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Induction of interleukin-1β mRNA after focal cerebral ischaemia in the rat
Abstract
The expression of interleukin-1β (IL-1β) mRNA in the brain in response to cerebral ischaemia in rats was examined using in situ hybridization histochemistry. Focal cerebral ischaemia was induced in spontaneously hypertensive rats by permanent occlusion of the left middle cerebral artery (MCAO). Whereas no IL-1β mRNA could be detected in non-operated and sham-operated rats, middle cerebral artery occlusion induced the expression of IL-1β mRNA within 15 min in the ischaemic brain regions prone to become necrotic after 1–2 days. The message appeared as spot-like signals, reached a peak after 3 h and then declined to undetectable levels within 4 days. Additionally, a pronounced but brief induction of IL-1β mRNA could be detected 1 h after MCAO in the meninges near the watershed zone. The results demonstrate that the inflammatory cytokine IL-1β is induced in a time-dependent way after brain ischaemia.
... All three cytokines are able to modulate the size of the ischemic damage in experimental stroke (focal cerebral ischemia) in rodents, and their levels increase in cerebrospinal fluid (CSF) and blood after ischemic stroke in humans (Allan et al, 2005;Simi et al, 2007;McCoy and Tansey, 2008;Whiteley et al, 2009). There is evidence that TNF and IL-1 in the stroke-lesioned rodent brain are produced by resident microglia, intrathecal macrophages, and infiltrating, monocyte-derived macrophages (Buttini et al, 1994;Davies et al, 1999;Lambertsen et al, 2005;Clausen et al, 2008), whereas IL-6 in addition is produced by neurons (Suzuki et al, 1999(Suzuki et al, , 2009. Although TNF, IL-1, and IL-6 are also among the best investigated cytokines in CSF and blood in human stroke patients, we still know very little about their availability and mechanism of action in human brain in the early phase, up till 4 to 6 hours, after induction of experimental stroke, corresponding to the therapeutic window in human stroke (Ginsberg, 2008). ...
... The ischemia-induced increase in IL-1b mRNA appears slightly delayed compared with the increase in TNF mRNA after both tMCAO and pMCAO in the mouse (Figures 3 and 4), but continues to increase through 12 and 24 hours after tMCAO and distal pMCAO, to decline toward baseline levels at day 5 (Table 2B and Supplementary Table 1). Very interestingly, in situ hybridization studies performed on tissues from mice and rats after pMCAO (Buttini et al, 1994;Clausen et al, 2005) have detected scattered IL-1b mRNA + cells in the peri-infarct down to 1 to 2 hours after stroke onset. Of additional interest, the same studies reported on aggregates and perivascular infiltrates of intensely labeled IL-1b mRNA + cells in the peri-infarct from 12 hours and even more so at 24 hours after the stroke. ...
... A similar phenomenon was reported by Davies et al (1999), who, in addition to the IL-1b + macrophage-like cells in the meninges 1 to 2 hours after pMCAO in the rat, reported on numerous IL-1b + microglial-like cells in the ischemic territory from 6 to 24 and 48 hours (Table 2B). Although, tempting to speculate that the meningeal infiltration might be ascribed to the craniectomy, which was performed in all three studies, it was specifically reported that IL-1b mRNA + and IL-1b + cells were absent from the meninges in the sham-operated animals (Buttini et al, 1994;Davies et al, 1999;Clausen et al, 2005). ...
Inflammation is a hallmark of stroke pathology. The cytokines, tumor necrosis factor (TNF), interleukin (IL)-1, and IL-6, modulate tissue injury in experimental stroke and are therefore potential targets in future stroke therapy. The effect of these cytokines on infarct evolution depends on their availability in the ischemic penumbra in the early phase after stroke onset, corresponding to the therapeutic window (<4.5 hours), which is similar in human and experimental stroke. This review summarizes a large body of literature on the spatiotemporal and cellular production of TNF, IL-1, and IL-6, focusing on the early phase in experimental and human stroke. We also review studies of cytokines in blood and cerebrospinal fluid in stroke. Tumor necrosis factor and IL-1 are upregulated early in peri-infarct microglia. Newer literature suggests that IL-6 is produced by microglia, in addition to neurons. Tumor necrosis factor- and IL-1-producing macrophages infiltrate the infarct and peri-infarct with a delay. This information is discussed in the context of suggestions that neuronal sensitivity to ischemia may be modulated by cytokines. The fact that TNF and IL-1, and suppossedly also IL-6, are produced by microglia within the therapeutic window place these cells centrally in potential future stroke therapy.
... [21] TNF-α is a depression-related proinflammatory cytokine that increases in response to ischemic conditions. [22] IL-18 can mediate delayed neuro-inflammatory processes in experimental hypoxic-ischemic brain injury. [23] To sum up, proinflammatory cytokines increases in acute ischemic stroke (AIS); it is also increased in psychiatric patients with depression and without stroke compared to controls. ...
... It is known that in studies concerning acute ischemia, an increase in proinflammatory cytokines and NSE serum levels were linearly related with infarction size, edema formation, and severity of neurological deficits whereas decreased BDNF serum levels were linearly related to increased stroke risk. [21][22][23]30,34] On the other hand, studies conducted with individuals with depression revealed an increase in levels of proinflammatory cytokines and a decrease in BDNF levels. [17][18][19][20]27,28] Although some authors reported that CSF levels of NSE were increased in psychiatric patients with major depression, [33] when studies regarding TNF-α, primarily proinflammatory serum cytokines and BDNF, are compared, studies concerning the relationship between major depression and NSE were found to be insufficient. ...
Background
Increased interest in the relationship between affective disorder and long-term health consequences has generated recent examinations of depression and stroke. Observations suggest that depressive disorder is associated with abnormal physiological and immunological responses and a resultant increase in inflammatory markers. Given the high prevalence of stroke and associated costs for the community, it is important to understand the mechanisms that may impact on the outcome to achieve the best possible prognosis.
Aims
The view that inflammatory factors contribute to depression is predicated on findings that circulating cytokines and other inflammatory factors are increased in depressed patients. Therefore, it has been hypothesized that inflammation could be one of the mechanisms by which depression increases risk for ischemic stroke. Our aim was to determine whether there is any relationship between major depression and tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), IL-18, brain-derived neurotrophic factor (BDNF), and neuron-specific enolase (NSE) in patients with acute ischemic stroke (AIS).
Study Design
This was as a cross-sectional design.
Materials and Methods
This study has a cross-sectional design, and it was conducted in Necmettin Erbakan University, the Meram Faculty of Medicine in Konya, Turkey, between 2014 and 2015. Fifty-three AIS patients admitted to the hospital within the first 24 h after stroke onset were recruited. Major depression was ascertained by means of the structured clinical interview for the diagnostic and statistical manual of mental disorders, Fourth Edition/Clinical Version. The enzyme-linked immunosorbent assay was used to measure the serum levels of TNF-α, IL-1 β, IL-18, BDNF, and NSE at admission.
Results
A total of 53 patients with a mean age of 65.9 years were recruited. Of these patients, 17 (32.1%) had major depression. Depressive and nondepressive patients had similar demographical and clinical features. There was no significant statistical difference between depressive and nondepressive patients with AIS with respect to levels of TNF-α, IL-1 β, IL-18, BDNF, and NSE.
Conclusion
This study suggests that in patients who have experienced AIS, there is no significant relationship between major depression and basal proinflammatory cytokines (TNF-α, IL-1 β, IL-18), BDNF, and NSE.
... In spite of its low basal expression, the induction of IL-1b has been reported after several kinds of injury, being the most extensively studied cytokine in neurodegeneration. In the adult brain, IL-1b is upregulated in response to traumatic brain injury (Giulian & Lachman, 1985;Woodroofe et al., 1991;Holmin et al., 1997), spinal cord damage (Bartholdi & Schwab, 1997;Wang et al., 1997;Streit et al., 1998), transient and permanent ischemia (Buttini et al., 1994;Minami et al., 1992;Yabuuchi et al., 1994;Zhai et al., 1997;Zhang et al., 1998;Orzylowska et al., 1999), excitotoxicity and seizures (Vezzani et al., 1999;Yabuuchi et al., 1993) and lipopolysaccharide FIG. 6. Cortical concentration of IL-6 protein following saline or NMDA injection assessed by an ELISA assay. In NMDA-lesioned animals, there is a mild increase at 4 h postinjection, but IL-6 levels are only signi®cantly higher (*P < 0.001) than in saline controls at 7 days postinjection. ...
... (LPS) peripheral injection (Van Dam et al., 1995). In general, after an excitotoxic or ischemic damage to the adult brain, IL-1b mRNA expression peaks within 6 h after the insult and remains high until days 3±7, when maximal IL-1 protein levels are achieved (Minami et al., 1992;Buttini et al., 1994;Zhai et al., 1997;Pearson et al., 1999;Vezzani et al., 1999). In the postnatal brain we have found even shorter induction times of IL-1b protein, which peaks at 10 h postinjury (see Results), in agreement with previous studies reporting IL-1b expression after excitotoxic or hypoxia-ischemia insults to the developing brain (Hagan et al., 1996;Sza¯arski et al., 1995;Hagberg et al., 1996). ...
Cytokines are important intercellular messengers involved in neuron–glia interactions and in the microglial-astroglial crosstalk, modulating the glial response to brain injury and the lesion outcome. In this study, excitotoxic lesions were induced by the injection of N-methyl-d-aspartate in postnatal day 9 rats, and the cytokines interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumour necrosis factor alpha (TNF) and transforming growth factor beta 1 (TGF-β1) analysed by ELISA and/or immunohistochemistry. Moreover, cytokine-expressing glial cells were identified by means of double labelling with glial fibrillary acidic protein or tomato lectin binding. Our results show that both neurons and glia were capable of cytokine expression following different patterns in the excitotoxically damaged area vs. the nondegenerating surrounding grey matter (SGM). Excitotoxically damaged neurons showed upregulation of IL-6 and downregulation of TNF and TGF-β1 before they degenerated. Moreover, in the SGM, an increased expression of neuronal IL-6, TNF and TGF-β1 was observed. A subpopulation of microglial cells, located in the SGM and showing IL-1β and TNF expression, were the earliest glial cells producing cytokines, at 2–10 h postinjection. Later on, cytokine-positive glial cells were found within the excitotoxically damaged area and the adjacent white matter: some reactive astrocytes expressed TNF and IL-6, and microglia/macrophages showed mild IL-1β and TGF-β1. Finally, the expression of all cytokines was observed in the glial scar. As discussed, this pattern of cytokine production suggests their implication in the evolution of excitotoxic neuronal damage and the associated glial response.
... Members of the IL-1 family of proinflammatory cytokines have long been associated with the modulation of depression (11). However, more recently, animal studies have shown that IL-1b (12) increases within the first few hours of cerebral ischaemia, particularly focal ischaemia (22). IL-1b is observed in the hippocampus and striatum (23), regions previously identified as contributing to the aetiology of depressive disorder (24). ...
... Animal studies reveal that depression-related proinflammatory cytokine, TNF-a (13), is a polypeptide that increases in response to ischaemic conditions (22). Tumour necrosis factor-a mRNA is present within an hour of partial acute middle cerebral artery occlusion (MCAO) (28). ...
Ischaemic stroke often precedes the appearance of clinical depression. Poststroke depression in turn influences the prognostic outcome. In the interest of advancing our understanding of the biological mechanisms underlying the development of poststroke depression, this systematic review explores the immunological processes driving the development of inflammation-related cell death in mood-related brain regions. Particular attention has been paid to cytokine-driven intrinsic apoptosis factors, including intracellular calcium, glutamate excitotoxicity and free radicals that appear in the brain following ischaemic damage and whose presence significantly increases the likelihood of clinically defined depression.
... Interleukine 1β ;Buttini et al., 1994;Boutin et al., 2001;Lambertsen et al., 2012) et le TNFα (Tumor necrosis factor ;Yoshimoto et al., 1997;Offner et al., 2006;Liu et al., 1994;Mastorakos et McGavern ,2019) qui permettent entre autres le recrutement, l'activation et l'adhérence des leucocytes sur l'endothélium vasculaire, puis leur infiltration au sein du parenchyme cérébral(Kriz, 2006;Mastorakos et McGavern, 2019). ...
Les accidents vasculaires cérébraux (AVC) constituent la 2ème cause de mortalité dans le monde et la 1ère chez les femmes en France. Pour les AVC ischémiques (AVCi), seules des stratégies de recanalisation pharmacologique ou mécanique ont été approuvées mais aucune stratégie protectrice n'est aujourd'hui disponible. Bien que le rôle délétère du stress oxydant ait été clairement établi dans les lésions neuronales et vasculaires à la suite d'une ischémie cérébrale (IC) dans les études précliniques, aucune stratégie anti-oxydante n'a démontré d'efficacité clinique à ce jour. Or, les nanoparticules d'oxyde de cérium (NPC) possèdent de multiples capacités antioxydantes (enzymatique et non enzymatique). Afin d'améliorer la biocompatibilité des NPC, la société Specific Polymers® a développé des copolymères de polyéthylène glycol (PEG)/ polyméthacrylate de méthyle/ phosphonate pour recouvrir leur surface. De plus, ces polymères peuvent être fonctionnalisés avec un peptide ciblant l'endothélium ce qui permettrait d'y concentrer l'effet antioxydant des NPC, afin de réduire la survenue d'hémorragies cérébrales, complications graves chez les patients victimes d'AVCi. L'objectif de cette thèse est d'évaluer l'impact du recouvrement des NPC sur leur potentiel thérapeutique dans l'IC. Les études ont été menées in vitro pour établir la toxicité, l'effet antioxydant et l'internalisation cellulaire des NPC et in vivo, pour examiner leur biodistribution et leur toxicité, ainsi que leur potentiel thérapeutique dans un modèle d'IC. Les études in vitro ont été effectuées sur des cellules endothéliales cérébrales murines de la lignée b.End3. Nous avons démontré que les NPC n'induisaient ni mortalité, ni perturbation de l'activité métabolique jusqu'à 100µg/ml. A 1000µg/mL, les NPC nues augmentent la mortalité, contrairement aux NPC PEGylées. Nous avons modélisé l'excitotoxicité survenant lors d'une IC et qui contribue au stress oxydant, grâce à un traitement des cellules par le glutamate. L'augmentation de la production d'espèces réactives de l'oxygène par les cellules b.End3 et l'oxydation des acides nucléiques dans ces conditions ont été réduites par les NPC, démontrant que leur recouvrement n'interfère pas avec leurs propriétés anti-oxydantes. La fonctionnalisation des NPC a permis le greffage d'un fluorophore pour suivre leur internalisation par cytométrie en flux et microscopie confocale. Nous avons ainsi mis en évidence que les NPC étaient rapidement internalisées dans les cellules b.End3. Des études de microscopie électronique ont ensuite montré que les NPC sont principalement localisées dans des endosomes périnucléaires. Enfin, nous avons réalisé le greffage sur les NPC d'un peptide ciblant une protéine d'adhésion vasculaire surexprimée lors de l'IC. La suite de ces études consistera à vérifier l'interaction spécifique de ces NPC avec la molécule d'adhésion. Les études in vivo ont permis d'établir la biodistribution des NPC chez des souris Swiss : des NPC sont retrouvées durant les premières heures suivant leur injection, avant leur élimination par voie rénale. L'histopathologie n'a révélé aucune toxicité des NPC sur le foie, les reins, la rate, les poumons et le cerveau de ces souris et aucune modification de leur numération sanguine n'a été observée. Les NPC ont ensuite été administrées dans un modèle murin d'IC, mais n'ont pas réduit le volume de la lésion dans nos conditions. En conclusion, le recouvrement des NPC par des polymères innovants a réduit leur toxicité sans altérer leurs capacités antioxydantes et leur internalisation dans des cellules endothéliales cérébrales. L'absence d'accumulation à long terme et de toxicité in vivo sont encourageantes quant à leur biocompatibilité. Bien que les NPC n'aient pas montré d'effet protecteur in vivo, celles ciblant l'endothélium pourraient réduire les lésions vasculaires et le risque hémorragique consécutif à une IC.
... Minami et al. observed IL-lβ mRNA expression in the forebrain of the ischemic rat model as soon as 15 minutes which peaks in the cortex, hippocampus, striatum, and thalamus at 30 min and 240 min [41]. Buttini etal observed that the IL-lβ mRNA expression was at 15 minutes, peaked at 3 hours and vanished within 4 hours in spontaneous hypertensive rat's ischemic brain using in situ hybridization technology [42]. The results of our study about IL-1β were consistent with Chu.et al. who established that mRNA of IL-1β, in addition to more important pro -inflammatory cytokines , TNF̠ -α and IL-6 were highly increased in the rat hippocampus after transient global cerebral I/R model through activation of P2X7 receptors [43]. ...
Background: Restriction of cerebral blood flow can disturb cellular homeostasis due to insufficient oxygen and nutrient delivery. However, the re-establishment of cerebral blood flow can aggravate the impairment of ischemic brain tissue contributing to a series of oxidative, inflammatory events resulting in cerebral ischemia-reperfusion (CI/R) injury, which eventually results in neuronal death and neurological disability. Method: An experimental model of 30 Sprague-Dawley rats were randomly allocated to five groups, sham group, I/R group, I/R+(DMSO as a vehicle),I/R+ intraperitoneal (i.p) Empagliflozin 5mg/kg 1 hour before induction of BCCAO, and I/R+intraperitoneal Empagliflozin 10mg/kg 1hour before induction of BCCAO. The brain tissue levels of IL-1β, ICAM-1, and F2-isoprostane were measured in each group in our study. Results: The two doses of (5mg/kg and 10mg/kg) Empagliflozin were significantly reduced the brain tissue level of IL-1β, ICAM-1, and F2-isoprostane as compared to I/R and I/R+vehicle groups.Conclusions: From the results above we concluded that Empagliflozin has a neuroprotective effect seeing that it's anti-inflammatory and anti-oxidant activity. Keywords: Ischemia-reperfusion injury I/R, Bilateral common carotid artery occlusion BCCAO, Empagliflozin,interleukin-1β (IL-β), intercellular adhesion molecule-1 (ICAM-1), F2-isoprostane.
... Several studies found a direct correlation between the increase secretion of IL-1 in IRI brain cortex and the worsening of infarct severity while IL-1Ra inhibited neuronal damage and improved the outcome in vivo ( Allan et al., 2005;Pang et al., 2015). IL-1 β mRNA increase has been recorded within 15-30 min' post-stroke induction (Buttini et al., 1994) with IL-1 β protein increased within hours ( Davies et al., 1998). After 20 min of transient global cerebral stroke in rats, both IL-1 β mRNA and protein expression increase not only during early reperfusion (1 h), but also after a delayed period (6-24 h) ( Haqqani et al., 2005). ...
Acquired brain ischemia-and reperfusion-injury (IRI), including both Ischemic stroke (IS) and Traumatic Brain injury (TBI), is one of the most common causes of disability and death in adults and represents a major burden in both western and developing countries worldwide. China’s clinical neurological therapeutic experience in the use of traditional Chinese medicines (TCMs), including TCM-derived active compounds, Chinese herbs, TCM formulations and decoction, in brain IRI diseases indicated a trend of significant improvement in patients’ neurological deficits, calling for blind, placebo-controlled and randomized clinical trials with careful meta-analysis evaluation. There are many TCMs in use for brain IRI therapy in China with significant therapeutic effects in preclinical studies using different brain IRI-animal. The basic hypothesis in this field claims that in order to avoid the toxicity and side effects of the complex TCM formulas, individual isolated and identified compounds that exhibited neuroprotective properties could be used as lead compounds for the development of novel drugs. China’s efforts in promoting TCMs have contributed to an explosive growth of the preclinical research dedicated to the isolation and identification of TCM-derived neuroprotective lead compounds. Tanshinone, is a typical example of TCM-derived lead compounds conferring neuroprotection toward IRI in animals with brain middle cerebral artery occlusion (MCAO) or TBI models. Recent reports show the significance of the inflammatory response accompanying brain IRI. This response appears to contribute to both primary and secondary ischemic pathology, and therefore anti-inflammatory strategies have become popular by targeting pro-inflammatory and anti-inflammatory cytokines, other inflammatory mediators, reactive oxygen species, nitric oxide, and several transcriptional factors. Here, we review recent selected studies and discuss further considerations for critical reevaluation of the neuroprotection hypothesis of TCMs in IRI therapy. Moreover, we will emphasize several TCM’s mechanisms of action and attempt to address the most promising compounds and the obstacles to be overcome before they will enter the clinic for IRI therapy. We hope that this review will further help in investigations of neuroprotective effects of novel molecular entities isolated from Chinese herbal medicines and will stimulate performance of clinical trials of Chinese herbal medicine-derived drugs in IRI patients.
... 37,38 Mechanisms leading to increased IL-1β in cerebral ischemia are still under debate. 30 Previous observations supported a major role of endothelial cells, microglia, and monocytes/macrophages, 34,39 whereas a recent study narrows the contribution to microglia and monocytes/macrophages with a primary contribution of infiltrating macrophages. 40 In our study, the systemic approach to silence JunD may have mainly affected endothelial and circulating cells. ...
Background and Purpose—
Inflammation is a major pathogenic component of ischemia/reperfusion brain injury, and as such, interventions aimed at inhibiting inflammatory mediators promise to be effective strategies in stroke therapy. JunD—a member of the AP-1 (activated protein-1) family of transcription factors—was recently shown to regulate inflammation by targeting IL (interleukin)-1β synthesis and macrophage activation. The purpose of the present study was to assess the role of JunD in ischemia/reperfusion-induced brain injury.
Methods—
WT (wild type) mice randomly treated with either JunD or scramble (control) siRNA were subjected to 45 minutes of transient middle cerebral artery occlusion followed by 24 hours of reperfusion. Stroke size, neurological deficit, plasma/brain cytokines, and oxidative stress determined by 4-hydroxynonenal immunofluorescence staining were evaluated 24 hours after reperfusion. Additionally, the role of IL-1β was investigated by treating JunD siRNA mice with an anti–IL-1β monoclonal antibody on reperfusion. Finally, JunD expression was assessed in peripheral blood monocytes isolated from patients with acute ischemic stroke.
Results—
In vivo JunD knockdown resulted in increased stroke size, reduced neurological function, and increased systemic inflammation, as confirmed by higher neutrophil count and lymphopenia. Brain tissue IL-1β levels were augmented in JunD siRNA mice as compared with scramble siRNA, whereas no difference was detected in IL-6, TNF-α (tumor necrosis factor-α), and 4-hydroxynonenal levels. The deleterious effects of silencing of JunD were rescued by treating mice with an anti–IL-1β antibody. In addition, JunD expression was decreased in peripheral blood monocytes of patients with acute ischemic stroke at 6 and 24 hours after onset of stroke symptoms compared with sex- and age-matched healthy controls.
Conclusions—
JunD blunts ischemia/reperfusion-induced brain injury via suppression of IL-1β.
... Relatively few publications have reported changes in expression of the IL-1 family, such as IL-1␣ and IL-1RI, after stroke (Hill et al., 1999;Yu and Lau, 2000), yet it has been assumed that IL-1 is the primary form of IL-1 involved in ischemic brain damage (Buttini et al., 1994;Davies et al., 1999;Touzani et al., 1999), and in other local and systemic responses to peripheral injury (Luheshi et al., 1997;Eriksson et al., 1999). Indeed Horai (1998) studying the same mice as those used in the present study, report that IL-1 KO mice, but not those lacking IL-1␣, exhibit reduced responses to the effects of systemic injection of turpentine on fever. ...
... In the CNS, IL-1b is mainly secreted by microglia, the resident macrophages of the CNS (Yao et al., 1992). In rats, IL-1b and TNF-a expression was upregulated before neuronal death (Buttini et al., 1994;Liu et al., 1994;Wang et al., 1994). Additionally, JEV infection induced IL-1b and TNF-a production in rat microglia, which subsequently caused neuronal death (Chen et al., 2010). ...
High interleukin (IL)-1β gene expression was observed in dead giant grouper brains after nervous necrosis virus (NNV) infection. To investigate the neuronal death caused by NNV infection, primary tissue culture of giant grouper brains (pGB) was performed. In NNV-infected pGB cells, the viral capsid protein was detected in both neurons and microglia; furthermore, microglial proliferation and neuronal death were observed. The culture supernatant (CS) of NNV-infected pGB cells contained IL-1β and tumor necrosis factor-α, which were mainly released from the microglia. A new batch of pGB cells was treated with CS, resulting in neuronal death, which could be prevented by blocking the IL-1β in the CS by using anti-IL-1β polyclonal antibodies. Moreover, pGB cells treated with recombinant IL-1β showed microglial proliferation and neuronal death. Thus, NNV infection may activate microglial proliferation and stimulate microglial secretion of IL-1β, which is a critical cytokine responsible for neuronal death in NNV-infected grouper brains.
... One explanation is that any anti-inflammatory action of IL-10 and TGF-β in the affected brains may have been limited because of the dramatic intensity of other inflammatory responses (Barry, 2011). TNF-α and IL-1β expressions have been suggested to be the fast response cytokines prior to neuronal death in rodents (Buttini et al, 1994;Liu et al, 1994;Wang et al, 1994). Clinical studies have shown correlation between the concentrations of inflammatory cytokines and the severity of the disease (Griffin et al, 1994;Krupinski et al, 1996;Doty et al, 2015). ...
... An advantage of using cell-based therapies in stroke, next to or in combination with recanalization therapies [22], is that cells, which actively infiltrate the neural parenchyma at the site of injury [56,59], may be able to modulate the inflammatory response in tissues at risk of being recruited into the expanding infarct. The inflammatory response elicited by stroke is orchestrated as a continuum, driven by both activated microglia and infiltrating leukocytes, both known producers of interleukin-1β (IL-1β) [8,10,15,19]. IL-1Ra is a competitive inhibitor of IL-1(α/β) signaling [6,20,39,60,61] when mediated through the IL-1 receptor type 1 (IL-1R1) found in low numbers on nearly all cells including cortical neurons [13,36]. The IL-1R2 acts as a decoy receptor [21], and the IL-1R3, which is also expressed on cortical neurons, lacks an IL-1Ra binding site [54]. ...
Migraine is a complex brain disorder, and understanding the complexity of this prevalent disease
could improve quality of life for millions of people. Migraine co-morbidity involves depression,
anxiety, and obsessive-compulsive disorder (OCD). Familial Hemiplegic Migraine type 2
(FHM2) is a subtype of migraine with aura and co-morbidities like epilepsy/seizures, cognitive
impairments and psychiatric manifestations. FHM2 disease-mutations locate to the ATP1A2 gene
encoding the astrocyte-located α2-isoform of the sodium-potassium pump (α2Na+/K+-ATPase).
We show that knock-in mice heterozygous for the FHM2-associated G301R-mutation (α2
+/G301R)
phenocopy FHM2 by mimicking migraine, mood depression and OCD. In vitro studies showed
impaired glutamate uptake in hippocampal mixed astrocyte-neuron cultures from α2
G301R/G301R
E17 embryonic mice, and moreover, induction of cortical spreading depression (CSD) resulted in
reduced recovery in α2
+/G301R mice. NMDA-type glutamate receptor antagonists or progestin-only
treatment reverted specific α2
+/G301R behavioral phenotypes, and our findings support that
haploinsufficiency of the α2-isoform encoding gene impairs K+ clearance and glutamate uptake.
This study demonstrate that psychiatric manifestations are part of the FHM2-pathology and link
the α2Na+/K+-ATPase to the glutamate system, with the female sex hormone cycle exerting
aggravating effects hereon.
... An advantage of using cell-based therapies in stroke, next to or in combination with recanalization therapies [22], is that cells, which actively infiltrate the neural parenchyma at the site of injury [56,59], may be able to modulate the inflammatory response in tissues at risk of being recruited into the expanding infarct. The inflammatory response elicited by stroke is orchestrated as a continuum, driven by both activated microglia and infiltrating leukocytes, both known producers of interleukin-1β (IL-1β) [8,10,15,19]. IL-1Ra is a competitive inhibitor of IL-1(α/β) signaling [6,20,39,60,61] when mediated through the IL-1 receptor type 1 (IL-1R1) found in low numbers on nearly all cells including cortical neurons [13,36]. The IL-1R2 acts as a decoy receptor [21], and the IL-1R3, which is also expressed on cortical neurons, lacks an IL-1Ra binding site [54]. ...
Cell-based therapies are emerging as new promising treatments in stroke. However, their functional mechanism and therapeutic potential during early infarct maturation has so far received little attention. Here, we asked if cell-based delivery of the interleukin-1 receptor antagonist (IL-1Ra), a known neuroprotectant in stroke, can promote neuroprotection, by modulating the detrimental inflammatory response in the tissue at risk. We show by the use of IL-1Ra-overexpressing and IL-1Ra-deficient mice that IL-1Ra is neuroprotective in stroke. Characterization of the cellular and spatiotemporal production of IL-1Ra and IL-1α/β identifies microglia, not infiltrating leukocytes, as the major sources of IL-1Ra after experimental stroke, and shows IL-1Ra and IL-1β to be produced by segregated subsets of microglia with a small proportion of these cells co-expressing IL-1α. Reconstitution of whole body irradiated mice with IL-1Ra-producing bone marrow cells is associated with neuroprotection and recruitment of IL-1Ra-producing leukocytes after stroke. Neuroprotection is also achieved by therapeutic injection of IL-1Ra-producing bone marrow cells 30 min after stroke onset, additionally improving the functional outcome in two different stroke models. The IL-1Ra-producing bone marrow cells increase the number of IL-1Ra-producing microglia, reduce the availability of IL-1β, and modulate mitogen-activated protein kinase (MAPK) signaling in the ischemic cortex. The importance of these results is underlined by demonstration of IL-1Ra-producing cells in the human cortex early after ischemic stroke. Taken together, our results attribute distinct neuroprotective or neurotoxic functions to segregated subsets of microglia and suggest that treatment strategies increasing the production of IL-1Ra by infiltrating leukocytes or microglia may also be neuroprotective if applied early after stroke onset in patients.
... In experimental ischemia involving reperfusion, both microglia activation as well as invasion of blood-borne cells is typically accelerated, starting as early as 22 hours after ischemia (100,(115)(116)(117)(118). Moreover, the up-regulation of cytokines released by glia cells occurs quite early in commonly used stroke models (119)(120)(121)(122)(123)(124). Thus, in order to develop novel treatment strategies for stroke, an experimental stroke model should be chosen to closely resemble the dynamics of postischemic inflammation according to the human situation (5). ...
The main challenge of stroke research is to translate promising experimental findings from the bench to the bedside. Many suggestions have been made how to achieve this goal, identifying the need for appropriate experimental animal models as one key issue. We here discuss the macrosphere model of focal cerebral ischemia in the rat, which closely resembles the pathophysiology of human stroke both in its acute and chronic phase. Key pathophysiological processes such as brain edema, cortical spreading depolarizations (CSD), neuroinflammation, and stem cell-mediated regeneration are observed in this stroke model, following characteristic temporo-spatial patterns. Non-invasive in vivo imaging allows studying the macrosphere model from the very onset of ischemia up to late remodeling processes in an intraindividual and longitudinal fashion. Such a design of pre-clinical stroke studies provides the basis for a successful translation into the clinic.
... 68 IL-1b expression increases early (within 2 hours) in focal ischemia. [69][70][71][72] Exogenous application of recombinant human interleukin-1b into the ventricle immediately after reperfusion resulted in increased edema, infarct size, number of infiltrating neutrophils, and number of endothelial-bound neutrophils. 73 As an upstream inflammatory stimulant of MMP expression, the increase in edema associated with IL-1b may be MMP-mediated. ...
Objective:
Compare the prevalence of brain magnetic resonance imaging abnormalities between patients with or without CD; determine if inflammatory biomarkers are increased in CD; and determine the efficacy of aspirin in reducing the rate of microembolization in these patients.
Methods:
500 consecutive patients with heart failure will undergo a structured cognitive evaluation, biomarker collection and search for microembolic signals on transcranial Doppler. The first 90 patients are described, evaluated with cognitive tests and brain magnetic resonance imaging to measure N-acetyl aspartate (NAA), choline (Cho), myo-inositol (MI) and creatine (Cr).
Results:
Mean age was 55±11 years, 51% female, 38 (42%) with CD. Mean NAA/Cr ratio was lower in patients with CD as compared to other cardiomyopathies. Long-term memory and clock-drawing test were also significantly worse in CD patients. In the multivariable analysis correcting for ejection fraction, age, sex and educational level, reduced NAA/Cr (p=0.006) and cognitive dysfunction (long-term memory, p=0.023; clock-drawing test, p=0.015) remained associated with CD.
Conclusion:
In this preliminary sample, CD was associated with cognitive impairment and decreased NAA/Cr independently of cardiac function or educational level.
... During reperfusion, the arachidonic acid, which is accumulated during ischemia, is metabolized by cyclooxygenase to produce prostaglandins and thromboxanes [28]. There is also a release of other pro-inflammatory mediators such as tumor necrosis factor alpha (TNFα) [29] and interleukin-1 (IL-1) [30]. Both TNFα and IL-1 appear to exacerbate cerebral injury and prostaglandine and thromboxane release leads to cerebral edema and leakage in the blood brain barrier [31]. ...
... IL-1β, rather than IL-1α is considered to be more engaged in ischemia pathogenesis [142]. IL-1β mRNA elevations occur within minutes following brain ischemia [123,143], and the corresponding protein increases a few hours later starting from the infarct core and spreading to the peri-infarct area [45,144]. In global cerebral ischemia models, IL-1β mRNA and protein expression appear biphasic, with an initial peak occurring as early as 1 h into reperfusion (following 20 minutes of forebrain ischemia), with a second peak occurring 6-24 h later [145]. ...
Brain infarction causes tissue death by ischemia due to occlusion of the cerebral vessels and recent work has shown that post stroke inflammation contributes significantly to the development of the ischemic pathology. Because secondary damage by brain inflammation may have longer therapeutic time window compared to the rescue of primary damage following arterial occlusion, controlling inflammation would be an obvious therapeutic target. A substantial amount of experimentally progress in this area has been made in recent years. However, it is difficult to elucidate the precise mechanisms of the inflammatory responses following ischemic stroke because inflammation is a complex series of interactions between inflammatory cells and molecules, all of which could be either detrimental or beneficial. We review recent advances in neuroinflammation and the modulation of inflammatory signaling pathways in brain ischemia. Potential targets for treatment of ischemic stroke will also be covered. The roles of the immune system and brain damage versus repair will help to clarify how immune modulation may treat stroke.
... IL-1β represents a crucial mediator of neurodegeneration induced by traumatic brain injury 33) . Focal brain ischemia in MCAo-reperfusion rats results in a significant induction of IL-1β mRNA [34][35][36] . In the current study, IL-1β mRNA and protein expressions were upregulated at 24 h and at 48 h after 4-VO, respectively, whereas in the sesamin-treatment group, these expressions were inhibited. ...
Objectives : Sesamin, a major lignan in sesame seeds, has been reported to have neuroprotective effects against in vitro ischemia and in vivo MCAo-reperfusion cerebral ischemia model, however, there is no reports in an in vivo global cerebral ischemia model. The purpose of the study was to investigate the neuroprotective effect of sesamin in global cerebral ischemia induced by four-vessel occlusion (4-VO) in rats through inhibition of microglial activation in this model. Methods : The neuroprotective effects were investigated using a 10 min of 4-VO ischemia rat model by measuring intact pyramidal neurons in the CA1 region of the hippocampus using Nissle staining. The antiinflammatory or reducing neurotoxicity effect was investigated using immunohistochemisty, RT-PCR and western blot analysis of inflammatory or neurotoxic mediators. Results : Intraperitoneal injection of sesamin at doses of 0.3, 1.0, 3.0, and 10.0 mg/kg at 0 min and 90 min after ischemia conferred 26.6%, 30.1%, 42.5%, and 30.5% neuroprotection, respectively, compared to the vehicle-treated control group. A 3.0 mg/kg dose of sesamin inhibited microglia activation and consequently, cyclooxygenase-2, inducible nitric oxide, and interleukine-1{\beta} expressions at 48 h after reperfusion. Conclusions : Sesamin protects neuronal cell death through inhibition of microglial activation or the production of neurotoxic metabolites and proinflammatory mediators by microglia such as COX-2, iNOS and IL-1{\beta} in global cerebral ischemia.
... 18 High levels of TNF-α mRNA has been shown 1 hour after middle cerebral artery occlusion (MCAO), with a peak level at 12 hours, and persistently high levels for 5 days after experimental brain ischemia caused by arterial occlusion. 19,20 A good example of neuroinflammation-mediated neuronal damage has been reported in heat stroke. In a study by Lin et al heat stroke, a reproducible model of brain injury, has been caused in rats exposed to a temperature of 42°C. ...
The brain is very actively involved in immune-inflammatory processes, and the response to several trigger factors such as trauma, hemorrhage, or ischemia causes the release of active inflammatory substances such as cytokines, which are the basis of second-level damage. During brain ischemia and after brain trauma, the intrinsic inflammatory mechanisms of the brain, as well as those of the blood, are mediated by leukocytes that communicate with each other through cytokines. A neuroinflammatory cascade has been reported to be activated after a traumatic brain injury (TBI) and this cascade is due to the release of pro- and anti-inflammatory cytokines and chemokines. Microglia are the first sources of this inflammatory cascade in the brain setting. Also in an ischemic stroke setting, an important mediator of this inflammatory reaction is tumor necrosis factor (TNF)-α, which seems to be involved in every phase of stroke-related neuronal damage such as inflammatory and prothrombotic events. TNF-α has been shown to have an important role within the central nervous system; its properties include activation of microglia and astrocytes, influence on blood–brain barrier permeability, and influences on glutamatergic transmission and synaptic plasticity. TNF-α increases the amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor density on the cell surface and simultaneously decreases expression of γ-aminobutyric acid receptor cells, and these effects are related to a direct neurotoxic effect. Several endogenous mechanisms regulate TNF-α activity during inflammatory responses. Endogenous inhibitors of TNF include prostaglandins, cyclic adenosine monophosphate, and glucocorticoids. Etanercept, a biologic TNF antagonist, has a reported effect of decreasing microglia activation in experimental models, and it has been used therapeutically in animal models of ischemic and traumatic neuronal damage. In some studies using animal models, researchers have reported a limitation of TBI-induced cerebral ischemia due to etanercept action, amelioration of brain contusion signs, as well as motor and cognitive dysfunction. On this basis, it appears that etanercept may improve outcomes of TBI by penetrating into the cerebrospinal fluid in rats, although further studies in humans are needed to confirm these interesting and suggestive experimental findings.
... Wealth of literature from experimental studies demonstrates an important role of interleukins in ischemic brain injury [3, 11, 40]. It has been reported that within minutes of transient brain ischemia, IL-1β mRNA expression increases in cerebral cortex, striatum, thalamus, hippocampus and olfactory bulb of rats and this change persists up to 7 days [220][221][222][223]. Application of exogenous IL-1β into the brain has been reported to worsen ischemic brain injury in rats [224,225]. ...
Ischemic stroke is caused when blood flow to the brain is hampered, leading to instant deficiency of nutrients and oxygen required for normal brain functioning. Reperfusion can alleviate damage from stroke if performed immediately after the onset of ischemia however the efficacy of reperfusion is tampered by secondary injury mechanisms. This multifarious sequence of events leads to the commencement of deleterious cycles of inflammation, oxidant stress and apoptosis that finally culminate in delayed death of neuronal cells even when the brain is effectively reperfused. Wealth of data from clinical as well as experimental studies points to a prominent role of inflammation in secondary injury. In this review we will discuss, in detail, the cellular and molecular mediators of inflammation and their possible therapeutic targets in both experimental and clinical forms of stroke.
... The exact cellular source of IL-1β after HI is still controversial. The major sources are considered to be endothelial cells and microglia (Buttini, Sauter and Boddeke 1994). However, it is reported in some studies that neurons, astrocytes, and oligodendrocytes, also express IL-1β after induction of HI (Sairanen et al. 1997). ...
... IL-1 is a pivotal contributor to ischemic brain damage and is also involved in the pathophysiology of chronic conditions that are primary risk factors for cerebrovascular disease and represent crucial determinants of stroke clinical outcome, such as hypertension, diabetes and obesity Dinarello, 2011). Both protein and mRNA brain levels of IL-1b have been shown to increase as soon as few hours after transient MCAo in rats (Buttini et al., 1994;Clausen et al., 2005) and we have previously shown that the distribution pattern and cellular source of the cytokine are strongly affected by the intensity and duration of the insult (Amantea et al., 2010). Although previous findings have clearly demonstrated that late elevation of IL-1b originates from macrophages/microglia (Lambertsen et al., 2012), we have observed that the cytokine is expressed in neurons and astrocytes early after MCAo in rats (Amantea et al., 2010). ...
The pathophysiological processes implicated in ischemic brain damage are strongly affected by an inflammatory reaction characterised by activation of immune cells and release of soluble mediators, including cytokines and chemokines. The pro-inflammatory cytokine interleukin (IL)-1β has been implicated in ischemic brain injury, however, to date, the mechanisms involved in the maturation of this cytokine in the ischemic brain have not been completely elucidated. We have previously suggested that matrix metalloproteases (MMPs) may be implicated in cytokine production under pathological conditions. Here, we demonstrate that significant elevation of IL-1β occurs in the cortex as early as 1h after the beginning of reperfusion in rats subjected to 2h middle cerebral artery occlusion (MCAo). At this early stage, we observe increased expression of IL-1β in pericallosal astroglial cells and in cortical neurons and this latter signal colocalizes with elevated gelatinolytic activity. By gel zymography, we demonstrate that the increased gelatinolytic signal at 1h reperfusion is mainly ascribed to MMP2. Thus, MMP2 seems to contribute to early brain elevation of IL-β after transient ischemia and this mechanism may promote damage since pharmacological inhibition of gelatinases by the selective MMP2/MMP9 inhibitor V provides neuroprotection in rats subjected to transient MCAo.
... The type I receptor is found on a variety of cells and binds both forms of IL-1 with similar affinity. The type II receptor is found on the cell surface of neutrophils, B lymphocytes, and macrophages and binds IL-1β with a higher affinity (Buttini et al. 1994;Dinarello 1996;Huang et al. 2006;Mayadas et al. 1993;Polazzi and Contestabile 2002;Zhang et al. 1998). IL-1, particularly IL-1β, induces the expression of ICAM-1, an adhesion molecule on the surface endothelial cells (Kaplanski et al. 1994). ...
Stroke is cerebrovascular injury that has been reported to be the third leading cause of death and the first leading cause of disability in the world (W. H.O. 2007). Currently, there is only one FDA approved treatment for stroke which is recombinant tissue plasminogen activator. This treatment has a narrow therapeutic window of three hours after ischemic stroke and can adversely cause the production of oxygen free radicals and intracranial hemorrhage. These limitations result in only 2-3% of all stroke victims as being candidates for this therapy as many patients do not arrive at the hospital in time to receive treatment, are not properly diagnosed, or do not know that they have had a stroke within this three hour time period. The purpose of these experiments was to elucidate alternative targets of stroke for the benefit of developing new treatments that stimulate neuroprotective and anti-inflammatory effects at the site of injury.
It has been shown that transfusion of human umbilical cord blood cells up to 48 hours after stroke significantly reduces infarction and we have examined other targets that mimic these effects. We have shown that sigma receptor activation by DTG, a high affinity universal sigma agonist, reduces infarct volume when administered 24 hours after stroke. This suggests that modulation of neurodegenerative and inflammatory responses can extend the therapeutic window of treatment. For the first time, evidence is provided that shows that the spleen enhances the neurodegeneration caused by stroke as splenectomy prior to stroke profoundly decreased infarction volume. Finally, we studied signaling mechanisms of the splenic reaction to stroke and determined that this response is not directly dependent on neurotransmission via the splenic nerve.
Denervation of the spleen prior to stroke showed no changes in neurodegenerative load at the site of injury in rat brains when compared to those subjected to stroke only. Overall, these experiments provide evidence showing that targets mediating neuroprotective and anti-inflammatory effects can lead to novel therapeutic interventions of stroke.
... Male Sprague-Dawley rats (180-200 g) were injected intravenously with 5 mg/kg LPS (E. coli, 055 B5 Westphal, Difco) dissolved in sterile saline (Buttini et al., 1994). Control animals received injections of 0.9% saline alone. ...
Chemokine receptors play a crucial role in the recruitment of immune cells to sites of inflammation. Although chronic diseases of the brain are often accompanied by inflammatory events, there is presently no information about the occurrence and regulation of these receptors in the central nervous system (CNS), Moreover, one CC-chemokine receptor, CKR5, has recently been identified as coreceptor for HIV-1 entry into macrophages, HIV-1 target cells in brain are macrophage-related microglia, which suggests that they are infected by the same mechanism (He et al,,: Nature 385:645-649, 1997), Although rats are not susceptible to HIV-1 infection, they can be used to study chemokine receptor regulation in a variety of brain pathologies. After cloning CC-CKR5 and establishing reverse transcriptase polymerase chain reaction (RT-PCR) for its ligands macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and regulated on activation, normal T cell-expressed and secreted (RANTES), we studied expression of these four mRNAs in purified microglia and compared it with their expression in rat brain, Lipopolysaccharide (LPS)-treated microglia showed transiently increased mRNA levels of both CKR5 and its ligands, Similar data were obtained from brains of LPS-injected rats, In middle cerebral artery occluded (MCAO)-animals, RANTES mRNA was unaffected, whereas CKR5 mRNA showed a sustained rise until 96 hr after surgery, MIPs exogenously added to microglial cultures markedly reduced CKR5 mRNA expression, whereas RANTES did not, MIP mRNAs, in contrast to RANTES and CKR5 mRNAs, were undetectable in normal brain, RANTES appears to play a role distinct from MIPs in brain, In summary, upregulation of CC-chemokines and CKR5 in the CNS upon bacterial infection or in ischemia may impact on microglial activation stage and result in increased risk of HIV-1 infection, J, Neurosci, Res. 53:16-28, 1998 (C) 1998 Wiley Liss, Inc.
... injury, stroke) insults (see Rothwell & Luheshi, 1994;Rothwell et al. 1997). In rodents, IL_1â mRNA expression is increased within 15-30 min, and protein within 1 h of experimental cerebral ischaemia (stroke), brain injury or infusion of excitotoxins (Minami et al. 1992;Liu et al. 1993;Buttini et al. 1994;Yabuuchi et al. 1994), all of which lead to neuronal death. Several groups have also reported increased expression of IL_1â protein after experimental brain damage (e.g. ...
The first report that inhibition of IL-1 reduces brain damage in vivo (Relton & Rothwell, 1992) demonstrated that i.c.v. injection of IL-1ra at the time of induction of permanent focal cerebral ischaemia (middle cerebral artery occlusion (MCAo)) in the rat inhibited subsequent brain damage (infarct volume) by almost 70 % (Fig. 3). Numerous studies have subsequently verified and extended this observation (e.g. Betz et al. 1995, 1996; Garcia et al. 1995; Loddick & Rothwell, 1996; Relton et al. 1996; Rothwell et al. 1996a, 1997; Stroemer & Rothwell, 1997). It is now known that even systemic injection of IL-1ra, at considerably higher doses (50–100 mg kg−1), also inhibits ischaemic brain damage (Garcia et al. 1995; Relton et al. 1996), and indeed both IL-1 and IL-1ra are actively transported into the brain from the circulation (Gutierrez et al. 1994). IL-1ra is neuroprotective when administered 30–60 min after focal cerebral ischaemia and reduces not only infarct volume but also oedema, glial activation and neuronal loss, and largely reverses neurological impairment caused by MCAo (Garcia et al. 1995; Relton et al. 1996). In addition to these effects on MCAo in the adult rat or mouse, IL-1ra also markedly reduces brain damage caused by hypoxia/ischaemia in neonatal rats (Martin et al. 1995), global cerebral ischaemia in gerbils (Martin et al. 1996), lateral, cortical fluid percussion injury in the rat (Toulmond & Rothwell, 1995a) and heat stroke damage in rabbits (Lin et al. 1995), and reduces the clinical symptoms of experimental allergic encephalomyelitis (EAE, a rodent model of multiple sclerosis) (Martin & Near, 1995). In several of these paradigms, IL-1ra is effective when administered up to 4 h after the insult, and these actions of IL-1ra are not associated with any changes in body temperature or cardiovascular parameters in normal or brain-damaged rats.
... More recently, iNOS transcription has been reported to be induced by hypoxia through binding of hypoxia-inducible factor-i to the promoter region of the iNOS gene in mouse macrophage (Meliilo et al., 1995). We demonstrate here that hypoxia induces expression of iNOS mRNA and protein in astrocytes, the effects synergistically enhanced by IL-i/I, the production of which is up-regulated in ischemic brain (Buttini et al., 1994;Saito et al., i 996). However, astrocytes treated with or without IL-i/I under hypoxia did not release NO in the culture supernatant and N0 2 accumulation was observed after reoxygenation. ...
To clarify mechanisms of neuronal death in the postischemic brain, we examined whether astrocytes exposed to hypoxia/reoxygenation exert a neurotoxic effect, using a coculture system. Neurons cocultured with astrocytes subjected to hypoxia/reoxygenation underwent apoptotic cell death, the effect enhanced by a combination of interleukin-1β with hypoxia. The synergistic neurotoxic activity of hypoxia and interleukin-1β was dependent on de novo expression of inducible nitric oxide synthase (iNOS) and on nitric oxide (NO) production in astrocytes. Further analysis to determine the neurotoxic mechanism revealed decreased Bcl-2 and increased Bax expression together with caspase-3 activation in cortical neurons cocultured with NO-producing astrocytes. Inhibition of NO production in astrocytes by NG-monomethyl-l-arginine, an inhibitor of NOS, significantly inhibited neuronal death together with changes in Bcl-2 and Bax protein levels and in caspase-3-like activity. Moreover, treatment of neurons with a bax antisense oligonucleotide inhibited the caspase-3-like activation and neuronal death induced by an NO donor, sodium nitroprusside. These data suggest that NO produced by astrocytes after hypoxic insult induces apoptotic death of neurons through mechanisms involving the caspase-3 activation after down-regulation of BCl-2 and up-regulation of Bax protein levels.
... In this process, the IL-1 family plays a pivotal role. Elevated levels of IL-1 as well as an increased expression of IL-1 mRNA were detected following experimental brain injury in rodents, respectively96979899100 . While IL-1 does not cause brain damage itself, injection of IL-1 increased cell death following various brain damage models101102103 . ...
Numerous multiple trauma and surgical patients suffer from accidental hypothermia. While induced hypothermia is commonly used in elective cardiac surgery due to its protective effects, accidental hypothermia is associated with increased posttraumatic complications and even mortality in severely injured patients. This paper focuses on protective molecular mechanisms of hypothermia on apoptosis and the posttraumatic immune response. Although information regarding severe trauma is limited, there is evidence that induced hypothermia may have beneficial effects on the posttraumatic immune response as well as apoptosis in animal studies and certain clinical situations. However, more profound knowledge of mechanisms is necessary before randomized clinical trials in trauma patients can be initiated.
... The neuroprotective effects of IL-1Ra are reduced when administration is delayed beyond 3 h [4], suggesting that IL-1 expressed early after the insult is important. IL-1b mRNA is detected within 3-6 h after cerebral ischemia [5,6] , although there is very little direct evidence that IL-1b protein is produced, and almost no information is available about IL-1a. In this study we sought to determine the spatial distribution of IL-1a and IL-1b in the mouse brain early (4 h) and late (24 h) after stroke induced by MCAo. ...
Cerebral ischemia is a devastating condition in which the outcome is heavily influenced by inflammatory processes, which can augment primary injury caused by reduced blood supply. The cytokines interleukin-1α (IL-1α) and IL-1β are key contributors to ischemic brain injury. However, there is very little evidence that IL-1 expression occurs at the protein level early enough (within hours) to influence brain damage after stroke. In order to determine this we investigated the temporal and spatial profiles of IL-1α and IL-1β expression after cerebral ischemia.
We report here that in mice, as early as 4 h after reperfusion following ischemia induced by occlusion of the middle cerebral artery, IL-1α, but not IL-1β, is expressed by microglia-like cells in the ischemic hemisphere, which parallels an upregulation of IL-1α mRNA. 24 h after ischemia IL-1α expression is closely associated with areas of focal blood brain barrier breakdown and neuronal death, mostly near the penumbra surrounding the infarct. The sub-cellular distribution of IL-1α in injured areas is not uniform suggesting that it is regulated.
The early expression of IL-1α in areas of focal neuronal injury suggests that it is the major form of IL-1 contributing to inflammation early after cerebral ischemia. This adds to the growing body of evidence that IL-1α is a key mediator of the sterile inflammatory response.
... Furthermore, TNF stimulates the production of inducible nitric oxide syn thase and nitric oxide in astrocytes (Brodie et al., 1998) as well as prostaglandin E2 and collagenase production by human mononuclear cells (Dayer et al., 1985). Tumor necrosis factor has also been shown to increase the syn thesis of and synergize with other inflammatory cyto kines like interleukin-ll3 and interleukin-6, which are expressed in cerebral ischemia (Buttini et al., 1994;Wang et al., 1995;Saito et al., 1996). Among these, interleukin-113 is known to contribute to ischemia induced nerve cell degeneration (Loddick and Rothwell, 1996;Stroemer and Rothwell, 1998). ...
The proinflammatory cytokine tumor necrosis factor (TNF) is known to be expressed in brain ischemia; however, its cellular and temporal appearance is not fully settled. In this study, nonradioactive in situ hybridization for murine TNF mRNA was performed on brain sections from adult C57x129 mice at 6 hours, 12 hours, 24 hours, 2 days, 5 days, or 10 days (six to eight mice per group) after induction of permanent focal cerebral ischemia. Cortical infarct volumes were estimated, and TNF mRNA-expressing cells were counted within the infarct and infarct border using Cast-Grid analysis. At 12 hours, a peak of 19.2 +/- 5.1 TNF mRNA-expressing cells/mm2 was counted, contrasting two to three times lower values at 6 and 24 hours (6.4 +/- 4.6 and 9.2 +/- 3.4 cells/mm2, respectively) and <2 cells/mm2 at 48 hours and later stages. The TNF mRNA-expressing cells were distributed along the entire rostrocaudal axis of the cortical infarcts and occasionally within the caudate putamen. At all time points, TNF mRNA colocalized with Mac-1-positive microglia/macrophages but not with Ly-6G (Gr-1)-positive polymorphonuclear leukocytes. Similarly, combined in situ hybridization for TNF mRNA and immunohistochemistry for glial fibrillary acidic protein at 12 and 24 hours revealed no TNF mRNA-expressing astrocytes at these time points. Translation of TNF mRNA into bioactive protein was demonstrated in the neocortex of C57B1/6 mice subjected to permanent middle cerebral artery occlusion. In summary, this study points to a time-restricted microglial/macrophage production of TNF in focal cerebral ischemia in mice.
... 34 35 Cerebral IL-1 and TNF␣ are increased acutely after cerebral ischaemia in animal stroke models, particularly in the first hours after injury. 11 60 61 100 These findings suggest that IL-1 and TNF␣ are released very early after injury, and explain partly why these two cytokines are often not detected in serum in clinical studies of brain injury. ...
... Cerebral insults initiate changes in expression of many proteins, including interleukin-1 beta (IL-1b), tumor necrosis factor alpha (TNFa), and the 70-kDa heat shock protein (HSP70). All these proteins have been shown to be expressed early after cerebral I-R: IL-1b within 15–30 minutes [44], TNFa within 1 hour [45], and HSP70 also within 1 hour [46]. IL-1b and TNF-a regulate nuclear factor interleukin-6 (NF-IL6), which stimulates OPN gene transcription [47]. ...
Osteopontin (OPN) is a pleiotropic protein implicated in various inflammatory responses including ischemia-reperfusion (I-R) injury. Two distinct forms of the protein have been identified: an extensively studied secreted form (sOPN) and a less-well-known intracellular form (iOPN). Studies have shown that increased OPN expression parallels the time course of macrophage infiltration into injured tissue, a late event in the development of cerebral infarcts. sOPN has been suggested to promote remodeling of the extracellular matrix in the brain; the function of iOPN may be to facilitate certain signal transduction processes. Here, we studied OPN expression in adult male Sprague-Dawley rats subjected to global forebrain I-R injury. We found iOPN in the cytoplasm of both cortices and the hippocampus, but unexpectedly only the right cortex exhibited a marked increase in the iOPN level after 45 min of reperfusion. Acetaminophen, a drug recently shown to decrease apoptotic incidence, caspase-9 activation, and mitochondrial dysfunction during global I-R, significantly inhibited the increase in iOPN protein in the right cortex, suggesting a role for iOPN in the response to I-R injury in the right cortex.
... Moreover, side effects resulting from administration of nimodipine occasionally limit its use (Topcuoglu and Singhal, 2006). There is an increasing body of evidence to suggest that inflammation has an important function in the pathological events arising as a consequence of cerebral ischemia (Huang et al, 2006a) and that the proinflammatory cytokine interleukin-1 (IL-1) is particularly implicated as an important mediator (Boutin et al, 2001; Buttini et al, 1994; Hara et al, 1997; Yamasaki et al, 1995). The IL-1RA is the naturally occurring antagonist of IL-1 and is the most widely studied putative neuroprotective agent in acute cerebrovascular disease (Banwell et al, 2009). ...
The naturally occurring antagonist of interleukin-1, IL-1RA, is highly neuroprotective experimentally, shows few adverse effects, and inhibits the systemic acute phase response to stroke. A single regime pilot study showed slow penetration into cerebrospinal fluid (CSF) at experimentally therapeutic concentrations. Twenty-five patients with subarachnoid hemorrhage (SAH) and external ventricular drains were sequentially allocated to five administration regimes, using intravenous bolus doses of 100 to 500 mg and 4 hours intravenous infusions of IL-1RA ranging from 1 to 10 mg per kg per hour. Choice of regimes and timing of plasma and CSF sampling was informed by pharmacometric analysis of pilot study data. Data were analyzed using nonlinear mixed effects modeling. Plasma and CSF concentrations of IL-1RA in all regimes were within the predicted intervals. A 500-mg bolus followed by an intravenous infusion of IL-1RA at 10 mg per kg per hour achieved experimentally therapeutic CSF concentrations of IL-1RA within 45 minutes. Experimentally, neuroprotective CSF concentrations in patients with SAH can be safely achieved within a therapeutic time window. Pharmacokinetic analysis suggests that IL-1RA transport across the blood-CSF barrier in SAH is passive. Identification of the practicality of this delivery regime allows further studies of efficacy of IL-1RA in acute cerebrovascular disease.
... a 17-kDa polypeptide and exists two isoforms, IL-1α and IL-1β and its endogenous inhibitor, IL-1 receptor antagonist (IL-1ra) [10]. In experimental stroke, IL-1beta mRNA elevations have been documented within 15–30 min after ischemia [221,222], with protein detected a few hours later [223]. Much of the data to date suggests that IL-1 potentiates brain injury in experimental stroke [224]. ...
This chapter will discuss the current knowledge of the contribution of systemic and local inflammation in acute and sub-chronic stages of experimental stroke in both the adult and neonate. It will review the role of specific cell types and interactions among blood cells, endothelium, glia, microglia, the extracellular matrix and neurons - cumulatively called "neurovascular unit" - in stroke induction and evolution. Intracellular inflammatory signaling pathways such as nuclear factor kappa beta and mitogen-activated protein kinases, and mediators produced by inflammatory cells such as cytokines, chemokines, reactive oxygen species and arachidonic acid metabolites, as well as the modifying role of age on these mechanisms, will be reviewed as well as the potential for therapy in stroke and hypoxic-ischemic injury.
... Tumor necrosis factor-a and interleukin-1 are the frequently investigated inflammatory cytokines in ischemic brain (Orzylowska et al., 1999;Han and Yenari, 2003). Complete ischemic brain injury was followed by overexpression of interleukin-1b mRNA with biphasic activity of protein upregulated during early and late survival times (Buttini et al., 1994;Davies et al., 1999;Haqqani et al., 2005). Moreover, upregulation and/or therapy with interleukin-1 receptor antagonist decrease infarct area (Mulcahy et al., 2003) but inactivating or knocking out interleukin-1 receptor mice led to a huge increase in brain ischemia injury (Pinteaux et al., 2006). ...
There is increasing evidence for influence of Alzheimer's proteins and neuropathology on ischemic brain injury. This review investigates the relationships between beta-amyloid peptide, apolipoproteins, presenilins, tau protein, alpha-synuclein, inflammation factors, and neuronal survival/death decisions in brain following ischemic episode. The interactions of these molecules and influence on beta-amyloid peptide synthesis and contribution to ischemic brain degeneration and finally to dementia are reviewed. Generation and deposition of beta-amyloid peptide and tau protein pathology are important key players involved in mechanisms in ischemic neurodegeneration as well as in Alzheimer's disease. Current evidence suggests that inflammatory process represents next component, which significantly contribute to degeneration progression. Although inflammation was initially thought to arise secondary to ischemic neurodegeneration, recent studies present that inflammatory mediators may stimulate amyloid precursor protein metabolism by upregulation of beta-secretase and therefore are able to establish a vicious cycle. Functional brain recovery after ischemic lesion was delayed and incomplete by an injury-related increase in the amount of the neurotoxic C-terminal of amyloid precursor protein and beta-amyloid peptide. Moreover, ischemic neurodegeneration is strongly accelerated with aging, too. New therapeutic alternatives targeting these proteins and repairing related neuronal changes are under development for the treatment of ischemic brain consequences including memory loss prevention.
... Außerdem konnte beobachtet werden, dass das IL-1RA-Protein bereits im menschlichen Fruchtwasser in einer höheren Konzentration als in den anderen maternalen Körperflüssigkeiten vorlag ( Calciumkonzentration, Freisetzung von Stickstoffmonoxid (NO) (Lee et al. 1993) und anderen freien Radikalen (Sullivan et al. 1989) sowie Aktivierung des Corticotropin Releasing Factors (CRF). So konnte im Rattenmodell eine erhöhte Expression der IL-1β-mRNA infolge ischämischer Insulte (Buttini et al. 1994; Liu et al. 1993; Minami et al. 1992; Yabuuchi et al. 1994b), die z.B. durch ein Geburtstrauma oder Schäden in der frühen Kindheit verursacht wurden, infolge lokaler Hirnverletzung (Woodroofe et al. 1991) und Infusion von Exzitotoxinen (Minami et al. 1990 1997). Dies ging mit einer erhöhten Anzahl an überlebenden Neuronen und verbesserter neurologischer Funktion einher (Garcia et al. 1995; Relton et al. 1996Fletcher et al. 1998; Seidman et al. 1994; Stone et al. 1998). ...
Except in response to localized conditions of infection or inflammation, polymorphonuclear (PMN) leukocytes and cells of the monocyte/macrophages lineage do not invade the brain parenchyma. Rather, the brain is a transit organ for these leukocyte subclasses. Importantly, the microvasculature provides the scaffolding for the cellular inflammatory response to ischemia. Both the humoral (i.e., cytokine, chemokine) and cellular components of the inflammatory response interact with stimulated microvessels to initiate post-ischemic vascular and tissue injury. In the ischemic basal ganglia, very early changes in microvessel integrin-extracellular matrix (ECM) interactions, PA and MMP release, and vascular cell activation occur in temporal and spatial association with the development of severe neuron injury. Specific changes in microvessel integrity and permeability (50, 94), loss of basal lamina integrity (92, 93), simultaneous decreases in specific endothelial cell and astrocyte integrins (207, 223), and changes in astrocyte ultrastructure (54, 78) occur during this early period. Selected events (e.g., VEGF upregulation) occur along with early evidence of inflammatory cell activation. Moreover, activation of cerebral microvessels within the ischemic core regions is evident within 1–2 hours following middle cerebral artery occlusion (MCA:O) in primate species. These events suggest relationships at multiple levels involving microvessel integrin-matrix responses, inflammatory cell invasion, and cellular activation to effect vascular, glial, and neuron injury following focal cerebral ischemia.
Neurogenesis persists in the forebrain subventricular zone (SVZ) where neural stem cells (NSCs) reside in a specific niche. Stroke stimulates SVZ NSCs, which offer reparative potential, but few new neurons survive long-term. Thus, the capacity for self-repair appears insufficient. This thesis focuses on NSC modulation by endothelial cells within the niche, and stroke or inflammation, with the goals of understanding how injury influences neurogenesis and whether stimulating injury-induced neurogenesis improves functional recovery.
Evaluation of the components of injury may improve our understanding of how it modulates SVZ neurogenesis. We examined the influence of in vivo exposure to hypoxia or inflammation, or both, on SVZ NSCs using the neurosphere (NS) assay. Mice exposed to acute hypoxia or systemic inflammation produced significantly more NS, neurons and oligodendrocytes. The combined insults, however, significantly reduced neurogenesis. This effect may be mediated by IL-1?? as IL-1?? deficient mice generated fewer NS and neurons.
NSCs reside in a vascular niche composed of glia and endothelial cells. Angiogenesis and neurogenesis interact in neurogenic regions stimulated by stroke. We hypothesized that factors secreted by intact or oxygen-glucose deprived (OGD) endothelial cells enhance SVZ neurogenesis. We found that
SVZ NS exposed to endothelial cell co-culture or endothelial cell conditioned media (ECCM) increased in numbers and generated neurons and glia that appeared more immature. NS exposure to OGD-ECCM, in contrast, stimulated neuronal maturation and migration. These data suggest that intact and injured endothelial cells secrete factors that differentially influence SVZ NSCs, and offer potential targets to stimulate NSC expansion and integration of new neurons after brain injury.
We also hypothesized that augmenting stroke-induced neurogenesis would enhance functional recovery. We exposed rats to retinoic acid (RA) and environmental enrichment (EE), to promote SVZ neurogenesis and post-stroke recovery. RA-treatment preserved striatal and hemispheric tissue, and combined RA/EE treatment increased SVZ cell proliferation and neurogenesis. These interventions did not improve behavioral recovery. Together, these studies underscore the complexity of how the stem cell niche and injury influence postnatal SVZ neurogenesis. Future work should target factors from endothelial cells, hypoxia and inflammation to promote neurogenesis and enhance the brain???s natural repair process.
Background:
Although the neuroprotective effect of ceftriaxone (CTX) has been reported, the underlying mechanisms are still uncertain. In this study, we investigated if rats recover better from CTX pretreatment against cerebral ischemia by inhibiting the inflammatory response.
Methods:
Rats were pretreated with CTX (200 mg/kg, 1/day, i.p.) for 5 d. At 24 h after the end of the last CTX pretreatment, focal cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 120 min in male Sprague Dawley rats. The neurological deficit scores (NDS) and infarct volumes were evaluated. Microglia cells were observed by immunofluorescence staining and IL-1β was assayed by ELISA and Western Blot.
Results:
The results showed that CTX pretreatment improved the neurological deficit scores and decreased the infarct volumes 24 h after reperfusion. The activation of microglia cells was reduced and the expression of IL-1β was partially inhibited 24 h after reperfusion.
Conclusion:
These findings demonstrate that CTX pretreatment may provide a neuroprotective effect against transient cerebral ischemic injury, partially inhibit in microglial activation and reduce the expression of IL-1β.
Apoptosis is a major form of cell death in cerebral ischemia/reperfusion (I/R) pathogenesis and may represent a target for treatment. Diosmin (DM), a micronized purified flavonoid drug, possesses an anti-apoptotic effect in the treatment of varicose veins and renal injury. However, the effect of DM in acute phase of cerebral I/R is not clear. This study investigated DM's role in cerebral I/R and its potential mechanism.
Male CD-1 mice were subjected to transient middle cerebral artery occlusion (tMCAO). Experiment 1 was used to evaluate the time course expression of Janus tyrosine kinase-2 (JAK2), signal transducer and activator of transcription-3 (STAT3), phosphorylated JAK2 (pJAK2) and phosphorylated STAT3 (pSTAT3) after cerebral I/R, and 6 time points were included. In experiment 2, DM was given orally at doses of 50 mg/kg or 100 mg/kg for six consecutive days before receiving tMCAO. At 24 h after reperfusion, neurological deficit, Nissl staining, brain water content and infarct volume were examined. Bcl-2, Bax, pJAK2, and pSTAT3 were detected by immunohistochemistry, qRT-PCR and western blot. Confocal microscope was used to observe the location of pSTAT3 in the cerebral cortex.
Compared with Vehicle group, the high does of DM significantly alleviated neurological deficit, brain water content, infarct volume, increased the Nissl-positive cells, upregulated the expression of pJAK2, pSTAT3 and Bcl-2 and downregulated Bax (P < 0.05).
These results showed that DM protected against cerebral I/R injury through activating JAK2/STAT3 signal pathway.
Edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one) is a free radical scavenger used for acute ischemic stroke. However, it is not known whether edaravone works only as a free radical scavenger or possess other pharmacological actions. Therefore, we elucidated the effects of edaravone on human brain microvascular endothelial cells (HBMECs) by 2 dimensional fluorescence difference gel electrophoresis (2D-DIGE). We found 38 protein spots the intensity of which was significantly altered 1.3 fold on average (p< 0.05) by the edaravone treatment and successfully identified 17 proteins of those. Four of those 17 proteins were cytoskeleton proteins or cytoskeleton-regulating proteins. Therefore, we subsequently investigated the change of size and shape of the cells, the actin network, and the tight junction of HBMEC by immunocytochemistry. As a result, most edaravone-treated HBMECs became larger and rounder compared with those that were not treated. Furthermore, edaravone-treated HBMECs formed gathering zona occludens (ZO)-1, a tight junction protein, along the junction of the cells. In addition, we found that edaravone suppressed interleukin (IL)-1β-induced secretion of monocyte chemoattractant protein-1 (MCP-1), which was reported to increase cell permeability. We found a novel function of edaravone is the promotion of tight junction formations of vascular endothelial cells partly via the down-regulation of MCP-1 secretion. These data provide fundamental and useful information in the clinical use of edaravone in patients with cerebral vascular diseases.
Microglia can be induced into an effector state in response to motor neuron injury. This response can modulate the extent of axonal repair or regeneration, and the process of microglial activation participates directly in the pathogenesis of the neurodegeneration of amyotrophic lateral sclerosis (ALS). The function of microglial activation in response to neuronal injury is complex and relates to ALS. The degeneration of motor neurons, whether induced by trauma, experimental neurotoxins, or in transgenic mice models, is accompanied by profound changes in the neuronal milieu. This change in milieu is modulated, to a significant extent, by microglia. Direct microglial/motor neuron contact does not seem to be required for this, although contact between microglia and neurons has been proposed to result in a shift in microglial function from neurotoxicity to neuroprotection. Experiments suggesting that the passive transfer of motor neuron injury is possible through microglia are of importance in bringing forward a potential mechanism of disease propagation in ALS.
The cytokine interleukin-1 (IL-1) has been implicated in ischaemic, traumatic and excitotoxic brain damage. The results presented here reveal novel actions of IL-1 in the striatum which markedly exacerbate cortical neuronal damage elicited by local excitotoxins in the striatum or cortex.
Intrastriatal infusion of IL-1 receptor antagonist, IL-1ra, markedly inhibited striatal neuronal damage caused by N-methyl-d-aspartate (NMDA) or α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) receptor activation in the rat. In contrast, intracortical infusion of IL-1ra failed to inhibit NMDA or AMPA receptor-induced damage in the cortex.
Intrastriatal co-infusion of IL-1β with the NMDA or AMPA receptor agonist did not affect local striatal damage induced by activation of either glutamate receptor subtype, but caused extensive cortical damage when administered into the striatum with AMPA. This secondary damage was significantly reduced by pretreatment with the NMDA receptor antagonist (MK-801), which did not affect local (striatal) damage caused by AMPA. Infusion of IL-1β into the striatum (but not the cortex) markedly enhanced cortical damage caused by infusion of an NMDA or AMPA receptor agonist into the cortex.
These data reveal selective actions of IL-1 and IL-1ra in the striatum, which influence cortical neuronal loss and suggest that IL-1 selectively enhances damage caused by AMPA receptor activation.
We have used northern blot analysis and quantitative reverse transcription polymerase chain reaction (RT-PCR) to determine the postinjury expression profile of the transforming growth factor-beta 1 (TGF-beta 1) gene in the contused rat spinal cord, Spectrophotometric estimates of total sample RNA and quantitative analyses of cyclophilin mRNA using RT-PCR served as controls for comparisons between samples, No changes in cyclophilin gene expression were found at any postinjury survival times, The results of the TGF-beta 1 analyses, which were carried out on spinal cord samples taken at postinjury intervals ranging from 6 h to 10 days, show that the amount of TGF-beta 1 mRNA present in spinal cord increases rapidly following injury, reaching maximum levels 7 days postinjury. Unoperated control samples contained approximately 2 x 10(8) molecules of TGF-beta 1 mRNA/0.5 mu g total RNA. By 1 day postinjury, the amount of TGF-beta 1 mRNA in the cord had increased by a factor of 2.5 to 5 x 10(8) molecules/0.5 mu g total RNA, At 7 days postinjury, there were approximately 15 x 10(8) molecules of TGF-beta 1 mRNA/0.5 mu g total RNA. By 10 days postinjury the amount of TGF-beta 1 mRNA present in the spinal cord had declined to 8 x 10(8) molecules of TGF-beta 1 mRNA/0.5 mu g total RNA, a value similar to that observed at 3 days postinjury, The roles that TGF-beta 1 might play in modifying cellular responses in injured spinal cord are discussed.
Significant morbidity and mortality associated with traumatic brain injury(TBI) are allied with secondary posttrauma inflammatory complications, Hypothermia has been suggested as a possible treatment to lessen or suppress these inflammatory reactions, We report here that interleukin 1 beta, a cytokine responsible for initiating inflammatory cascades, is elevated in rat cortex within 6 h of TBI in the rat, Nerve growth factor (NGF) RNA and protein also increased subsequently, and NGF protein remained elevated for up to 7 days, Four hours of whole body hypothermia (32 degrees C), applied immediately after the TBI, attenuated the posttrauma increase in IL-1 beta RNA and eliminated the increase in NGF RNA and protein observed in cerebral cortex following TBI, Thus, hypothermia may be an effective therapy to diminish the posttrauma inflammatory cascade in the brain (as suggested by the decrease in IL-1 beta), However, the same treatment may hinder the brain's intrinsic repair mechanisms, Optimal treatment may, therefore, require supplemental administration of neurotrophic factors or other agents along with hypothermia.
Tumor necrosis factor-α (TNF) plays a prominent role in the brain damage and functional deficits that result from ischemic stroke. It was recently reported that the thalidomide analog 3,6'-dithiothalidomide (3,6'-DT) can selectively inhibit the synthesis of TNF in cultured cells. We therefore tested the therapeutic potential of 3,6'-DT in a mouse model of focal ischemic stroke. Administration of 3,6'-DT immediately prior to a stroke or within 3 hr after the stroke reduced infarct volume, neuronal death, and neurological deficits, whereas thalidomide was effective only when administered prior to stroke. Neuroprotection was accompanied by decreased inflammation; 3,6'-DT-treated mice exhibited reduced expression of TNF, interleukin-1β, and inducible nitric oxide synthase; reduced numbers of activated microglia/macrophages, astrocytes, and neutrophils; and reduced expression of intercellular adhesion molecule-1 in the ischemic brain tissue. 3,6'-DT treatment attenuated stroke-induced disruption of the blood-brain barrier by a mechanism that appears to involve suppression of matrix metalloproteinase-9 and preservation of occludin. Treatment with 3,6'-DT did not reduce ischemic brain damage in mice lacking TNF receptors, consistent with a critical role for suppression of TNF production and TNF signaling in the therapeutic action of 3,6'-DT. These findings suggest that anti-inflammatory mechanisms underlie the therapeutic actions of 3,6-DT in an animal model of stroke. © 2013 Wiley Periodicals, Inc.
Tanshinone IIA is a good candidate for treating cerebral ischemia, but its short half-life and poor permeability across the blood-brain-barrier (BBB) limit its curative efficacy. In this study, we successfully developed cationic bovine serum albumin-conjugated tanshinone IIA PEGylated nanoparticles (CBSA-PEG-TIIA-NPs). A cerebral ischemia rat model was established to evaluate the treatment efficacy and protective mechanism of CBSA-PEG-TIIA-NPs. CBSA-PEG-TIIA-NPs showed the mean particle size 118 ± 14 nm with drug loaded ratio and encapsulation efficiency 5.69 ± 0.6% and 83.2 ± 2.6%, respectively. The pharmacokinetics demonstrated that CBSA-PEG-TIIA-NPs could significantly prolong circulation time and increase plasma concentration compared with intravenously administrated TIIA solution. The biodistribution and brain uptake study confirmed that CBSA-PEG-TIIA-NPs possessed better brain delivery efficacy with a high accumulation in brain. CBSA-PEG-TIIA-NPs obviously ameliorated infarct volume, neurological deficit and histopathological severity. Treatment with CBSA-PEG-TIIA-NPs markedly inhibited the levels of the MPO, TNF-α, IL-1β and IL-6. Furthermore, CBSA-PEG-TIIA-NPs significantly decreased the mRNA expressions of iNOS and p38MAPK, upregulated PPARγ expression, and inhibited the protein levels of iNOS, GFAP and p38MAPK phosphorylation. These results demonstrated that CBSA-PEG-TIIA-NPs possessed remarkable neuroprotective effects on ischemic stroke through modulation of inflammatory cascades and neuronal signal pathways involved in cerebral ischemia.
Interleukin-1 beta (IL-1β) 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-1β-mediated neurodegeneration. We have investigated the expression of IL-1β protein by glial cells in vivo in response to NMDA receptor-mediated excitotoxicity in the rat parietal cortex and striatum.Expression of IL-1β 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-1β 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-1β expression by microglia and astrocytes. However, IL-1β-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-1β expression.These studies reveal that IL-1β is expressed specifically by microglia during the early response to excitotoxicity in the adult rat cortex and striatum. However, the widespread and delayed IL-1β expression by astrocytes suggests diverse roles for IL-1β in response to excitotoxicity. GLIA 25:311–323, 1999. © 1999 Wiley-Liss, Inc.
The importance of cytokines and the complement system in the propagation and maintenance of the brain inflammatory response to injury are emphasised. Much data supports the case that ischemia and trauma elicit an inflammatory response in the injured brain. This inflammatory response consists of mediators (cytokines, complement activation, chemokines and adhesion molecules) followed by cells (neutrophils early after the onset of brain injury and then a later monocyte infiltration). De novo up-regulation of pro-inflammatory cytokines, chemokines and endothelial-leukocyte adhesion molecules occurs soon following focal ischemia and trauma and at a time when the tissue injury is evolving. The significance of this brain inflammatory response and its contribution to brain injury is now better understood. In this review, we discuss the role of TNFα and IL-1β in traumatic and brain injury and associated inflammation, and the co-operative actions of the complement system, chemokines and adhesion molecules in this process. Celluar stress and cellular stress signalling is key to the neurodegenerative process in brain injury. Therefore, we also address novel approaches to target cytokines and reduce the brain inflammatory response, and thus brain injury, in stroke and neurotrauma. The mitogen-activated protein kinase (MAPK), p38, has been linked to inflammatory cytokine production and cell death following cellular stress. Stroke-induced p38 enzyme activation in the brain has been demonstrated, and treatment with p38 MAPK inhibitors can provide a significant reduction in infarct size, neurological deficits and increased inflammatory cytokines/proteins expression produced by focal stroke. p38 MAPK inhibition can also provide direct protection of cultured brain tissue to in vitro ischemia. This robust neuroprotection that can be produced by inhibition of p38 MAPK signalling emphasizes a significant opportunity for targeting MAPK pathways CNS injury/disease. Many examples of the roles of inflammation, cellular oxidative stress and MAPK signalling in Psychiatric and Neurodegenerative Diseases are also provided. As a whole, the available data suggests that inflammation, cellular stress and p38 MAPK signalling are important in nervous disease pathologies and that inhibition of cellular stress signalling should be considered for improving outcome in many CNS diseases.
Le coup de chaleur est une pathologie grave sans thérapeutique spécifique. Les animaux en coup de chaleur souffrent d’une inflammation accompagnée d’un déséquilibre métabolique en dépit de l’induction de « heat shock proteins » (Hsp70) et de la sécrétion de glucocorticoïdes. Le rôle relatif des ARNm Hsp70 et des glucocorticoïdes dans la tolérance à la chaleur est analysé. Les animaux vigiles intolérants à la chaleur présentent : une hyperthermie et une déshydratation sévères, un déséquilibre métabolique, une moindre sécrétion de glucocorticoïdes, des signes d’hyperactivation et d’agression cellulaires ainsi qu’une activation des processus inflammatoires. L’expression des ARNm Hsp70 est dépendante de l’intensité de l’agression et apparaît comme un mécanisme suiveur. Les glucocorticoïdes sont impliqués dans la tolérance en réduisant le développement des processus inflammatoires locaux et en favorisant l’expression des ARNm du facteur inhibiteur κBα (IκBα).