Fever and feeding in the rat: Actions of intrahypothalamic interleukin-6 compared to macrophage inflammatory protein-1β (MIP-1β)

The chemokines, macrophage inflammatory protein-1 (MIP-1) and its subunit MIP-1β, induce an intense fever in the rat when they are injected directly into the anterior hypothalamic, pre-optic area (AH/POA), a region containing thermosensitive neurons. The purpose of this study was to compare the central action on body temperature (T_b) of MIP-1β with that of interleukin-6 (IL-6), which also has been implicated in the cerebral mechanism underlying the pathogenesis of fever. Following the stereotaxic implantation in the AH/POA of guide cannulae for repeated micro-injections, radio transmitters which monitor T_b continuously were inserted intraperitoneally in each of 15 male Sprague-Dawley rats. Each micro-injection was made in a site in the AH/POA in a volume of 1.0 μl of pyrogen-free artificial CSF, recombinant murine MIP-1β, or recombinant human IL-6. MIP-1β in a dose of 25 pg evoked an intense fever characterized by a short latency, a mean maximum rise in T_b of 2.4 ± 0.21°C reached by 3.7 ± 0.42 hr, and a duration exceeding 6.5 hr. Injected into homologous sites in the AH/POA, IL-6 induced a dose dependent fever of similar latency and a mean maximal increase in T_b of 1.2 ± 0.25°C, 1.8 ± 0.15°C, and 2.1 ± 0.22°C and duration of 6.2 ± 1.28 hr, 6.7 ± 0.49 hr, and 6.8 ± 0.65 hr when given in doses of 25, 50, and 100 ng, respectively. These results show that MIP-1β and the highest dose of IL-6 induce a fever of comparable intensity, but MIP-1β exerts its action in a much lower concentration. Thus, the de novo synthesis and subsequent action of the MIP-1 family of cytokines on neurons of the AH/POA in response to a pyrogen challenge apparently play a functional role in the pathogenesis of fever. Further, the endogenous activity of IL-6 in the hypothalamus which is enhanced in response to a lipopolysaccharide also may reflect its essential part in the acute phase response to a bacterial challenge. Copyright © 1994 Wiley-Liss, Inc.     

Fever induced by macrophage inflammatory protein-1 (MIP-1) in rats: hypothalamic sites of action.

The purpose of this study was to clarify the central site of action as well as functional characteristics of the febrile response of the cytokine, macrophage inflammatory protein-1 (MIP-1). Guide cannulae for microinjection were implanted stereotaxically in the rat just above the pyrogen and thermosensitive area of the anterior hypothalamic, preoptic area (AH/POA). Following postoperative recovery, the body temperature of each rat (Tbo) was monitored during an experiment by a colonic thermistor probe at 0.5-1.0-h intervals. When MIP-1 was microinjected in a 0.5-microliter volume into the AH/POA in one of eight concentrations ranging from 0.0028 nanograms (ng) to 9.0 ng, an intense monophasic or biphasic fever was evoked. The MIP-1-induced increase in the Tbo of the rat was characterized by its short latency of 15 to 30 min and an inverse dose-response curve. Measures of mean latency and maximal rise in Tbo following MIP-1 confirmed the potency of this dose. Although the dose of 0.028 ng produced a fever of over 2.0 degrees C with a latency of only 15 min or less, the hyperthermic response became less intense as the dose of MIP-1 was increased. An anatomical mapping of sites of microinjection which reacted to MIP-1 in mediating fever revealed that the medial portion of the POA of the rat just rostral to the border of the AH was the region of maximum sensitivity to the cytokine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Macrophage inflammatory protein-1: unique action on the hypothalamus to evoke fever

Macrophage inflammatory protein (MIP-1) administered systemically causes a fever not blocked by a prostaglandin (PGE) synthesis inhibitor. The purpose of this study was to examine the central mechanism of pyrexic action of this cytokine in the unrestrained rat. After guide cannulae for microinjection were implanted stereotaxically just above the anterior hypothalamic preoptic area (AH/POA), the body temperature of each rat was monitored by a colonic thermistor probe. Saline control vehicle or MIP-1 was microinjected into the AH/POA in one of eight concentrations ranging from 0.0028-9.0 ng per 0.5 mu 1 volume. MIP-1 induced a biphasic or monophasic fever of short latency characterized by an inverse dose-response curve. The potency of MIP-1 was in the femtomolar (10(-15)) range with the lowest dose of 0.028 ng producing a fever of over 2.0 degrees C with a latency of 15 min or less. To determine whether a PGE mediates MIP-1 fever, indomethacin was administered either intraperitoneally in a dose of 5.0 mg/kg or directly into the MIP-1 injection site in a dose of 0.5 microgram/0.5 mu 1, both injected 15 min before MIP-1. Pretreatment of the injection site in the AH/POA with indomethacin failed to prevent the febrile response evoked by MIP-1 injected at the same locus. Further, the dose of systemic indomethacin, which blocks PGE-induced fever in the rat, attenuated only partially the MIP-1 fever. The results demonstrate that MIP-1 is the most potent endopyrogen discovered thus far, and that its action is directly in the region of the hypothalamus which contains both thermosensitive and pyrogen-sensitive neurons. The local action of MIP-1 on cells of the AH/POA in evoking fever is unaffected by the PGE inhibitor which indicates, therefore, that a cellular mechanism operates in the hypothalamus to evoke fever independently of the central synthesis of a PGE.     

Antibodies to macrophage inflammatory protein-1β in preoptic area of rats fail to suppress PGE2 hyperthermia

This study determined whether macrophage inflammatory protein-1β (MIP-1β) plays a role in the hyperthermia caused by prostaglandin E₂ (PGE₂) given intracerebroventricularly (i.c.v.) in the rat. In these experiments, anti-murine MIP-1β antibody (anti-MIP-1β) was micro-injected in the anterior hypothalamic, preoptic area (AH/POA) just before i.c.v. PGE₂. The results showed that anti-MIP-1β failed to alter the PGE₂ hyperthermia. However, immunocytochemical studies revealed MIP-1β immunoreactivity detectable in both the organum vasculosum laminae terminalis (OVLT) and AH/POA in the febrile rat. These data thus demonstrate that MIP-1β is sequestered in diencephalic structures underlying thermoregulation even though it is not involved in PGE₂ hyperthermia. This dissociation supports the viewpoint that at least two distinct systems exist in the brain which underlie a febrile response: MIP-1β underlies one component whereas PGE₂ comprises the other.     

Fever evoked by macrophage inflammatory protein-1 (MIP-1) injected into preoptic or ventral septal area of rats depends on intermediary protein synthesis

Macrophage inflammatory protein-1 (MIP-1), a novel cytokine composed of α/β subunits, is released from macrophages during infection, MIP-1 injected intravenously in the rabbit or into the anterior hypothalamic, preoptic area (AH/POA) of the rat causes an intense fever, which is not blocked by prostaglandin synthesis inhibitors, ibuprofin or indomethacin, respectively. The purpose of this study was to determine the role of de novo protein synthesis on the fever evoked by MIP-1 applied to thermosensitive cells of the AH/POA. Guide cannulae were implanted bilaterally above the AH/POA or ventral septal area (VSA) and medially above the third cerebral ventricle in each of 11 male Sprague-Dawley rats. Following postoperative recovery, body temperature (T_b) was monitored by a colonic thermistor probe. The bilateral microinjection of MIP-1 in a dose of 14 pg per 0.5 μ1 into the AH/POA caused a biphasic elevation in T_b to 0.9 ± 0.2 °C within 3.0 h, and persisted for over 6.0 h. An identical injection of MIP-1 into the VSA increased T_b biphasically to 0.1 ± 0.1 °C within 1.0 h and to 0.8 ± 0.3 °C within 3.0 h. The infusion into the third ventricle of 80 μg/10 μ1 of the inhibitor of protein synthesis, anisomycin, either 10 or 30 min before the microinjection of MIP-1 into the AH/POA, attenuated significantly the rise in T_b for 1.0 to 3.0 h or 2.5 to 3.0 h, respectively. These results coincide with the earlier finding that anisomycin inhibits both endotoxin- and IL-1β-induced fevers. Further, the synthesis of a new protein factor may be required functionally for the initiation and maintenance of a fever whose mechanism of induction apparently is metabolically independent of the cyclooxygenase pathway.     

Anorexia and adipsia: dissociation from fever after MIP-1 injection in ventromedial hypothalamus and preoptic area of rats.

Certain cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1) act centrally to affect eating behavior and thermoregulation and may be involved in the physiological mechanisms leading to anorexia, adipsia and loss in body weight. The newly discovered macrophage inflammatory protein-1 (MIP-1) infused into the anterior hypothalamic, preoptic area (AH/POA) evokes an intense hyperthermia. The present experiments were designed to determine whether MIP-1 affects the feeding mechanism in the ventromedial hypothalamus (VMH) independently of the thermoregulatory mechanism in the AH/POA. For the microinjection of MIP-1, guide cannulae were implanted stereotaxically in the rat just above the VMH or AH/POA. Following postoperative recovery, each unrestrained rat was adapted to procedures whereby body temperature and intakes of food and water available ad lib were monitored at predetermined intervals. When an efficacious dose of 5.6 picograms (pg) MIP-1 was microinjected in a volume of 0.5 microliters into the VMH, the intake of food in the rat was reduced significantly in the short term and throughout the following 22 h. Within intervals of 30 min and 4.0 h following MIP-1, the amount of food consumed was 4.0 and 10 g, respectively, below that eaten by control rats given the saline solvent vehicle injected at the same site in the VMH. Over the entire test period, the intake of water was similarly significantly below that of the control rats. Whereas MIP-1 injected into the AH/POA evoked fever accompanied by a transient decline in feeding, the body temperature of the rats was unaffected by the cytokine injected in the VMH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Corticosterone Controls lnterleukin-1β Expression and Sickness Behavior in the Rat

We studied the effect of corticosterone on interleukin (IL)-1β synthesis, body temperature, general activity, food consumption and fluid intake in rats treated with bacterial lipopolysaccharide (LPS). Radiotelemetry was used to assess body temperature and locomotor activity in combination with continuous automated recordings of feeding and drinking. This technique was developed as a novel method to identify and measure sickness behavior in rodents. The animals were (a) sham-operated, (b) adrenalectomized or (c) sham-operated and treated with corticosterone (10 mg/kg, subcutaneously). They were then intraperitoneally injected with vehicle or LPS at a dose (100 μg/kg) that in sham-operated rats induced fever and anorexia, reduced spontaneous activity and increased IL1-β mRNA in spleen and adrenals as determined by Northern blot analysis. Adrenalectomized rats produced larger amounts of splenic IL-1β mRNA, reduced their general activity much more and developed a mild adipsia as compared with adrenal-intact animals. Administration of corticosterone 1 h before LPS lowered the splenic IL-1β mRNA content compared to LPS-treated adrenal-intact rats that did not receive corticosterone and inhibited fever and anorexia, whereas the glucocorticoid did not attenuate the endotoxin-induced suppression of locomotor activity. Our data suggest that during inflammatory conditions body temperature, sickness behavior and the synthesis of IL-1β are controlled by corticosterone. Different components of sickness behavior seem to be independently regulated and are under differential control by glucocorticoids.     

Differential sensitivities of pyrogenic chemokine fevers to cyclooxygenase isozymes antibodies

It has been proposed that prostaglandin (PG)E(2) production via a process catalyzed by the inducible isoform of cyclooxygenase (COX)-2 and activation of specific PGE(2) receptor subtypes within the preoptic/anterior hypothalamus (AH/POA) is the last step and unique pathway in the induction of a fever. However, many data support the existence of a PG-independent pathway. That is, other more rapid mechanisms, which involve the constitutive COX-1 isozyme, may be more critical for a PG-dependent fever. Thus, we examined the role of both COX isoforms in the AH/POA in fevers induced by macrophage inflammatory protein (MIP)-1beta, a PG-independent pyrogen, and RANTES (regulated on activation, normal T-cells expressed and secreted), a PG-dependent pyrogen. In freely moving rats, two independent polyclonal antibodies were used which neutralize COX-1 and COX-2. The microinjection of either MIP-1beta or RANTES into the pyrogen-sensitive region of the AH/POA induced an intense fever of rapid onset. Peripheral pretreatment with an antipyretic dose of dexamethasone which prevents COX-2 expression, or the microinjections into the AH/POA of either anti-COX-1 or anti-COX-2, blocked the febrile response induced by RANTES but not that induced by MIP-1beta. These results provide strong evidence for the existence of rapid mechanisms in the AH/POA which involve both COX isozymes during the fever induced by RANTES, and further support the existence of an alternative PG-independent pathway in the febrile response.     

Cytokines and Thermoregulation: Interleukin-9 Injected in preoptic area fails to evoke fever in rats

A number of the members of the family of cytokines including IL-1, IL-2, IL-6, and IL-11 act directly in the brain to induce a febrile response in the rat and other species. The purpose of this study was to examine the effect of interleukin-9 (IL9) when this cytokine is applied directly to the thermosensitive and pyrogen reactive region of the anterior hypothalamic, preoptic area (AH/POA). In male Sprague-Dawley rats, guide cannulae for microinjection into the AH/POA were implanted stereotaxically, and radio transmitters for monitoring body temperature (T_b) were placed intraperitoneally. Following postoperative recovery, recombinant murine macrophage inflammatory protein (MIP)-1β was microinjected in the AH/POA of each rat in a dose of 28 pg/1μl to identify pyrogen reactive sites in the AH/POA. Then recombinant human IL-9 was suspended in pyrogen-free CSF vehicle and microinjected in the same sites in concentrations of 2.4, 24, and 240 U/μl. In contrast to the pyrexic action of MIP-1β, IL-9 failed to elicit a significant alteration in the T_b of the rats at any of the doses tested. IL-9 was also without effect on the intakes of either water or food. These results demonstrate that IL-9 applied to the region of the diencephalon in which other cytokines act to evoke fever may not play a direct role in the thermogenic component underlying the acute phase response. However, as demonstrated in several different cell systems, IL-9 may require a cofactor related to pyrogen for a febrile response to develop.     

Effect of Endotoxin and Interleukin-1β on Corticotropin-Releasing-Factor and Prostaglandin Release by Rat Brainstem Slices

This study investigated the effects of lipopolysaccharide (LPS) and interleukin-1 β (IL-1 β ) on corticotropin releasing factor (CRF) and prostaglandin E₂ (PGE₂) release by brainstem slices in vitro . First, we characterized our experimental model and demonstrated that high potassium stimulates CRF release from rat brainstem slices in a calcium dependent way. The direct stimulation of brainstem slices with IL-1 β (3–25  pM) did not modify basal or potassium-stimulated CRF release, although IL-1 β at the dose of 25  pM increased PGE₂ production. Peripheral injection (ip) of LPS (1–10  μg/kg) or IL-1 β (1–10  μg/kg) evoked a dose-related potentiation of the ex-vivo release of CRF and PGE₂ from brainstem slices. However, central (icv) administration of LPS (10–500  ng/rat) potentiated the release of CRF and PGE₂ only at the dose of 500  ng/rat, whereas IL-1 β (1–100  ng/rat) failed to modify significantly the ex vivo production of both CRF and PGE₂. The results of the present study provide evidence that peripheral, rather than central, endotoxin and IL-1 β administration induce the activation of brainstem CRF and PGE₂, supporting the hypothesis that peripheral cytokine signalling to the CNS is mediated by stimulation of peripheral afferents.     

Central thermosensitivity during fever produced by intra-PO/AH and intravenous injections of pyrogen

LIPTON, J. M. AND J. I. KENNEDY. Central thermosensitivity during fever produced by intra-PO/AH and intravenousinjections of pyrogen. BRAIN RES. BULL. 4(1) 23–34, 1979.—Squirrel monkeys with thermodes implanted in the preoptic/ anterior hypothalamic (PO/AH) region and the medulla oblongata were used to examine three questions about central thermoresponsiveness in fever: Does thermoresponsiveness of the PO/AH region and medulla change during fevers caused by injection of bacterial endotoxin IV or directly into the PO/AH region? Does thermosensitivity of these brain regions determine the upper fever limit? Is thermoresponsiveness of the PO/AH region affected by local injections of salicylate? Changes in rectal temperature and oxygen consumption in response to heating and cooling the PO/AH region were reduced during fever caused by intra-PO/AH injections of bacterial endotoxin compared with changes produced during afebrile periods. PO/AH thermosensitivity was also reduced during fever caused by IV administration of bacterial pyrogen. Prolonged cooling of the PO/AH region or the medulla oblongata during fever produced by peripheral and central pyrogen injections did not cause rectal temperature (T_re) to rise above 41.1°C although local heating reduced T_re or limited the fever maximum. From the latter result it is concluded that both pools of central thermoreceptors can limit maximal fever by reacting to local high temperature but that lowered temperature in neither region can raise T_re above a level determined by antagonistic input from thermoreceptors in other parts of the body. Injections of sodium salicylate into the PO/AH region had no effect on thermoresponsiveness of the region. This finding reinforces the idea that salicylates do not produce antipyresis by acting directly on thermosensitive cells of the central temperature control system.     

Fever produced by intrahypothalamic pyrogen: effect of protein synthesis inhibition by anisomycin

In the unrestrained cat, the inhibition of protein synthesis by anisomycin, given either subcutaneously (5.0--25.0 mg/kg) or directly into the anterior hypothalamic, preoptic area (1.0--25.0 micrograms) impaired the development of a bacterial fever. S. typhosa infused intravenously (1:10 dilution in 1 ml) or into AH/POA (1.0 microliter) evoked an intense fever which was either significantly delayed or prevented by anisomycin. Conversely, anisomycin failed to affect the typical hyperthermia evoked by 100 ng PGE2 or 1.0--7.0 micrograms 5-HT similarly infused into AH/POA. These data demonstrate that an intermediary humoral factor of unknown nature is required in the hyperthermic effector pathway underlying the febrile response.     

Peripheral Lipopolysaccharide Administration Induces Cytokine mRNA Expression in the Viscera and Brain of Fever-Refractory Mice Lacking Microsomal Prostaglandin E Synthase-1

We examined the expression of interleukin (IL)-1β, IL-6 and tumour necrosis factor (TNF) α in mice lacking microsomal prostaglandin E synthase-1 (mPGES-1), which neither produce prostaglandin E₂, nor mount a febrile response upon immune challenge. Intraperitoneal lipopolysaccharide (LPS) injection resulted in a strongly induced expression of all three cytokines in the brain and viscera, similar to wild-type animals. Several brain regions additionally showed modest induction of receptors for these cytokines in both genotypes. Telemetric recordings of body temperature showed that the mPGES-1 deficient mice remained afebrile upon LPS challenge, in contrast to the prominent fever displayed by the wild-type mice. These data demonstrate that LPS-induced cytokine expression occurs independently of prostaglandin E₂, and imply that endogenously expressed IL-1β, IL-6, and TNFα are not pyrogenic per se , supporting the role of prostaglandin E₂ as the final and obligatory mediator of LPS-induced fever.     

Apolipoproteins and β Amyloid Transport Pathway

Abstract: Cholesterol metabolism has been viewed as an important step in the development of Alzheimer's disease, since it was shown that the ɛ4 allele of apolipoprotein E ( APOE ) gene is a genetic risk and modifies age-at-onset of Alzheimer's disease. Although the knowledge of the effect of cholesterol in the neuronal cell has been recently accumulated, the link between systemic and brain cholesterol metabolism remains to be elucidated. Lipoproteins in cerebrospinal fluid (CSF) are fractionated only to high-density lipoprotein (HDL), and contain apolipoprotein (apo) A-I, E, A-II, and J. Whereas apoE is produced in the brain, apoA-I and apoA-II in cerebrospinal fluid, the major components of plasma HDL cholesterol, originate from plasma. Plasma HDL is thought to act in reverse cholesterol transport, and in vitro experiments indicated that these apolipoproteins and albumin show a high affinity binding to β amyloid. In patients with Alzheimer's disease, plasma apoA-I and apoA-II levels are significantly decreased, which is possibly related to the deposition of β amyloid in the brain, and to the β amyloid transport pathway.     

β-Carbolines: Endogenous Ligands for the Benzodiazepine Receptor

Abstract: The interaction of benzodiazepines (BDZ) and β -carbolines with metal cations was investigated. Δmong the numerous transition metal cations, only four, Co²⁺, Ni², Cu²⁺ and Zn²⁺, specifically affected the receptor binding of [³H]diazepam and [³H] β -carboline-3-carboxylic acid ethyl ester ( β -CCE). The effects of these cations on [³H]diazepam binding were exactly opposite to those on [³H] β -CCE binding. An intraperitoneal injection of β -carboline-3-carboxylic acid methyl ester ( β -CCM) produced spike discharges and β-CCM induced spike discharges were prevented by an intramuscular injection of BDZ. These findings suggest that β -carbolines could be related to the proposed endogenous ligand and that BDZ might be antagonistic rather than agonistic of the naturally occurring ligand.     

Distribution of β-amyloid protein in the brain following severe head injury

Deposits of β-amyloid protein (PAP) can be found in the brains of 30% of fatally head-injured patients: they have been found in children and after survival times of only 4 h. The principal aims of this study were to map the distribution of βAP in 14 patients aged 65 years or less in whom it was known that the protein had been deposited, and to correlate its distribution with the pathologies of traumatic brain injury. The results show that βAP is widely distributed, and that there is no correlation between its presence and cerebral contusions, intracranial haematoma, axonal injury, ischaemic brain damage, brain swelling or the pathology of raised intracranial pressure. These findings suggest that the deposition of βAP is a consequence of the acute phase response of nerve cells to stress in susceptible individuals. Further studies will be required to establish the possible relationship between the deposition of βAP following head injury and the molecular neuropathology of Alzheimer's disease.     

Neutralization of interleukin-1β modifies the inflammatory response and improves histological and cognitive outcome following traumatic brain injury in mice

Interleukin-1β (IL-1β) may play a central role in the inflammatory response following traumatic brain injury (TBI). We subjected 91 mice to controlled cortical impact (CCI) brain injury or sham injury. Beginning 5 min post-injury, the IL-1β neutralizing antibody IgG2a/k (1.5 μg/mL) or control antibody was infused at a rate of 0.25 μL/h into the contralateral ventricle for up to 14 days using osmotic minipumps. Neutrophil and T-cell infiltration and microglial activation was evaluated at days 1–7 post-injury. Cognition was assessed using Morris water maze, and motor function using rotarod and cylinder tests. Lesion volume and hemispheric tissue loss were evaluated at 18 days post-injury. Using this treatment strategy, cortical and hippocampal tissue levels of IgG2a/k reached 50 ng/mL, sufficient to effectively inhibit IL-1β in vitro . IL-1β neutralization attenuated the CCI-induced cortical and hippocampal microglial activation ( P  <   0.05 at post-injury days 3 and 7), and cortical infiltration of neutrophils ( P  <   0.05 at post-injury day 7). There was only a minimal cortical infiltration of activated T-cells, attenuated by IL-1β neutralization ( P  <   0.05 at post-injury day 7). CCI induced a significant deficit in neurological motor and cognitive function, and caused a loss of hemispheric tissue ( P  <   0.05). In brain-injured animals, IL-1β neutralizing treatment resulted in reduced lesion volume, hemispheric tissue loss and attenuated cognitive deficits ( P  <   0.05) without influencing neurological motor function. Our results indicate that IL-1β is a central component in the post-injury inflammatory response that, in view of the observed positive neuroprotective and cognitive effects, may be a suitable pharmacological target for the treatment of TBI.     

Importance of the Different |β Subunits in the Membrane Expression of the α1A and α2 Calcium Channel Subunits: Studies Using a Depolarization-sensitive α1A Antibody

The plasma membrane expression of the rat brain calcium channel subunits α1A, α2-Δ and the β subunits β1b, β2a, β3b and β4 was examined by transient expression in COS-7 cells. Neither α1A nor α2-Δ localized to the plasma membrane, either alone or when coexpressed. However, coexpression of α1A or α2-Δ/α1A with any of the p subunits caused α1A and α2 to be targetted to the plasma membrane. The α1A antibody is directed against an exofacial epitope at the mouth of the pore, which is not exposed unless cells are depolarized, both for native α1A channels in dorsal root ganglion neurons and for α1A expressed with a β subunit. This subsidiary result provides evidence that either channel opening or inactivation causes a conformational change at the mouth of the pore of α1A. Immunostaining for α1A was obtained in depolarized non-permeabilized cells, indicating correct orientation in the membrane only when it was coexpressed with a subunit. In contrast, β1b and β2a were associated with the plasma membrane when expressed alone. However, this is not a prerequisite to target α1A to the membrane since β3 and β4 alone showed no differential localization, but did direct the translocation of α1A to the plasma membrane, suggesting a chaperone role for the β subunits     

Interleukin-1β is increased in the cerebrospinal fluid of patients with small infarcts

Background and purpose:  Interleukin-1beta (IL-1β) and interleukin-6 (IL-6) are involved in inflammatory responses during large vessel occlusion in animal models. The aim of this study was to investigate the intrathecal levels of cytokines in patients with acute small infarcts.
Methods:  Forty patients with acute minor stroke and 32 non-stroke patients (including 29 age- and gender-matched subjects) who received operations with spinal anesthesia were studied prospectively and underwent measurements of cerebrospinal fluid (CSF) IL-1β and IL-6 levels.
Results:  After an age- and gender-matched analysis of 58 patients (29 pairs), the mean intrathecal levels of IL-1β were 0.80 pg/ml in patients with small infarcts and 0.59 pg/ml in non-stroke patients ( P  <   0.0001). In addition, the mean CSF levels of IL-6 were 21.54 pg/ml and 7.52 pg/ml in the stroke and control groups, respectively ( P  =   0.38). These results were consistent with the data without matching. The CSF levels of IL-1β in the 40 stroke patients were significantly higher than in the 32 non-stroke controls ( P  <   0.0001).
Conclusions:  The proinflammatory cytokine IL-1β, but not IL-6, remained elevated in the CSF of patients in the acute stage of small infarcts.     

A Comparative Study of α2- and β-Adrenoceptor Distribution in Pigeon and Chick Brain

The pharmacological properties and anatomical distribution of α₂, β₁ and β₂-adrenoceptors in pigeon and chick brains were studied by both homogenate binding and tissue section autoradiography. [³H]Bromoxidine (α₂-adrenoceptor-), [³H]CGP 12177 (β-adrenoceptor) and [¹²⁵1]cyanopindolol (β-adrenoceptor) were used as radioligands. In both species, [³H]bromoxidine binding to avian brain tissue showed a pharmacological profile similar to that previously reported for α₂-adrenoceptors in mammals. Regarding the anatomical distribution, the areas with the highest densities of α₂-adrenoceptors in the pigeon brain included the hyperstriatum, nuclei septalis, tectum opticum and some brainstem nuclei. Most β-adrenoceptors found in tissue membranes and sections from chick and pigeon brain were of the β₂ subtype, in contrast to what has been reported in the mammalian brain, where the β₁ subtype is predominant. A striking difference was found between the two species regarding the densities of these receptors: while pigeon brain was extremely rich in [¹²⁵1]cyanopindolol binding throughout the brain (mainly cerebellum) in the pigeon, the levels of labelling in the chick brain were much lower; the exception was the cerebellum, which displayed a higher density than other parts of the brain in both species. Overall, our results support the proposed anatomical equivalences between a number of structures in the avian and mammalian encephalon.