scholarly journals Delayed Administration of Interleukin-1 Receptor Antagonist Reduces Ischemic Brain Damage and Inflammation in Comorbid Rats

2012 ◽  
Vol 32 (9) ◽  
pp. 1810-1819 ◽  
Author(s):  
Jesus M Pradillo ◽  
Adam Denes ◽  
Andrew D Greenhalgh ◽  
Herve Boutin ◽  
Caroline Drake ◽  
...  
Keyword(s):  
Risk Factors ◽  
Brain Injury ◽  
Receptor Antagonist ◽  
Brain Damage ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Experimental Stroke ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Interleukin 1 Receptor Antagonist

Many neuroprotective agents have been effective in experimental stroke, yet few have translated into clinical application. One reason for this may be failure to consider clinical comorbidities/risk factors in experimental models. We have shown that a naturally occurring interleukin-1 receptor antagonist (IL-1Ra) is protective against ischemic brain damage in healthy animals. However, protective effects of IL-1Ra have not been determined in comorbid animals. Thus, we tested whether IL-1Ra protects against brain injury induced by experimental ischemia in aged JCR-LA (corpulent) rats, which have clinically relevant risk factors. Male, aged, lean, and corpulent rats exposed to transient (90 minutes) occlusion of the middle cerebral artery (tMCAO) were administered two doses of IL-1Ra (25 mg/kg, subcutaneously) during reperfusion. Brain injury and neuroinflammatory changes were assessed 24 hours after tMCAO. Our results show that IL-1Ra administered at reperfusion significantly reduced infarct volume measured by magnetic resonance imaging (50%, primary outcome) and blood–brain barrier disruption in these comorbid animals. Interleukin-1Ra also reduced microglial activation, neutrophil infiltration, and cytokines levels in the brain. These data are the first to indicate that IL-1Ra protects against ischemic brain injury when administered via a clinically relevant route and time window in animals with multiple risk factors for stroke.

scholarly journals Attenuation of Stroke Size in Rats Using an Adenoviral Vector to Induce Overexpression of Interleukin-1 Receptor Antagonist in Brain

1995 ◽  
Vol 15 (4) ◽  
pp. 547-551 ◽  
Author(s):  
A. Lorris Betz ◽  
Guo-Yuan Yang ◽  
Beverly L. Davidson
Keyword(s):  
Brain Injury ◽  
Receptor Antagonist ◽  
Recombinant Adenovirus ◽  
Infarct Volume ◽  
Interleukin 1 ◽  
Adenovirus Vector ◽  
Histochemical Staining ◽  
Artery Occlusion ◽  
Central Administration ◽  
Interleukin 1 Receptor Antagonist

Adenoviruses have been proposed as potential vectors for gene therapy in the central nervous system, but there are no reports of their use in the treatment of a brain disease. Because central administration of interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain damage, we determined whether a recombinant adenovirus vector carrying the human IL-1ra cDNA (Ad.RSV IL-1ra) could be used to ameliorate brain injury in permanent focal ischemia. Groups of six rats received intraventricular injections of Ad.RSV IL-1ra or a control adenovirus containing the Escherichia coli β-galactosidase gene (Ad.RSV lacZ). Histochemical staining for β-galactosidase 5 days after virus injection indicated that transgene expression was confined primarily to the cells lining the ventricle. The concentrations of IL-1ra were fivefold to 50-fold higher in the Ad.RSV IL-1ra-injected animals, achieving levels of 9.1 ± 3.3 ng/g in brain and 23.7 ± 22.5 ng/ml in CSF. In these animals, cerebral infarct volume resulting from 24 h of permanent middle cerebral artery occlusion was reduced 64%. These studies demonstrate that adenoviral vectors can be used to deliver genes that attenuate brain injury.

scholarly journals Attenuation of Ischemic Inflammatory Response in Mouse Brain Using an Adenoviral Vector to Induce Overexpression of Interleukin-1 Receptor Antagonist

1998 ◽  
Vol 18 (8) ◽  
pp. 840-847 ◽  
Author(s):  
Guo-Yuan Yang ◽  
Xiao-Hong Liu ◽  
Chitoshi Kadoya ◽  
Yong-Jie Zhao ◽  
Ying Mao ◽  
...  
Keyword(s):  
Brain Injury ◽  
Basal Ganglia ◽  
Inflammatory Response ◽  
Receptor Antagonist ◽  
Adenoviral Vector ◽  
Interleukin 1 ◽  
Saline Control ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Interleukin 1 Receptor Antagonist

It has been demonstrated that administration of an interleukin-1 receptor antagonist protein (IL-1ra) reduces ischemic brain injury; however, the detrimental mechanism initiated by interleukin-1 (IL-1) in ischemic brain injury is unclear. In this study, we used mice that were transfected to overexpress human IL-1ra to elucidate the role of IL-1 in the activation of the inflammatory response after middle cerebral artery occlusion (MCAO). Myeloperoxidase (MPO) activity and immunohistostaining were used as a marker of polymorphonuclear leukocytes (PMNL) infiltration. Adenoviral vector (1 × 109 particles) was administered by injection into the right lateral ventricle in mice. Five days later, MCAO was performed on the mice using a suture technique. Permanent MCAO was achieved for 24 hours in the Ad.RSV IL-1ra-transfected, Ad.RSV lacZ-transfected, and saline (control) mice. Myeloperoxidase activity was quantified in each region and localization of MPO was determined by immunohistochemistry. After 2 hours of MCAO, the surface cerebral blood flow was reduced to 13.5% ± 3.4%, 10.75% ± 2.6%, and 10.9% ± 2.6% of baseline in the ischemic hemisphere in Ad.RSV IL-1ra-transfected, Ad.RSV- lacZ-transfected, and saline-treated mice, respectively. The MPO activity in the ischemic hemisphere in the Ad.RSV lacZ group was similar to that in the saline control group (cortex: 0.40 ± 0.22 versus 0.33 ± 0.11; basal ganglia: 0.46 ± 0.23 versus 0.49 ± 0.17; P > 0.05); however, it was significantly reduced in the Ad.RSV IL-1ra group (cortex: 0.18 ± 0.07; basal ganglia: 0.26 ± 0.15; P < 0.05). Myeloperoxidase immunohistochemistry showed that the massive accumulation of MPO-positive cells in the ischemic cortex, striatum, and corpus callosum regions was greatly attenuated in Ad.RSV IL-1ra-transfected mice. Our results indicate that Ad.RSV IL-1ra-transfected mice provide a useful tool to study the mechanism of action of IL-1. The MPO activity assay and immunostaining after 24 hours of focal ischemia were significantly reduced in IL-1ra gene-transfected mice, suggesting that IL-1 may play an important role in the activation of inflammatory cells during focal cerebral ischemia.

scholarly journals Protective Role for Type 4 Metabotropic Glutamate Receptors against Ischemic Brain Damage

2010 ◽  
Vol 31 (4) ◽  
pp. 1107-1118 ◽  
Author(s):  
Slavianka G Moyanova ◽  
Federica Mastroiacovo ◽  
Lidia V Kortenska ◽  
Rumiana G Mitreva ◽  
Erminia Fardone ◽  
...  
Keyword(s):  
Brain Damage ◽  
Metabotropic Glutamate Receptors ◽  
Infarct Volume ◽  
Focal Ischemia ◽  
Protective Role ◽  
Ischemic Brain Damage ◽  
Systemic Injection ◽  
Ischemic Brain ◽  
Metabotropic Glutamate ◽  
Transient Focal Ischemia

We examined the influence of type 4 metabotropic glutamate (mGlu4) receptors on ischemic brain damage using the permanent middle cerebral artery occlusion (MCAO) model in mice and the endothelin-1 (Et-1) model of transient focal ischemia in rats. Mice lacking mGlu4 receptors showed a 25% to 30% increase in infarct volume after MCAO as compared with wild-type littermates. In normal mice, systemic injection of the selective mGlu4 receptor enhancer, N-phenyl-7-(hydroxyimino)cyclopropa[b]chromen-1a-caboxamide (PHCCC; 10 mg/kg, subcutaneous, administered once 30 minutes before MCAO), reduced the extent of ischemic brain damage by 35% to 45%. The drug was inactive in mGlu4 receptor knockout mice. In the Et-1 model, PHCCC administered only once 20 minutes after ischemia reduced the infarct volume to a larger extent in the caudate/putamen than in the cerebral cortex. Ischemic rats treated with PHCCC showed a faster recovery of neuronal function, as shown by electrocorticographic recording and by a battery of specific tests, which assess sensorimotor deficits. These data indicate that activation of mGlu4 receptors limit the development of brain damage after permanent or transient focal ischemia. These findings are promising because selective mGlu4 receptor enhancers are under clinical development for the treatment of Parkinson's disease and other central nervous system disorders.

scholarly journals Macamide B Pretreatment Attenuates Neonatal Hypoxic-Ischemic Brain Damage of Mice Induced Apoptosis by Regulates Autophagy Via The PI3K/AKT Signaling Pathway

2021 ◽  
Author(s):  
Xiaoxia Yang ◽  
Mengxia Wang ◽  
Qian Zhou ◽  
Yanxian Bai ◽  
Jing Liu ◽  
...  
Keyword(s):  
Signaling Pathway ◽  
Brain Damage ◽  
Infarct Volume ◽  
Neuroprotective Effect ◽  
Akt Signaling ◽  
Akt Signaling Pathway ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Induced Apoptosis ◽  
The Impact

Abstract Lepidium meyenii (Maca) is an annual or biennial herb from South America that is a member of the genus Lepidium L. in the family Cruciferae. This herb has antioxidant, anti-apoptotic, and enhances autophagy functions and can prevent cell death, and protect neurons from ischemic damage. Macamide B, an effective active ingredient of maca, has a neuroprotective role in neonatal hypoxic-ischemic brain damage (HIBD), and the underlying mechanism of its neuroprotective effect is not yet known. The purpose of this study is to explore the impact of macamide B on HIBD-induced autophagy and apoptosis and its potential mechanism for neuroprotection. The modified Rice-Vannucci method was used to induce HIBD on 7-day-old (P7) macamide B and vehicle-pretreated pups. TTC staining was used to evaluate the cerebral infarct volume of pups, brain water content was measured to evaluate the neurological function of pups, neurobehavioral testing was used to assess functional recovery after HIBD, TUNEL and FJC staining was used to detect cell autophagy and apoptosis, and western blot analysis was used to detect the expression levels of the pro-survival signaling pathway phosphatidylinositol-3-kinase/protein kinase B (PI3K/AKT) and autophagy and the apoptosis-related proteins. The results show that macamide B pretreatment can significantly decrease brain damage, improve the recovery of neural function after HIBD. At the same time, macamide B pretreatment can induce the activation of PI3K/AKT signaling pathway after HIBD, enhance autophagy, and reduce hypoxic-ischemic (HI)-induced apoptosis. In addition, 3-methyladenine (3-MA), an inhibitor of PI3K/AKT signaling pathway, significantly inhibits the increase in autophagy levels, aggravates HI-induced apoptosis, and reverses the neuroprotective effect of macamide B on HIBD. Our data indicate that macamide B pretreatment might regulate autophagy through PI3K/AKT signaling pathway, thereby reducing HIBD-induced apoptosis and exerting neuroprotective effects on neonatal HIBD. Macamide B may become a new drug for the prevention and treatment of HIBD.

Abstract T P210: Splenectomy Attenuates Sex Differences in Infarct Volume Following Experimental Stroke in Mice

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Jianming Wang ◽  
Sheetal Bodhankar ◽  
Halina Offner ◽  
Stephanie J Murphy
Keyword(s):  
Sex Differences ◽  
Blood Glucose ◽  
Brain Injury ◽  
Infarct Volume ◽  
Blood Gases ◽  
Experimental Stroke ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Male And Female ◽  
Female Mice

It is now increasingly clear that human stroke can have other serious consequences besides brain damage that can impact on patient survival and recovery. For example, many stroke patients succumb to CNS injury-induced immunodepression and fatal infections. Our prior work suggests that evolving cerebral ischemic injury elicits a cycle of injury from brain-to-spleen-to-brain that is strongly influenced by sex. We determined if splenic immunocytes are important in contributing to sex differences in post-ischemic brain injury. Male and female C57BL/6J mice were splenectomized 14 days before experimental stroke. Male and female mice with or without splenectomy (n=9-10 per group) then underwent 60 min of middle cerebral artery occlusion (MCAO) via intraluminal filament. Laser-Doppler flowmetry (LDF) was used to monitor cortical perfusion. All mice were euthanized and brains collected at 96 hours of reperfusion. Infarct volume (% corrected contralateral structure) was determined by image analysis of coronal brain slices stained with 2,3,5-triphenyltetrazolium chloride. Mean arterial blood pressure (MABP), blood gases (pH, P a O 2 , P a CO 2 ), and blood glucose were measured at 30 min MCAO and at 15 min of reperfusion in separate groups of male and female mice with or without splenectomy (n=5 per group). Relative LDF changes (% baseline), MABP, blood gases, and blood glucose during and after MCAO were comparable among the experimental groups. We observed that infarct volume in females (cortex, 41±4%; striatum, 55±6%) was smaller ( P <0.05) compared to males (cortex, 52±3%; striatum, 75±3%) at 96 hours of reperfusion. However, no differences (cortex, P =0.313; striatum, P =0.601) in infarct volume were seen between splenectomized male (cortex, 43±4%; striatum, 51±7%) and female (cortex, 38±4%; striatum, 46±5%) mice. Our data suggest that removal of all splenocyte lineages via splenectomy attenuates sex differences in post-ischemic brain injury. Future studies will evaluate the role of different splenic immunocyte subsets, such as T or B lymphocytes, on male vs. female ischemic brain outcomes. This study was supported by National Institutes of Health grant NS076013.

scholarly journals The role of oxidative stress in perinatal hypoxic-ischemic brain injury

2012 ◽  
Vol 140 (1-2) ◽  
pp. 35-41 ◽  
Author(s):  
Brankica Vasiljevic ◽  
Svjetlana Maglajlic-Djukic ◽  
Miroslava Gojnic ◽  
Sanja Stankovic
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Brain Damage ◽  
Ischemic Brain Injury ◽  
Ischemic Brain Damage ◽  
Ischemic Brain ◽  
Hypoxic Ischemic Brain Injury ◽  
Gpx Activity ◽  
Neurodevelopment Outcome

Introduction. The pathogenesis of perinatal hypoxic-ischemic brain damage is highly complex. Objective. The aim of this study was to assess the role of oxidative stress in hypoxic-ischemic brain injury and subsequent abnormal neurological outcome in infants with perinatal hypoxic-ischemic encephalopathy (HIE). We estimated perinatal oxidative brain damage measuring activity of glutathione peroxidase (GPX) in cerebrospinal fluid (CSF) as an indirect biomarker of free radical production during cerebral hypoxia-ischemia in correlation with the level of intracellular enzyme neuron specific enolase (NSE) in CSF as a biomarker of extend of brain injury. Methods. Ninety neonates (>32 GA) with perinatal HIE were enrolled prospectively. HIE was categorized into three stages according Sarnat and Sarnat clinical scoring system and changes seen on amplitude integrated EEG. CSF for GPX analysis and NSE analysis was taken in the first 72 hours of life. Neurodevelopment outcome was assessed at 12 months of corrected gestational age. Results. GPX activity in CSF was in good relation with clinical stage of HIE (p<0.0001) and GA (p<0.0001) and significantly corresponded with subsequent neurodevelopment outcome (p<0.001). GPX activity in CSF showed a strong correlation with NSE levels in CSF (p<0.001) as the biomarker of extent of brain injury. Conclusion. Our results suggest that oxidative stress might be important contributing factor in perinatal hypoxic-ischemic brain damage, particularly in preterm neonates.

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