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Biomedical subjects

N J Rothwell

Publications and source records attributed to N J Rothwell.

At least 37 records · Page 2Linked to original sources
PubMed2000

Cortical death caused by striatal administration of AMPA and interleukin-1 is mediated by activation of cortical NMDA receptors.

Striatal coadministration of interleukin-1beta (IL-1beta) with alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) in rats results in widespread cortical cell death not caused by either treatment alone. This cortical damage was unaffected by cortical infusion of the AMPA-receptor antagonist NBQX. Cortical infusion of an NMDA-receptor antagonist D-AP5 significantly inhibited (57%; P < 0.05) cortical death, but had no effect on the local striatal death. Thus, cortical neuronal death induced by striatal S-AMPA and human recombinant interleukin-1beta (hrIL-1beta) is mediated by activation of NMDA receptors in the cortex. The authors propose that IL-1beta actions on AMPA-receptor mediated cell death may involve the activation of polysynaptic pathways from the striatum to the cortex.

2-Amino-5-phosphonovalerate↗
PubMed2000

Interleukin (IL)-6 release and fever induced by a pre-formed pyrogenic factor (PFPF) derived from LPS-stimulated macrophages.

A novel pre-formed pyrogenic factor (PFPF), released by LPS-stimulated macrophages, has been identified, that induces an indomethacin-resistant fever. Its activity has to date not been found to match that of any described cytokine. In this study we observed that PFPF induced the release of large amounts of IL-6 from rat peritoneal macrophages. A combination of anti-cytokine antibodies and heat treatment excluded IL-1, tumor necrosis factor (TNF)-alpha and lipopolysaccharide (LPS) as being responsible for this effect. PFPF also induced interleukin (IL)-1, IL-6 and TNF-alpha in a subcutaneous air pouch, as well as increasing plasma IL-6, and induced a fever of 0.58 +/- 0.07 degrees C (3 hours) that was not reduced by indomethacin (2 mg/kg, ip). Preparative isoelectric focusing (IEF) showed that the material responsible for inducing IL-6 release had a pI between 4.7 and 5.8 and corresponded to the IEF pool that induced fever when injected intracerebroventricularly.

Animals↗
PubMed1999

Tumor necrosis factor alpha is a critical component of interleukin 13-mediated protective T helper cell type 2 responses during helminth infection.

In vivo manipulation of cytokine and/or cytokine receptor expression has previously shown that resistance to infection with the caecum-dwelling helminth Trichuris muris is dependent on interleukin (IL)-4 and IL-13 while susceptibility is associated with a T helper cell type 1 (Th1) cytokine response. Using gene-targeted mice deficient in tumor necrosis factor (TNF) receptor signaling and anti-TNF-alpha monoclonal antibody treatment, we have extended these studies to reveal a critical role for TNF-alpha in regulation of Th2 cytokine-mediated host protection. In vivo blockade of TNF-alpha in normally resistant mice, although not altering IL-4, IL-5, or IL-13 production in the draining lymph node, significantly delayed worm expulsion for the duration of treatment. IL-13-mediated worm expulsion in IL-4 knockout (KO) mice was also shown to be TNF-alpha dependent, and could be enhanced by administration of recombinant TNF-alpha. Furthermore, TNF receptor KO mice failed to expel T. muris, producing high levels of parasite-specific immunoglobulin G2a and the generation of a predominantly Th1 response, suggesting that the absence of TNF function from the onset of infection dramatically alters the phenotype of the response. These results provide the first demonstration of the role of TNF-alpha in regulating Th2 cytokine-mediated responses at mucosal sites, and have implications for the design of rational therapies against helminth infection and allergy.

Aging↗
PubMed1999

Brain sites of action of endogenous interleukin-1 in the febrile response to localized inflammation in the rat.

1. Interleukin (IL)-1 is a potent endogenous pyrogen which causes fever when injected into a number of brain sites. However, the brain sites at which endogenous IL-1 acts to influence body temperature remain equivocal. The aim of this study was to determine the effect of local administration of the interleukin-1 receptor antagonist (IL-1ra) into specific sites in the hypothalamus, and other brain regions known to contain receptors for IL-1, on the febrile response of rats to peripheral injection of lipopolysaccharide (LPS) into a subcutaneous air pouch (intrapouch, i.p.o.) that does not lead to LPS appearance in the circulation. 2. Injection of LPS (100 microgram kg-1, i.p.o.) induced a rise in body temperature which commenced 1.5 h after injection and was maximal at 3 h (38.9 +/- 0.2 C, compared with 37.0 +/- 0.1 C at 0 h, n = 6, P < 0.001). Intracerebroventricular (i.c.v.) IL-1ra (500 microgram in 5 microliter) significantly attenuated LPS fever (IL-1ra, 37.7 +/- 0.2 C; saline, 38.9 +/- 0.2 C; n = 6, P < 0.001). Unilateral microinjection of IL-1ra (50 microgram in 0.5 microliter at 0 + 1 h) into the anterior hypothalamus (AH), paraventricular hypothalamic nucleus (PVH), peri-subfornical organ, subfornical organ (SFO) or hippocampus (dentate gyrus and CA3 region) also significantly reduced the fever induced by LPS. 3. The same dose of IL-1ra had no effect on fever when administered into the ventromedial hypothalamus (VMH), organum vasculosum lamina terminalis (OVLT), CA1 field of the hippocampus, striatum or cortex. 4. These data indicate that the action of endogenous IL-1 in the brain during fever is site specific, acting at the AH, PVH, SFO and hippocampus, but not the VMH, OVLT and striatum or cortex.

Animals↗
PubMed1999

Leptin actions on food intake and body temperature are mediated by IL-1.

Leptin regulates energy balance through its actions in the brain on appetite and energy expenditure and also shares properties with cytokines such as IL-1. We report here that leptin, injected into rats intracerebroventricularly or peripherally, induces significant dose-dependent increases in core body temperature as well as suppression of appetite. Leptin failed to affect food intake or body temperature in obese (fa/fa) Zucker rats, which posses a defective leptin receptor. Furthermore, injection of leptin increased levels of the proinflammatory cytokine IL-1beta in the hypothalamus of normal Sprague-Dawley rats. Central injection of IL-1 receptor antagonist (IL-1ra) inhibited the suppression of food intake caused by central or peripheral injection of leptin (60 and 84%, respectively) and abolished the leptin-induced increase in body temperature in both cases. Mice lacking (gene knockout) the main IL-1 receptor (80 kDa, R1) responsible for IL-1 actions showed no reduction in food intake in response to leptin. These data indicate that leptin actions in the brain depend on IL-1, and we show further that the effect of leptin on fever, but not food intake, is abolished by a cyclooxygenase inhibitor. Thus, we propose that in addition to its role in body weight regulation, leptin may mediate neuroimmune responses via actions in the brain dependent on release of IL-1 and prostaglandins.

Animals↗
PubMed1999

Dissociation between the effects of interleukin-1 on excitotoxic brain damage and body temperature in the rat.

The cytokine interleukin-1beta (IL-1beta) mediates and exacerbates excitotoxic brain damage in the rat striatum. Co-injection of the selective glutamate receptor agonist alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) with human recombinant IL-1beta (hrIL-1beta) in the striatum of rats results in both local (striatal) damage and extensive, distant neuronal death in the cortex. The objective of the present study was to investigate the mechanisms underlying IL-1beta actions on excitotoxic damage, and to determine whether this effect of IL-1beta, a potent pyrogen, is due to modification of body temperature. Striatal infusion of S-AMPA (7.5 nmol) in anaesthetised rats produced localised striatal damage. Intrastriatal co-infusion of hrIL-1beta (10 ng) with S-AMPA caused similar striatal damage, but also produced extensive cortical damage, together with a modest increase in body temperature (0.9 degrees C) compared to rats infused with S-AMPA alone. Infusion of S-AMPA into the striatum, together with intracerebroventricular (i.c.v.) injection of hrIL-1beta, produced a similar rise in temperature to striatal co-infusion of S-AMPA and hrIL-1beta, but resulted in only local (striatal) neuronal damage, that was similar to that caused by striatal infusion of S-AMPA alone. These data suggest that the effects of IL-1beta on AMPA-receptor mediated neuronal damage in the striatum can be dissociated from its pyrogenic effects on body temperature.

Animals↗
PubMed1999

Excitotoxic brain damage in the rat induces interleukin-1beta protein in microglia and astrocytes: correlation with the progression of cell death.

Interleukin-1 beta (IL-1beta) has been proposed as a mediator of several forms of brain damage, including that induced by excitotoxins. In vitro studies suggest that glial cells are the effector cells of IL-1beta-mediated neurodegeneration. We have investigated the expression of IL-1beta protein by glial cells in vivo in response to NMDA receptor-mediated excitotoxicity in the rat parietal cortex and striatum. Expression of IL-1beta by glial cells was investigated using immunocytochemistry 30 min to 7 days after infusion of the NMDA agonist cis-2,4-methanoglutamate (MGlu; 10 nmol) into the cortex. Early expression (1-4 h) of IL-1beta by microglia was directly related to lesion development. Later expression by microglia (up to 24 h), and by astrocytes (2-7 days), was widespread compared to the area involved in excitotoxic cell death and co-localised with areas of reactive gliosis. Infusion of MGlu into the striatum induced a similar temporal pattern of IL-1beta expression by microglia and astrocytes. However, IL-1beta-expressing glial cells were localised strictly to the area of striatal cell death. Infusion of PBS or a subtoxic dose of MGlu into the cortex or striatum induced only limited neuronal death and negligible glial IL-1beta expression. These studies reveal that IL-1beta is expressed specifically by microglia during the early response to excitotoxicity in the adult rat cortex and striatum. However, the widespread and delayed IL-1beta expression by astrocytes suggests diverse roles for IL-1beta in response to excitotoxicity.

Animals↗
PubMed1999

Hypothalamic control of feeding.

Our understanding of the hypothalamic control of energy homeostasis has increased greatly since the discovery of leptin, the adipose cell derived protein. Recent studies have identified several new hypothalamic neuropeptides that affect food intake and energy balance. By studying these molecules and their neuronal systems, receptors and interactions, we are beginning to unravel the circuitry between peripheral adipogenic signals and hypothalamic effector pathways.

Animals↗
PubMed1999

The progression and topographic distribution of interleukin-1beta expression after permanent middle cerebral artery occlusion in the rat.

The cytokine interleukin-1 (IL-1) has been implicated in the exacerbation of ischemic damage in the brains of rodents. This study has ascertained the cellular localization and chronologic and topographic distribution of pro/mature interleukin-1beta (IL-1beta) protein 0.5, 1, 2, 6, 24, and 48 hours after ischemia by subjecting rats to permanent unilateral occlusion of the middle cerebral artery. Interleukin-1beta was localized immunocytochemically in vibratome sections of perfusion-fixed brains. The cells that expressed IL-1beta had the morphologic features of microglia and macrophages. Interleukin-1beta was first detected 1 hour after occlusion in ipsilateral meningeal macrophage-like cells. By 6 hours, pro/mature IL-1beta-immunoreactive (IL-1(beta)ir) putative microglia were present in the ischemic cerebral cortex, corpus callosum, caudoputamen, and surrounding tissue. By 24 and 48 hours after ischemia, the number and spread of IL-1(beta)ir cells increased greatly, including those resembling activated microglia and macrophages, as the core of the infarct became infiltrated. Interleukin-1(beta)ir cells also were present in apparently undamaged tissue, adjacent to the lesion ipsilaterally, and contralaterally in the cerebral cortex, dorsal corpus callosum, dorsal caudoputamen, and hippocampus. These results support the functional role of IL-1 in ischemic brain damage and reveal a distinct temporal and spatial expression of IL-1beta protein in cells believed to be microglia and macrophages.

Animals↗
PubMed1999

Central administration of rat IL-6 induces HPA activation and fever but not sickness behavior in rats.

Interleukin (IL)-6 has been proposed to mediate several sickness responses, including brain-mediated neuroendocrine, temperature, and behavioral changes. However, the exact mechanisms and sites of action of IL-6 are still poorly understood. In the present study, we describe the effects of central administration of species-homologous recombinant rat IL-6 (rrIL-6) on the induction of hypothalamic-pituitary-adrenal (HPA) activity, fever, social investigatory behavior, and immobility. After intracerebroventricular administration of rrIL-6 (50 or 100 ng/rat), rats demonstrated HPA and febrile responses. In contrast, rrIL-6 alone did not induce changes in social investigatory and locomotor behavior at doses of up to 400 ng/rat. Coadministration of rrIL-6 (100 ng/rat) and rrIL-1beta (40 ng/rat), which alone did not affect the behavioral responses, reduced social investigatory behavior and increased the duration of immobility. Compared with rhIL-6, intracerebroventricular administration of rrIL-6 (100 ng/rat) induced higher HPA responses and early-phase febrile responses. This is consistent with a higher potency of rrIL-6, compared with rhIL-6, in the murine B9 bioassay. We conclude that species-homologous rrIL-6 alone can act in the brain to induce HPA and febrile responses, whereas it only reduces social investigatory behavior and locomotor activity in the presence of IL-1beta.

Adrenocorticotropic Hormone↗
PubMed1998

An integrated analysis of the progression of cell responses induced by permanent focal middle cerebral artery occlusion in the rat.

Defining the chronology and severity of cell damage in an evolving lesion after ischemia is important for understanding the underlying mechanisms in the development of therapeutic intervention. In the present study, we used a combination of histological and immunocytochemical methods to evaluate cell responses from 30 min to 48 h after permanent occlusion of the middle cerebral artery (MCAO) in the rat. Specific immunocytochemical markers clearly revealed acute early responses in neurons (neurofilament protein 200), astrocytes (glial fibrillary acidic protein), and microglia/macrophages (OX-42 and ED-1) such as enlarged, convoluted neuronal processes, and disintegration of glia. Progressive topographic changes in the developing lesion, pinpointed by immunolabeling, indicated the severity and extension of the cell damage. Proliferation and hypertrophy of astrocytes and microglia around the infarct, and contralaterally, occurred 24-48 h after MCAO and coincided with mass necrosis and infiltration of neutrophils and macrophages into the core. These observations corroborate the suggestion that the inflammatory process is involved in the progression of the infarct.

Animals↗
PubMed1998

Interleukin-1 beta and interleukin-1 receptor antagonist do not affect glutamate release or calcium entry in rat striatal synaptosomes.

The cytokine interleukin-1 beta (IL-1 beta) has been implicated in various forms of neurodegeneration, and several lines of evidence indicate that it also modulates synaptic transmission in the central nervous system. Excessive release of the excitatory neurotransmitter L-glutamate results in cell death and probably mediates many neurodegenerative conditions. We set out to test the hypothesis that involvement of IL-1 beta in neurodegeneration results in some interaction with excitatory amino acid-mediated synaptic transmission in the rat striatum, either by modifying glutamate release or actions. Presynaptic effects of IL-1 beta and the IL-1 receptor antagonist (IL-1ra) on glutamate release and calcium entry were investigated in isolated nerve terminals (synaptosomes) prepared from the striatum. In order to evaluate the involvement of IL-1 in neuronal damage caused by glutamate receptor over-activation, the effect of IL-1ra was studied on N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor-mediated brain damage in the rat striatum and cortex in vivo. Neither rat recombinant IL-1 beta (rrIL-1 beta: 0.01-2 nM) or human recombinant IL-1ra (hrIL-1ra: 0.2 microM) had any significant effect on the KCl-evoked glutamate efflux or calcium entry in striatal synaptosomes, indicating that their actions are unlikely to be presynaptic. In contrast, intrastriatal infusion of hrIL-1ra markedly inhibited (by 43-46%, P < 0.05) neuronal damage caused by striatal NMDA or AMPA receptor activation in the rat in vivo, whereas no effect was seen on damage induced in the cortex. Thus, our data suggest that IL-1 beta and IL-1ra influence neuronal damage in the striatum by acting to modify events that occur after excitatory amino acid receptor activation.

Animals↗
PubMed1998

Cloning of rat brain interleukin-18 cDNA.

The interleukin-1 (IL-1) family comprises IL-1 alpha and IL-1 beta and an endogenous IL-1 receptor antagonist (IL-1ra). IL-1 has diverse actions in the brain and has been implicated in both acute and chronic neurodegeneration. However, neither IL-1 alpha nor IL-1 beta are neurotoxic per se in vivo, so other IL-1 related ligands may be important in neurodegeneration. The cytokine interleukin-18 (also called interferon gamma inducing factor, IGIF) was first isolated from the liver of mice during toxic shock. It was later proposed as a member of the IL-1 family, based on protein sequence homology with IL-1 beta and IL-1ra, and has tentatively been called IL-1 gamma. We cloned IL-18 from adult rat brain and demonstrated, by RT-PCR, that it is expressed constitutively in cerebellum, hippocampus, hypothalamus, cortex and striatum. Rat brain IL-18 shows close homology to mouse and human IL-18, and to the recently published sequence from the rat adrenal gland. Mouse pro-IL-18 and pro-IL-1 beta are processed by caspase-1. We demonstrate that caspase-1 also cleaves rat IL-18 in vitro and that the caspase inhibitor, zVAD-DCB inhibits this cleavage.

Adrenal Glands↗
PubMed1998

Effect of annexin-1 on experimental autoimmune encephalomyelitis (EAE) in the rat.

Annexin-1, a calcium-dependent phospholipid binding protein, has been shown to act as an endogenous central neuroprotectant, notably against cerebral ischaemic damage. In the present study we extend these findings to an animal model of multiple sclerosis, EAE, and report that endogenous annexin-1 is expressed in ED1+ macrophages and resident astrocytes localized within the lesions in the central nervous system (CNS). Intracerebroventricular (i.c.v.) administration of an NH2-terminal fragment spanning amino acids 1-188 of annexin-1 after the onset of the clinical symptoms significantly reduced both the neurological severity as well as weight loss of mild EAE. Immunoneutralization of endogenous brain annexin-1 failed to exacerbate the clinical features of EAE. Thus, although the role of endogenous annexin-1 in the pathogenesis of EAE remains to be determined, our findings suggest that annexin-1 may be of therapeutic benefit to the treatment of multiple sclerosis.

Animals↗