Brain Levels Of IL-1β Research Articles

The effects of methylated flavonoids on depression-like activity and pro-inflammatory cytokine thresholds in mice induced by repeated finasteride administration

The aim of the study was to investigate the influence of naringenin (NGN) and its methylated derivatives (50 or 100 mg kg−1) on finasteride-caused depression-like performance in mice to identify the effects on behavior and biomarkers of inflammation in the management of depression. Depression-like behavior was induced by repeated dose of finasteride (100 mg kg−1, subcutaneously) in mice. The effects of the naringenin (50 or 100 mg kg−1) or its methylated derivatives (Ngn-M; 50 or 100 mg kg−1 or Ngn-DM; 50 or 100 mg kg−1) and duloxetine (DXT, 10 mg kg−1) were evaluated for the immobility time in tail suspension and forced swimming tests following finasteride pre-treatment. The levels of brain pro-inflammatory cytokines such as IL-1β and TNF-α were also measured by Enzyme-Linked Immunosorbent Assay to further evaluate the impact of naringenin and its methylated derivatives on inflammation. Pre-treatment with finasteride substantially increased both the immobility time spent in tail suspension and forced swimming tests and brain levels of IL-1β and TNF–α in mice. Doluxetine (DLX) was given at a dose of 10 mg kg−1, and Naringenin or its methylated derivatives were given at doses of 50 and 100 mg kg−1 orally. It reduced immobility time in both tests, restored the preference to sucrose solution, and normalized cytokine levels (p < 0.01) in mice. Similar effects were observed with DTX (10 mg kg−1) as positive control. The increased brain levels of malondialdehyde (MDA) or nitrite were considerably (p < 0.05) decreased while substantially (p < 0.05) increased glutathione (GSH), superoxide dismutase (SOD), and catalase (CAT) levels after finasteride pre-treatment relative to vehicle-control by naringenin or its methylated derivatives (50 or 100 mg kg−1). These findings demonstrated the potential for methylated flavonoids as safe and effective anti-depressive agents.

Anti-edema effect of Aloe vera leaf extract following traumatic brain injury: Role of pro-inflammatory cytokines.

Objective:Based on anti-inflammatory effects of Aloe vera, the effect of aqueous extract of this plant on brain edema and changes in some pro-inflammatory cytokines was investigated after traumatic brain injury (TBI).Materials and Methods:In this study, adult male Wistar rats were divided into 5 groups: Sham, TBI, vehicle (Veh), and low dose (LA) and high dose (HA) Aloe vera. The vehicle and aqueous extract of Aloe vera were injected intraperitoneally 30 min after induction of diffuse TBI by Marmarou’s method. Brain edema (brain water content), and transforming growth factor beta (TGF-β), tumor necrosis factor alpha (TNFα), interleukin 6 (IL-6) and IL-1β levels in serum and brain were measured 24 hr after TBI induction.Results:Increased brain edema by TBI was reduced by both LA and HA (p<0.01 and p<0.05, respectively). IL-6 increased in the brain of TBI group compared to sham, and which was inhibited by both Aloe vera doses compared to Veh (p<0.001). The differences in the IL-6 serum levels among Veh, LA and HA groups were not significant. Increases in serum and brain IL-1β levels were reduced only in the HA group (p<0.001). Although only in the brain, TNF-α level increased after trauma, but both LA and HA inhibited it in a dose-dependent manner (p<0.01 and p<0.05, respectively) . The amount of TGF-β in the brain was reduced by both doses of the extract (p<0.001). Conclusion:These results indicated that Aloe vera has a neuroprotective effect induced by reducing brain edema. The probable mechanism particularly for HA is decreasing levels of pro-inflammatory cytokines such as TGF-β, TNF-α, IL-6 and IL-1β.

Eff ects of hyperbaric oxygen on NLRP3 infl ammasome activation in the brain aft er carbon monoxide poisoning

Neuroinflammation plays an important role in brain damage after acute carbon monoxide poisoning (ACOP). The nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing (NLRP) 3 inflammasome triggers the activation of inflammatory caspases and maturation of interleukin (IL)-1β and -18, and has been linked to various human autoinflammatory and autoimmune diseases. In this study we investigated the effects of hyperbaric oxygen (HBO2) on NLRP3 inflammasome activation after ACOP. Mice were randomly divided into four groups: sham group (exposure to normobaric air – i.e., 21% O2 at 1 atmosphere absolute); HBO2-only group; CO + normobaric air group; and CO + HBO2 group. Cognitive function was evaluated with the Morris water maze; myelin injury was assessed by Fluoro-Myelin GreenTM fluorescent myelin staining and myelin basic protein (MBP) immunostaining; and mRNA and protein levels of NLRP3 inflammasome complex proteins were measured by quantitative real-time PCR and Western blot, respectively. Additionally, serum and brain levels of IL-1β and -18 and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase were determined by enzyme-linked immunosorbent assay. It was found that HBO2 improved learning and memory, and alleviated myelin injury in mice subjected to acute CO exposure. Furthermore, HBO2 decreased NLRP3, absent in melanoma 2 (AIM2), caspase-1, and apoptosis-associated speck-like protein containing a C-terminal caspase recruitment domain mRNA and protein levels, and reduced brain and serum concentrations of IL-1β and -18 and NADPH oxidase. These results indicate that HBO2 suppresses the inflammatory response after ACOP by blocking NLRP3 inflammasome activation, thereby alleviating cognitive deficits.

Repeated social defeat induces transient glial activation and brain hypometabolism: A positron emission tomography imaging study

Psychosocial stress is a risk factor for the development of depression. Recent evidence suggests that glial activation could contribute to the development of depressive-like behaviour. This study aimed to evaluate in vivo whether repeated social defeat (RSD) induces short- and long-term inflammatory and metabolic alterations in the brain through positron emission tomography (PET). Male Wistar rats (n = 40) were exposed to RSD by dominant Long-Evans rats on five consecutive days. Behavioural and biochemical alterations were assessed at baseline, day 5/6 and day 24/25 after the RSD protocol. Glial activation (11C-PK11195 PET) and changes in brain metabolism (18F-FDG PET) were evaluated on day 6, 11 and 25 (short-term), and at 3 and 6 months (long-term). Defeated rats showed transient depressive- and anxiety-like behaviour, increased corticosterone and brain IL-1β levels, as well as glial activation and brain hypometabolism in the first month after RSD. During the third- and six-month follow-up, no between-group differences in any investigated parameter were found. Therefore, non-invasive PET imaging demonstrated that RSD induces transient glial activation and reduces brain glucose metabolism in rats. These imaging findings were associated with stress-induced behavioural changes and support the hypothesis that neuroinflammation could be a contributing factor in the development of depression.

Brain Interleukin-1 Facilitates Learning of a Water Maze Spatial Memory Task in Young Mice

The proinflammatory cytokine interleukin-1 (IL-1) is produced by many types of cells, including immune cells in the periphery and glia and neurons in the brain. The type I IL-1 receptor (IL-1r1) is primarily responsible for transmitting the inflammatory effects of IL-1 and mediates several biological functions by binding to either IL-1α or IL-1β. IL-1β activation is associated with hippocampus-dependent memory tasks. Although IL-1β impairs spatial memory under certain pathophysiological conditions, IL-1β may be required for the normal physiological regulation of hippocampal plasticity and memory. In addition, brain IL-1β levels are thought to change in the hippocampus in an age-dependent manner. These findings suggest that IL-1β may have a beneficial, temporary effect on learning and memory in young mice, but the matter remains unclear. Therefore, we hypothesized that hippocampal IL-1β has a beneficial effect on spatial learning and memory in young mice via IL-1r1, which is diminished in adults. We investigated the performance of young (3-month-old) and adult (6-month-old) wild-type mice, IL-1β knockout mice (IL-1βko) and IL-1r1 knockout mice (IL-1r1ko) in learning a spatial memory task with a fixed platform in a water maze (WM) and measured the levels of IL-1β and IL-1α in the hippocampus and cortex of adult and young mice by using homogeneous time-resolved fluorescence (HTRF). Learning was significantly impaired in the training trials of the WM spatial memory task in young IL-1βko and IL-1r1ko mice but not in adult IL-1βko and IL-1r1ko mice. Moreover, young IL-1r1ko mice but not IL-1βko mice showed an impairment in long-term memory extinction, suggesting that IL-1α might facilitate memory extinction. In this study, the cytokine assay using HTRF did not indicate a higher expression of hippocampal IL-1 in young mice but cortical IL-1β and IL-1α were significantly increased in adult mice. We need to investigate the role of cortical IL-1 and the local IL-1 expression in the hippocampal neurons in the future.

Magnesium sulfate (MG) prevents maternal inflammation induced offspring cerebral injury evident on MRI but not via IL-1β

Objective: As maternal treatment with magnesium sulfate (MG) may protect the fetal brain, we sought to assess the inflammation associated neuroprotective potential of MG and its association to interleukin 1β (IL-1β). Methods: Pregnant Sprague–Dawley rats at 18-day gestation received i.p. lipopolysaccharide (LPS) or saline. Dams were randomized to treatment with s.c. saline (control), or MG prior to or following the i.p. injection, resulting in three groups. At the end of the treatment, fetal brain IL-1β was quantified for 18 pregnant rats (six of each group). Another 18 pregnant rats delivered spontaneously and pups were allowed to mature. At postnatal day 25, female offspring were examined by magnetic resonance imaging (MRI) and analyzed using voxel based analysis. Apparent diffusion coefficient (ADC) and T2 relaxation protocols were performed to assess white and gray matter injury. Results: Offspring of LPS-treated dams exhibited (1) significantly increased T2 levels, and (2) increased ADC levels in white and gray matter, consistent with diffuse cerebral injury. Offspring of MG-treated LPS dams demonstrated similar T2 and ADC levels as control dams. Fetal brain IL-1β was significantly increased following maternal LPS compared to control (0.125±0.01 vs 0.100±0.01u, p<0.05). No significant decrease in IL-1β level was observed in response to maternal MG. Conclusions: Maternal LPS-induced neonatal brain injury can be prevented by maternal MG. Maternal MG therapy may be effective in human deliveries associated with maternal/fetal inflammation. The absence of a decrease in fetus brain levels of IL-1β following MG treatment implies that the mechanism of MG is not through inhibition of IL-1β production. Significance statementIntrauterine fetal exposure to maternal inflammation and pro-inflammatory cytokines is associated with adverse offspring neurological outcomes. Although its precise mechanism is not elucidated, magnesium sulfate (MG) is commonly used as neuroprotection for white matter brain injuries in preterm fetuses. A proposed mechanism involves the ability of MG to reduce pro-inflammatory cytokine levels. In the current study, we used a rat model of LPS-induced maternal inflammation to investigate the short-term effect of MG on fetal brain IL-1β levels, and its long-term neuroprotective effect on the offspring brain by using MRI.We demonstrated that maternal administration of MG can prevent long-term neonatal brain injury but, since no decrease was observed in fetal brain IL-1β levels, the neuro-protective mechanism of MG is not mediated by inhibition of IL-1β production.

Neutralizing anti-interleukin-1β antibodies reduce ischemia-related interleukin-1β transport across the blood–brain barrier in fetal sheep

Hypoxic ischemic insults predispose to perinatal brain injury. Pro-inflammatory cytokines are important in the evolution of this injury. Interleukin-1β (IL-1β) is a key mediator of inflammatory responses and elevated IL-1β levels in brain correlate with adverse neurodevelopmental outcomes after brain injury. Impaired blood–brain barrier (BBB) function represents an important component of hypoxic-ischemic brain injury in the fetus. In addition, ischemia–reperfusion increases cytokine transport across the BBB of the ovine fetus. Reducing pro-inflammatory cytokine entry into brain could represent a novel approach to attenuate ischemia-related brain injury. We hypothesized that infusions of neutralizing IL-1β monoclonal antibody (mAb) reduce IL-1β transport across the BBB after ischemia in the fetus. Fetal sheep were studied 24-h after 30-min of carotid artery occlusion. Fetuses were treated with placebo- or anti-IL-1β mAb intravenously 15-min and 4-h after ischemia. Ovine IL-1β protein expressed from IL-1β pGEX-2T vectors in Escherichia coli (E. coli) BL-21 cells was produced, purified, and radiolabeled with 125I. BBB permeability was quantified using the blood-to-brain transfer constant (Ki) with 125I-radiolabeled-IL-1β. Increases in anti-IL-1β mAb were observed in the brain of the mAb-treated group (P<0.001). Blood-to-brain transport of 125I-IL-1β was lower (P<0.04) across brain regions in the anti-IL-1β mAb-treated than placebo-treated ischemic fetuses. Plasma 125I-IL-1β counts were higher (P<0.001) in the anti-IL-1β mAb- than placebo-treated ischemic fetuses. Systemic infusions of anti-IL-1β mAb reduce IL-1β transport across the BBB after ischemia in the ovine fetus. Our findings suggest that conditions associated with increases in systemic pro-inflammatory cytokines and neurodevelopmental impairment could benefit from an anti-cytokine therapeutic strategy.

Protocatechuic acid ameliorates neurocognitive functions impairment induced by chronic intermittent hypoxia.

Chronic intermittent hypoxia (CIH) is a serious consequence of obstructive sleep apnoea (OSA) and has deleterious effects on central neurons and neurocognitive functions. This study examined if protocatechuic acid (PCA) could improve learning and memory functions of rats exposed to CIH conditions and explore potential mechanisms. Neurocognitive functions were evaluated in male SD rats by step-through passive avoidance test and Morris water maze assay following exposure to CIH or room air conditions. Ultrastructure changes were investigated with transmission electron microscopy, and neuron apoptosis was confirmed by TUNEL assays. Ultrastructure changes were investigated with transmission electron microscope and neuron apoptosis was confirmed by TUNEL assays. The effects of PCA on oxidative stress, apoptosis, and brain IL-1β levels were investigated. Expression of Bcl-2, Bax, Cleaved Caspase-3, c-fos, SYN, BDNF and pro-BDNF were also studied along with JNK, P38 and ERK phosphorylation to elucidate the molecular mechanisms of PCA action. PCA was seen to enhance learning and memory ability, and alleviate oxidative stress, apoptosis and glial proliferation following CIH exposure in rats. In addition, PCA administration also decreased the level of IL-1β in brain and increased the expression of BDNF and SYN. We conclude that PCA administration will ameliorate CIH-induced cognitive dysfunctions.

Synapse-specific IL-1 receptor subunit reconfiguration augments vulnerability to IL-1β in the aged hippocampus

In the aged brain, synaptic plasticity and memory show increased vulnerability to impairment by the inflammatory cytokine interleukin 1β (IL-1β). In this study, we evaluated the possibility that synapses may directly undergo maladaptive changes with age that augment sensitivity to IL-1β impairment. In hippocampal neuronal cultures, IL-1β increased the expression of the IL-1 receptor type 1 and the accessory coreceptor AcP (proinflammatory), but not of the AcPb (prosurvival) subunit, a reconfiguration that potentiates the responsiveness of neurons to IL-1β. To evaluate whether synapses develop a similar heightened sensitivity to IL-1β with age, we used an assay to track long-term potentiation (LTP) in synaptosomes. We found that IL-1β impairs LTP directly at the synapse and that sensitivity to IL-1β is augmented in aged hippocampal synapses. The increased synaptic sensitivity to IL-1β was due to IL-1 receptor subunit reconfiguration, characterized by a shift in the AcP/AcPb ratio, paralleling our culture data. We suggest that the age-related increase in brain IL-1β levels drives a shift in IL-1 receptor configuration, thus heightening the sensitivity to IL-1β. Accordingly, selective blocking of AcP-dependent signaling with Toll-IL-1 receptor domain peptidomimetics prevented IL-1β-mediated LTP suppression and blocked the memory impairment induced in aged mice by peripheral immune challenge (bacterial lipopolysaccharide). Overall, this study demonstrates that increased AcP signaling, specifically at the synapse, underlies the augmented vulnerability to cognitive impairment by IL-1β that occurs with age.

Prion pathogenesis in the absence of NLRP3/ASC inflammasomes.

The accumulation of the scrapie prion protein PrPSc, a misfolded conformer of the cellular prion protein PrPC, is a crucial feature of prion diseases. In the central nervous system, this process is accompanied by conspicuous microglia activation. The NLRP3 inflammasome is a multi-molecular complex which can sense heterogeneous pathogen-associated molecular patterns and culminates in the activation of caspase 1 and release of IL 1β. The NLRP3 inflammasome was reported to be essential for IL 1β release after in vitro exposure to the amyloidogenic peptide PrP106-126 and to recombinant PrP fibrils. We therefore studied the role of the NLRP3 inflammasome in a mouse model of prion infection. Upon intracerebral inoculation with scrapie prions (strain RML), mice lacking NLRP3 (Nlrp3-/-) or the inflammasome adaptor protein ASC (Pycard-/-) succumbed to scrapie with attack rates and incubation times similar to wild-type mice, and developed the classic histologic and biochemical features of prion diseases. Genetic ablation of NLRP3 or ASC did not significantly impact on brain levels of IL 1β at the terminal stage of disease. Our results exclude a significant role for NLRP3 and ASC in prion pathogenesis and invalidate their claimed potential as therapeutic target against prion diseases.

Effects of the total flavonoid extract of Xiaobuxin-Tang on depression-like behavior induced by lipopolysaccharide and proinflammatory cytokine levels in mice

Ethnopharmacological relevanceXiaobuxin-Tang (XBXT), a traditional Chinese herbal decoction, has been used for the treatment of depressive disorders from ancient clinic. The aim of the study was to explore the involvement of inflammation or inflammatory markers in the antidepressant-like effects of XBXT-2. Materials and methodsDepression-like behavior was induced by lipopolysaccharide (LPS, 0.2mg/kg, i.p) in tail suspension test (TST) and forced swimming test (FST) in mice. The effects of the total flavonoids (XBXT-2) extracted from XBXT (25, 50, and 100mg/kg, p.o.) and duloxetine (DLX, 10mg/kg, p.o.) on the immobility time in TST and FST were determined 24h after LPS pretreatment. The locomotor activity was also determined to eliminate the false-positive activity. Additionally, in order to further evaluate the effect of XBXT-2 on inflammation, the levels of brain proinflammatory cytokines including IL-1β and TNF-α were assessed by ELISA. ResultsThe pretreatment with LPS significantly increased the immobility time in TST and FST in mice, as well as the brain levels of IL-1β and TNF-α. XBXT-2 (25, 50, and 100mg/kg, p.o.) administration decreased the duration of immobility in TST and FST, and normalized the cytokines levels. The positive control DLX (10mg/kg, p.o.) exerted similar effects. Meanwhile, neither LPS pretreatment nor drugs treatment had any effect on mouse locomotor activity. ConclusionsThese results suggest that inflammation and inflammatory cytokines may be involved in the antidepressant-like effects of XBXT-2.

Vulnerability Imposed by Diet and Brain Trauma for Anxiety-Like Phenotype: Implications for Post-Traumatic Stress Disorders

Mild traumatic brain injury (mTBI, cerebral concussion) is a risk factor for the development of psychiatric illness such as posttraumatic stress disorder (PTSD). We sought to evaluate how omega-3 fatty acids during brain maturation can influence challenges incurred during adulthood (transitioning to unhealthy diet and mTBI) and predispose the brain to a PTSD-like pathobiology. Rats exposed to diets enriched or deficient in omega-3 fatty acids (n-3) during their brain maturation period, were transitioned to a western diet (WD) when becoming adult and then subjected to mTBI. TBI resulted in an increase in anxiety-like behavior and its molecular counterpart NPY1R, a hallmark of PTSD, but these effects were more pronounced in the animals exposed to n-3 deficient diet and switched to WD. The n-3 deficiency followed by WD disrupted BDNF signaling and the activation of elements of BDNF signaling pathway (TrkB, CaMKII, Akt and CREB) in frontal cortex. TBI worsened these effects and more prominently in combination with the n-3 deficiency condition. Moreover, the n-3 deficiency primed the immune system to the challenges imposed by the WD and brain trauma as evidenced by results showing that the WD or mTBI affected brain IL1β levels and peripheral Th17 and Treg subsets only in animals previously conditioned to the n-3 deficient diet. These results provide novel evidence for the capacity of maladaptive dietary habits to lower the threshold for neurological disorders in response to challenges.

Abstract TP292: Thrombin-induced Cerebral Hemorrhage: Role Of Protease-activated Receptor-1

Background and Purpose: Thrombin causes blood-brain barrier disruption and this study examined whether thrombin can cause brain hemorrhage through protease-activated receptor-1 (PAR-1). Methods: Male wild type and PAR-1 knockout mice had an intracerebral injection of thrombin or saline. Mice then underwent serial T2 magnetic resonance imaging and were euthanized for brain hemoglobin, iron and interleukin-1β measurements. Results: Mortality after intracerebral thrombin injection was not significantly different in WT (11%) and PAR-1 KO mice (9%). Thrombin but not saline resulted in massive T2 lesions in WT mice. MRI studies showed that the T2 lesions induced by thrombin were smaller in PAR-1 KO mice compared to those in WT mice (p&lt;0.05). An examination of brain sections after thrombin injection showed areas of hemorrhage in the ipsilateral hemisphere. This hemorrhage was examined using Perls’ staining for iron and by measuring brain hemoglobin. Perls’ staining showed that thrombin caused significant brain hemorrhage in WT mice and that hemorrhage peaked at day-3. Perls’ positive cells were less in PAR-1 KO mice (p&lt;0.05). Brain hemoglobin content was measured at day-3 after thrombin injection to assess hemorrhage volume. Thrombin-induced marked hemoglobin accumulation in the ipsilateral hemisphere in WT-type mice and this was markedly reduced in PAR-1 KO mice (hemoglobin: 327±134 vs. 913±221 μg in the WT mice, p&lt;0.01). The role of PAR-1 in brain IL-1β levels after thrombin stimulation was also examined. The time course of brain IL-1β levels following thrombin injection in WT mice was examined. Brain IL-1β levels peaked at 12 hours and returned to low levels after 24 hours. We then measured brain IL-1β levels in WT and PAR-1 KO mice and found that thrombin-induced upregulation of brain IL-1β was basically absent in PAR-1 KO mice (p&lt;0.01). Conclusions: Thrombin increases interleukin-1β levels and induces intracerebral hemorrhage through PAR-1 activation.

Involvement of IL-1β in acute stress-induced worsening of cerebral ischaemia in rats

Stress is known to be one of the risk factors of stroke. Most of the knowledge on the effects of stress on cerebrovascular disease in humans is restricted to catecholamines and glucocorticoids effects on blood pressure and/or development of atherosclerosis. However, few experimental studies have examined the possible mechanisms by which stress may affect stroke outcome. We have used an acute stress protocol consisting of the exposure of male Fischer rats to an acute, single exposure immobilisation protocol (6 h) prior to permanent middle cerebral artery occlusion (MCAO), and we have found that stress worsens behavioural and neurological outcomes and increased infarct size after MCAO. The possible regulatory role of the TNFα and IL-1β was studied by looking at the release of these cytokines in brain. The results of the present study showed an increase in IL-1β release in cerebral cortex after exposure to acute stress. Brain levels of IL-1β are also higher in previously stressed MCAO rats than in MCAO animals without stress. Pharmacological blockade of IL-1β with an antibody anti-IL-1β led to a decrease in the infarct size as well as in neurological and behavioural deficits after MCAO. In summary, our results indicate that IL-1β, but not TNFα, accounts at least partly for the worsening of MCAO consequences in brain of rats exposed to acute stress.

651 POSTER A Phase 1 dose escalation study of ARQ 197, a selective inhibitor of the c-Met receptor in patients with metastatic solid tumors

Peripheral infections in mammals are characterised by local, systemic and CNS effects. The latter give rise to sickness behaviour. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) are thought to be important mediators of this neuro-immune signalling (Cartmell et al., 1999). There is anecdotal evidence suggesting that peripheral infections in patients with Alzheimer’s disease have more severe behavioural consequences than those in otherwise healthy elderly subjects, and it is well known that brain microglia are activated in the elderly and in Alzheimer’s disease (McGeer et al., 1987). Using ME7-induced murine prion disease as a model of chronic neurodegeneration that displays chronic microglial activation, and the intra-peritoneal injection of bacterial lipopolysaccharide to mimic a peripheral infection, we have shown that the temperature and activity responses of animals with pre-clinical prion disease were exaggerated compared with controls, and that this was associated with a significant increase in brain levels of IL-1β. We hypothesise that prior priming of microglia by the degenerative process, followed by further activation through signalling from the periphery, resulted in increased brain IL-1β synthesis and the consequent acute sickness behavioural responses.These findings demonstrate an interaction between peripheral infection and pre-existing CNS inflammation and suggest that further stimulation of an already primed microglial population by a peripheral infection may drive disease progression in chronic inflammatory conditions such as Alzheimer’s disease and prion disease.

Peripheral infection evokes exaggerated sickness behaviour in pre-clinical murine prion disease

Peripheral infections in mammals are characterised by local, systemic and CNS effects. The latter give rise to sickness behaviour. Pro-inflammatory cytokines such as interleukin-1β (IL-1β) are thought to be important mediators of this neuro-immune signalling ( Cartmell et al., 1999). There is anecdotal evidence suggesting that peripheral infections in patients with Alzheimer’s disease have more severe behavioural consequences than those in otherwise healthy elderly subjects, and it is well known that brain microglia are activated in the elderly and in Alzheimer’s disease ( McGeer et al., 1987). Using ME7-induced murine prion disease as a model of chronic neurodegeneration that displays chronic microglial activation, and the intra-peritoneal injection of bacterial lipopolysaccharide to mimic a peripheral infection, we have shown that the temperature and activity responses of animals with pre-clinical prion disease were exaggerated compared with controls, and that this was associated with a significant increase in brain levels of IL-1β. We hypothesise that prior priming of microglia by the degenerative process, followed by further activation through signalling from the periphery, resulted in increased brain IL-1β synthesis and the consequent acute sickness behavioural responses. These findings demonstrate an interaction between peripheral infection and pre-existing CNS inflammation and suggest that further stimulation of an already primed microglial population by a peripheral infection may drive disease progression in chronic inflammatory conditions such as Alzheimer’s disease and prion disease.

Effects of vagotomy on lipopolysaccharide-induced brain interleukin-1β protein in rats

The production of interleukin-1β (IL-1β) in brain is thought to be a critical step in the induction of central manifestations of the acute phase response, and the vagus nerve has been implicated in immune-to-brain communication. Thus, this study examined the effects of intraperitoneal (i.p.) injections of lipopolysaccharide (LPS) on brain IL-1β protein levels in control and subdiaphragmatically vagotomized rats. In the first experiment, vagotomized and sham-operated male Sprague–Dawley rats were injected i.p. with one of three doses (10, 50, 100 μg/kg) of LPS or vehicle (sterile, pyrogen-free saline) and sacrificed 2 h after the injection. In the second experiment, vagotomized and sham-operated rats were injected i.p. with 100 μg/kg LPS or vehicle and sacrificed 1 h after the injection. The i.p. injection of LPS dose-dependently increased IL-1β protein levels in the hypothalamus, hippocampus, dorsal vagal complex, cerebellum, posterior cortex, and pituitary 2 h after the injection. Brain and pituitary IL-1β levels were also significantly increased 1 h after the injection of 100 μg/kg LPS. There were no significant differences in brain IL-1β levels between sham-operated and vagotomized rats at either the 2 h or 1 h time points. The current data are consistent with previous studies showing increases in brain IL-1β after peripheral injections of LPS, and support the notion that brain IL-1β is a mediator in the illness-induction pathway. Furthermore, these data indicate that, at the doses and times tested, subdiaphragmatic vagal afferents are not crucial for LPS-induced brain IL-1β protein.