synthesized and act locally within the brain to influence neuronal and glial function, and has been strongly implicated in normal brain development and responses to brain injury. A number of distinct sites and mechanisms of action have been proposed to explain these diverse effects of IL-1 in the brain, probably involving multiple receptor subtypes and complex interactions with neurotransmitters and neuropeptides.

Animals↗
PubMed1991

Interleukin-6 is a centrally acting endogenous pyrogen in the rat.

Intracerebroventricular (i.c.v.) injection of human recombinant interleukin-6 (IL-6; 20-100 ng) caused significant increases in colonic temperature and resting oxygen consumption (VO2) in conscious rats. These effects were prevented by pretreatment with a cyclooxygenase inhibitor (flurbiprofen, 1 mg/kg, i.p.) or a corticotrophin-releasing factor antagonist (alpha-helical CRF9-41, 25 micrograms, i.c.v.). Higher doses of IL-6 (i.c.v.) caused only small changes in VO2 and temperature, and very high doses given intravenously (i.v.) (4 micrograms/kg) were required to stimulate these parameters. Central injection of anti-rat IL-6 antibody inhibited the effects of interleukin-1 beta (i.c.v.) or endotoxin injection (i.p.) on colonic temperature and VO2 in conscious rats. These data indicate that IL-6 is an important endogenous pyrogen that acts within the central nervous system.

Animals↗
PubMed1991

Mechanisms of early and late hypermetabolism and fever after localized tissue injury in rats.

Inflammation and localized tissue injury were induced in rats by intramuscular injection of turpentine. This caused rapid and sustained (2-24 h) increases in colonic temperature (Tc; up by 2.5 degrees C) and oxygen consumption (VO2; up by 30%) as well as hypophagia (57%). The early responses (0-2 h) were attenuated by anesthesia, C-fiber deafferentation, peripheral but not central injection of a cyclooxygenase inhibitor, or central injection of a neutralizing antibody to corticotropin-releasing factor (CRF). In contrast, the later (18-20 h) changes in Tc and VO2 were unaffected by anesthesia, C-fiber deafferentation, or central injection of a CRF antibody but were inhibited by either peripheral or central administration of a cyclooxygenase inhibitor. beta-Adrenoceptor blockade reduced both phases of the response, and brown adipose tissue activity was significantly elevated from 4 to 24 h after turpentine injection. These data suggest that different mechanisms mediate the metabolic response to localized tissue injury, the early phase involving neural mechanisms characteristic of stress and inflammation, whereas the later phase appears to depend on humoral factors that are commonly associated with infection.

Adrenergic beta-Antagonists↗
PubMed1991

Dose-dependent effects of an anabolic steroid, nandrolone phenylpropionate (Durabolin), on body composition and muscle protein metabolism in female rats.

The effects of three doses (1, 4 and 10 mg/kg body weight) of an anabolic steroid, nandrolone phenylpropionate (NPP), on body weight and composition, and muscle protein metabolism were investigated in female rats. Daily injections of 1 mg/kg of NPP for 10 days caused a significant increase in weight gain which was associated with an increase in body protein (9%) without affecting body fat. At higher doses this effect on body weight was attenuated, resulting in no change in body weight at 10 mg/kg. However body protein content was still increased (9%) whereas body fat content was significantly reduced (32%). NPP did not affect metabolizable energy intake at any dose tested. Body energy gain and gross energetic efficiency were both significantly reduced in animals treated with a dose of 10 mg/kg. The mass and protein content of gastrocnemius muscle were significantly increased in animals injected with NPP at all doses. Muscle protein synthesis measured in vivo was also significantly stimulated at 1 and 4 mg/kg but was not affected at 10 mg/kg. These data confirm an anabolic action of NPP and suggest highly dose-dependent effects on other parameters such as body weight, fat deposition and muscle protein synthesis.

Anabolic Agents↗
PubMed1991

Brown adipose tissue activity and oxygen consumption after scald injury in the rat.

Scald injury (30% surface scald) in the rat caused rapid (1-3 h) and transient decreases in oxygen consumption (VO2 20%), colonic temperature (1.1 degree C), and brown adipose tissue (BAT) thermogenic activity (22%). Three days after injury, VO2 was slightly increased in injured rats, and sympathetically mediated heat production (assessed from the inhibitory effect of a beta-adrenergic antagonist on VO2) was significantly greater than than for controls. At this time, BAT activity (in vitro mitochondrial GDP binding) was 35% higher in injured than control rats. Food intake was inhibited for only 24 h in injured animals, but weight gain was suppressed for at least 3 days. The data indicate that sympathetic modification of BAT thermogenesis may contribute to the changes in metabolic rate and body weight gain after scald injury in the rat.

Adipose Tissue, Brown↗
PubMed1990

Effects of the beta 2-adrenoceptor agonist, clenbuterol, on muscle atrophy due to food deprivation in the rat.

The effects of a beta 2-adrenoceptor agonist, clenbuterol, on body weight and protein metabolism of gastrocnemius muscle, heart, and liver were studied in rats subjected to 50% food restriction or fasting. Food restriction by 50% for 7 days caused a complete cessation of growth and reductions in the mass, protein, and RNA content of muscle, heart, and liver. The ratio of RNA to protein content was also suppressed in muscle and heart, but not in liver. Fasting for 3 days caused loss of body weight (BW), reductions in the mass, protein, and RNA content, and the ratio of RNA to protein of gastrocnemius muscle, heart, and liver. Oral administration of clenbuterol (approximately 0.6 mg/kg BW/d) to food-restricted animals did not affect BW, but did increase in the mass, protein, and RNA content, and the ratio of RNA to protein of gastrocnemius muscle. The protein content of heart was also increased. Twice-daily injections of clenbuterol (2 mg/kg body weight/d) to fasting animals had no effect on BW or the mass or protein content of gastrocnemius muscle or liver, but both parameters were stimulated in heart. The results indicate that the anabolic action of clenbuterol are maintained when substrate availability is reduced by food restriction, but this effect is lost during severe protein and energy deficit (fasting).

Adrenergic beta-Agonists↗
PubMed1990

Central effects of CRF on metabolism and energy balance.

CRF is recognised for its actions on pituitary ACTH release, but also has direct effects within the brain which are important in mediating physiological responses to stress. Behavioral effects of CRF include increased locomotor activity and inhibition of food intake and its actions on metabolism are mediated mainly by activation of the sympathetic nervous system. CRF appears to be important in the regulation of energy balance and body weight, influencing both food intake and sympathetically-mediated thermogenesis. A defect in the synthesis or release of CRF has been implicated in the development of obesity in laboratory animals, since the condition is alleviated by adrenalectomy, hypophysectomy or exogenous CRF treatment. Recent data have revealed an additional role for CRF as a mediator of the neuroendocrine and metabolic responses to immune signals, particularly cytokines. The central actions of CRF are independent of the pituitary but may involve release of proopiomelanocortin products within the brain. CRF is thus emerging as an important integrator of the physiological responses to stress, infection and immunity, a finding which may have important implications for future therapies.

Animals↗
PubMed1990

Central activation of thermogenesis by prostaglandins: dependence on CRF.

Central (intracerebroventricular) injections of PGE2, PGF2 alpha caused dose dependent increases in oxygen consumption (VO2) and colonic temperature in conscious rats. The effects of combined injection of maximal doses of CRF and PGE2 were additive, whereas PGF2 alpha and CRF were not. A CRF receptor antagonist, (alpha helical CRF 9-41, 25 micrograms icv) markedly inhibited the effects of PGF2 alpha on VO2 and temperature, but did not affect the actions of PGE2. These data indicate that PGF2 alpha and PGE2 stimulate thermogenesis by two different mechanisms, the former depending on CRF release. PGF2 alpha may be involved in the thermogenic actions of interleukin-1 beta which is also a potent thermogenic agent acting via CRF.

Analysis of Variance↗
PubMed1990

Sympathetically mediated hypermetabolic response to cerebral ischemia in the rat.

Cerebral ischemia, induced in rats by occlusion of the middle cerebral artery resulted in infarcts affecting the basal ganglia and adjacent frontoparietal cortex. Resting oxygen consumption was similar for sham-operated and ischaemic rats immediately after surgery but was elevated in the latter group (peak value 18-21% above controls) 5-6 h post occlusion. By 24 h, these values had returned to control levels. The increase in VO2 was inhibited by injection of the beta-adrenergic antagonist propranolol but was unaffected by injection of the cyclooxygenase inhibitor ibuprofen. The thermogenic activity of brown adipose tissue was assessed from in vitro binding of guanosine diphosphate to mitochondria isolated from intact and surgically denervated lobes of sham-operated and ischemic rats, 6 h after surgery. Brown adipose tissue specific guanosine diphosphate (GDP) binding was elevated by 86% in intact tissue from ischemic compared with sham-operated rats but was identical in denervated tissue from the two groups. Brown adipose tissue activity correlated with resting oxygen consumption in the ischemic group (r = 0.85, p less than 0.01) but not in controls (r = -0.35, NS). Thus occlusion of the middle cerebral artery in the rat may provide a representative model for both stroke and head injury in man. It is associated with a transient increase in metabolic rate and by sympathetically mediated activation of brown adipose tissue in the rat.

Adipose Tissue, Brown↗
PubMed1990

Lipocortin 1 fragment modifies pyrogenic actions of cytokines in rats.

Lipocortins form a group of proteins that have been proposed as mediators of the anti-inflammatory actions of glucocorticoids. Intracerebroventricular injection of a recombinant fragment of lipocortin 1 (NH2-terminal 1-188) caused dose-dependent (0.4-1.2 micrograms) reductions in the acute increases in colonic temperature and oxygen consumption, which occurred in response to central injections of recombinant interleukin 1 beta and gamma-interferon in conscious rats. In contrast the lipocortin fragment did not affect the response to prostaglandin E2, and its activity was prevented by heat treatment or by pretreatment of animals with polyclonal antiserum raised to the fragment. Central injection of antiserum significantly enhanced the thermogenic responses to interleukin 1 beta in rats treated with dexamethasone without affecting the responses in normal animals. These results support a physiological role for lipocortin in the central effects of glucocorticoids.

Animals↗
PubMed1990

Anabolic beta-2-agonist clenbuterol fails to modify muscle atrophy due to femur fracture.

Unilateral femur fracture in rats resulted in a significant reduction in body weight gain and food intake. The former was reversed by addition of the beta 2-adrenoceptor agonist clenbuterol to the diet (4 mg/kg) but food intake was unaffected. Neither resting oxygen consumption (VO2) nor brown adipose tissue GDP binding (measured on day 4) was affected either by femur fracture or by administration of clenbuterol. Femur fracture caused reductions in the mass, protein, and RNA content of gastrocnemius muscle from the fractured leg but not from the intact leg. Clenbuterol did not modify the reduction in the mass or protein content of muscle from the fractured leg, but stimulated these parameters in the intact leg and in heart. The ratio of RNA to protein was enhanced by clenbuterol in gastrocnemius muscle from both legs and heart. These data confirm the anabolic effect of clenbuterol in intact limb muscle but suggest that this agent is unable to prevent muscle atrophy at the site of femur fracture in the rat.

Adipose Tissue, Brown↗
PubMed1990

Dopamine beta-hydroxylase inhibition reveals a selective influence of endotoxin on catecholamine content of rat tissues.

Endotoxin is known to affect sympathetic nervous system (SNS) activity. However, it is unknown whether selective activation occurs in different tissues. The present work assessed SNS activity in several tissues of endotoxin-treated rats by measuring the accumulation of dopamine following dopamine beta-hydroxylase inhibition with disulfiram. Twenty-four hours following endotoxin injection (1 mg/kg), body weight and food intake were significantly reduced. The weight of spleen and liver was significantly greater in endotoxin-injected rats compared to either control animals or rats pair-fed the same quantity of food ingested by the endotoxin-treated rats. Norepinephrine (NE) content of heart, liver, and brown adipose tissue (BAT) was significantly lower in endotoxin-injected animals, but it was unchanged in spleen and gastrocnemius muscle. Endotoxin caused a significant elevation in the dopamine content of heart, liver, BAT, and gastrocnemius muscle, whereas it had no effect on spleen. The results suggest that SNS activity is increased in heart, liver, BAT, and gastrocnemius muscle 26 h after endotoxin injection.

Adipose Tissue, Brown↗
PubMed1990

Adrenalectomy reverses the impaired pyrogenic responses to interleukin-beta in obese Zucker rats.

Interleukin-1 is an important endogenous pyrogen which stimulates thermogenesis in normal animals by a central action which is dependent on release of corticotrophin releasing factor (CRF). Central injection of murine recombinant interleukin-1 beta (IL-1 beta, 5 ng) in conscious lean (+/?) Zucker rats produced significant increases in resting oxygen consumption (VO2, 26 per cent), colonic temperature (1.3 degrees C) and thermogenic activity (mitochondrial GDP binding) of brown adipose tissue (BAT, 24 per cent). In contrast, genetically obese (fa/fa) Zucker rats showed nonsignificant changes in VO2 (4 per cent), temperature (0.5 degrees C) and BAT activity (0 per cent). Bilateral surgical adrenalectomy (ADX) dramatically enhanced the effects of IL-1 beta on VO2 (45 per cent) body temperature (1.8 degrees C) and BAT activity (44 per cent) in obese mutants, but only slightly increased responses in lean rats. These data suggest that impaired responses to IL-1 beta in obese mutants may be due to inhibitory actions of glucocorticoids on either prostaglandin synthesis or CRF release within the hypothalamus.

Adrenal Cortex Hormones↗
PubMed1989

Central activation of thermogenesis and fever by interleukin-1 beta and interleukin-1 alpha involves different mechanisms.

Interleukin-1 exists in two forms (alpha and beta) which are assumed to act on the same receptor. Both forms of the molecule stimulated fever and thermogenesis in the rat when injected into the brain, but interleukin-1 beta was more effective, and combined injection of alpha and beta elicited additive responses. The actions of interleukin-1 beta were inhibited by pretreatment of the animals with either a receptor antagonist or monoclonal antibody to corticotrophin releasing factor. The effects of interleukin-1 alpha were unaltered by these treatments. The results indicate that brain corticotrophin releasing factor mediates thermogenesis and fever induced by interleukin-1 beta but not by interleukin-1 alpha.

Animals↗