scholarly journals Reduced Ischemic Brain Injury in Interleukin-1β Converting Enzyme—Deficient Mice

1998 ◽  
Vol 18 (2) ◽  
pp. 180-185 ◽  
Author(s):  
Gerald P. Schielke ◽  
Guo-Yuan Yang ◽  
Brenda D. Shivers ◽  
A. Lorris Betz
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Interleukin 1 ◽  
Active Form ◽  
Brain Lesion ◽  
Biologically Active ◽  
Ischemic Brain Injury ◽  
Converting Enzyme ◽  
Ischemic Brain

A variety of recent studies suggest a role for both inflammatory cytokines such as interleukin-1 beta (IL-1β), and apoptosis in ischemic brain injury. Because IL-1β converting enzyme (ICE) is required for the conversion of proIL-1β to its biologically active form, and has homology with proteins that regulate apoptosis in invertebrates, we studied the effect of cerebral ischemia on brain injury in mutant mice deficient in the ICE gene (ICE knockout [KO] mice). Focal cerebral ischemia, produced by occlusion of the middle cerebral artery, resulted in brain edema (increased water and sodium content) at 4 hours and a histologically defined brain lesion at 24 hours. Both of these markers of brain injury were significantly reduced in the ICE KO mice as compared to wild-type C57BL/6 mice. Regional cerebral blood flow, determined using the flow tracer, N-isopropyl [methyl 1,3-14C] p-iodoamphetamine (14C-IMP), was similar in the two strains of mice, indicating that the reduced brain injury in the KO mice was not a result of a lesser degree of ischemia. These data show that ICE contributes to the development of ischemic brain damage, and that it plays a role at an early time in the pathologic process. Although the mechanism of this effect is uncertain, our results suggest that pharmacologic inhibition of ICE may be a useful treatment for stroke.

Polyethylene glycol-conjugated superoxide dismutase and catalase reduce ischemic brain injury

1989 ◽  
Vol 256 (2) ◽  
pp. H589-H593 ◽  
Author(s):  
T. H. Liu ◽  
J. S. Beckman ◽  
B. A. Freeman ◽  
E. L. Hogan ◽  
C. Y. Hsu
Keyword(s):  
Hydrogen Peroxide ◽  
Superoxide Dismutase ◽  
Polyethylene Glycol ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Free Radical Scavengers ◽  
Ischemic Brain Injury ◽  
Ischemic Brain

Superoxide dismutase and catalase enzymatically scavenge superoxide and hydrogen peroxide, respectively. Conjugation of polyethylene glycol to superoxide dismutase (PEG-SOD) or catalase (PEG-CAT) prolongs the circulatory half-life of the native enzymes and enhances their intracellular access. We studied the protective effect of these free radical scavengers on ischemic brain injury using a rat model of focal cerebral ischemia, which is suitable for therapeutic trials. Intravenous administration of PEG-SOD (10,000 U/kg) and PEG-CAT (10,000 U/kg) before ischemia reduced the infarct volume (treatment, 139 +/- 9 mm3, means +/- SE, N = 38; placebo, 182 +/- 8 mm3, n = 37, P less than 0.002). This finding supports the concept that superoxide and hydrogen peroxide contribute to brain injury following focal cerebral ischemia.

Abstract T MP53: Whole Blood Immuno-Chromatography for Rapid Detection of Cerebral Ischemia in the Pre-Hospital Setting

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Luther C Pettigrew ◽  
Melissa A Bradley-Whitman ◽  
Mark A Lovell
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Whole Blood ◽  
Focal Cerebral Ischemia ◽  
Infarct Volume ◽  
Hospital Setting ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Ischemic Reperfusion ◽  
Arterial Blood

BACKGROUND: Pre-hospital detection of ischemic brain injury will exclude stroke mimics and refine patient triage. Using “dipstick” immuno-chromatography, we validated a rapid-sequence method to identify visinin-like protein-1 (VILIP-1), a neuronal injury marker, in blood sampled after focal cerebral ischemia in rats. METHODS: Transgenic (Tg) rats were constructed to over-express tumor necrosis factor-alpha (TNFα) in brain. Suture-occlusion of the middle cerebral artery (MCAO) was performed in TNFα-Tg animals and wild type (WT) littermates for 1 hr. Arterial blood was sampled at pre-ischemic baseline, after 60 min of MCAO, and at 15 min or 24 hrs of post-ischemic reperfusion. VILIP-1 immuno-reactivity was normalized to pre-ischemic baseline and compared to sham-ischemic animals. Brain infarct volume was measured at 24 hrs. VILIP-1 immuno-reactivity was then correlated with infarct volume to derive Pearson product moment. RESULTS: VILIP-1 immuno-reactivity was increased after 24 hrs of post-ischemic reperfusion in TNFα-Tg animals (133 ± 13 [SD]% of baseline) compared to sham-ischemic rats (100 ± 22; p ≤ 0.05; ANOVA; n = 5 per group). At 15 min (159 ± 36%) and 24 hrs (above), VILIP-1 expression was greater than pre-ischemic baseline ( p ≤ 0.05). Immuno-reactivity of VILIP-1 at 15-min post-ischemic reperfusion was strongly correlated with infarct volume measured at 24 hrs in TNFα-Tg rats (Pearson 0.79; p ≤ 0.01). CONCLUSIONS: Whole blood immuno-chromatography of VILIP-1 is feasible and correlates positively with infarct volume measured at 24 hrs in the rat. These promising results underscore the need to study VILIP-1 immuno-reactivity as an indicator of ischemic brain injury in the pre-hospital setting.

scholarly journals Mice Deficient in Interleukin-1 Converting Enzyme are Resistant to Neonatal Hypoxic-Ischemic Brain Damage

1999 ◽  
Vol 19 (10) ◽  
pp. 1099-1108 ◽  
Author(s):  
Xiao-Hong Liu ◽  
Deborah Kwon ◽  
Gerald P. Schielke ◽  
Guo-Yuan Yang ◽  
Faye S. Silverstein ◽  
...  
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Injury Severity ◽  
Apoptotic Cell ◽  
Focal Cerebral Ischemia ◽  
Interleukin 1 ◽  
Converting Enzyme ◽  
Wild Type ◽  
Doppler Flowmetry ◽  
Severity Of Injury

Interleukin-1 (IL-1) converting enzyme (ICE) is a cysteine protease that cleaves inactive pro-IL-1β to active IL-1β. The pro-inflammatory cytokine IL-1β is implicated as a mediator of hypoxic-ischemic (HI) brain injury, both in experimental models and in humans. ICE is a member of a family of ICE-like proteases (caspases) that mediate apoptotic cell death in diverse tissues. The authors hypothesized that in neonatal mice with a homozygous deletion of ICE (ICE-KO) the severity of brain injury elicited by a focal cerebral HI insult would be reduced, relativefto wild-type mice. Paired litters of 9- to 10-day-old ICE-KO and wild-type mice underwent right carotid ligation, followed by 70 or 120 minutes of exposure to 10% O2, In this neonatal model of transient focal cerebral ischemia followed by reperfusion, the duration of hypoxia exposure determines the duration of cerebral ischemia and the severity of tissue damage. Outcome was evaluated 5 or 21 days after lesioning; severity of injury was quantified by morphometric estimation of bilateral cortical; striatal, and dorsal hippocampal volumes. In animals that underwent the moderate HI insult (70-minute hypoxia), damage was attenuated in ICE-KO mice, when evaluated at 5 or 21 days post-lesioning. In contrast, in mice that underwent the more severe HI insult (120-minute hypoxia), injury severity was the same in both groups. Reductions in intra-HI CBF, measured by laser Doppler flowmetry, and intra- and post-HI temperatures did not differ between groups. These results show that ICE activity contributes to the progression of neonatal HI brain injury in this model. Whether these deleterious effects are mediated by proinflammatory actions of IL-lβ and/or by pro-apoptotic mechanisms is an important question for future studies.

Gingko biloba Extract (EGb 761) Prevents Increase of Bad-Bcl-XL Interaction Following Cerebral Ischemia

2009 ◽  
Vol 37 (05) ◽  
pp. 867-876 ◽  
Author(s):  
Phil-Ok Koh
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemic Brain Injury ◽  
Egb 761 ◽  
Adult Rats ◽  
Male Adult ◽  
Ischemic Brain ◽  
Gingko Biloba

A standardized extract of Gingko biloba, EGb 761, has been shown to exert a neuroprotective effect against permanent and transient focal cerebral ischemia. This study investigated whether EGb 761 modulates Bcl-2 family proteins in ischemic brain injury. Male adult rats were treated with EGb 761 (100 mg/kg) or vehicle prior to middle cerebral artery occlusion (MCAO), brain tissues were collected 24 hours after MCAO. EGb761 administration significantly decreased the number of TUNEL-positive cells in the cerebral cortex. Ischemic brain injury induced decrease of Bcl-2 and Bcl- X L levels. EGb 761 prevented not only the injury-induced decrease of Bcl-2 and Bcl- X L levels, but also the injury-induced increase of Bax. Moreover, in the presence of EGb 761, the interaction of Bad and Bcl- X L decreased compared to that of vehicle-treated animals. In addition, EGb 761 prevented the injury-induced increase of cleaved PARP. The finding suggests that EGb 761 prevents cell death against ischemic brain injury and EGb 761 neuroprotection is affected by preventing the injury-induced increase of Bad and Bcl- X L interaction.

Abstract TP273: High Fat Diet Worsens Long Term Stroke Outcome

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Weiguo Li ◽  
Roshini Prakash ◽  
Handong Ma ◽  
Adviye Ergul
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
High Fat Diet ◽  
Focal Cerebral Ischemia ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
High Fat ◽  
Long Term Outcomes ◽  
Ischemic Brain

Introduction: Obesity is a risk factor for stroke and diet-induced obesity is the most common type of obesity in humans. Yet, the effects of high fat diet (HFD) on neurovascular function and the extent of ischemic brain injury after ischemic stroke are not well understood. Previously we showed that HFD worsens functional hyperemia, vascular function and short-term (24 h) outcomes of ischemic brain injury induced by 3/21 h middle cerebral artery occlusion (MCAO)/reperfusion. The goal of this study is to test the hypotheses that HFD beginning early in life will exacerbate vascular injury and worsen long-term outcomes after focal cerebral ischemia. Methods: Starting at 4 weeks, Wistar rats were fed control (CD) or HFD diet for 8 weeks. The outcomes of cerebral ischemia were evaluated after 90 min MCAO and 5 d reperfusion by measuring neurological deficit, infarct size and hemorrhagic transformation (HT) frequency and severity. The sham groups were treated with same diet and surgical process without artery occlusion. Results: The HFD group had significantly increased body weight and adiposity. In MCAO animals, the infarct volume (37.02 ± 3.68% vs. 19.25 ± 5.52%, p<0.05), HT occurrence (5 out of 7 vs. 2 out of 8) and excess hemoglobin (100.9 ± 55.8 vs. 18.6 ± 4.7 mg/g protein) were greater in the HFD group. After ischemia and reperfusion, the HFD animals showed worse neurological function compared to the CD group. There was no difference between the sham groups. Conclusion and Translational Impact: These results indicate that the HFD started in the early life time lowers the threshold of ischemia to induce HT, exacerbates neurovascular injury and worsens the long term outcomes of focal cerebral ischemia. Given that obesity and stroke incidences are on the rise in young population, diet control should be implemented early to prevent and/or reduce ischemic brain injury.

Abstract W P243: Multiple Therapeutic Effects of Progranulin on Experimental Acute Ischemic Stroke

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Masato Kanazawa ◽  
Kunio Kawamura ◽  
Tetsuya Takahashi ◽  
Minami Miura ◽  
Yoshinori Tanaka ◽  
...  
Keyword(s):  
Brain Injury ◽  
Cerebral Ischemia ◽  
Growth Factor ◽  
Therapeutic Potential ◽  
Focal Cerebral Ischemia ◽  
Dynamic Change ◽  
Therapeutic Effects ◽  
Ischemic Brain Injury ◽  
In Vivo Models ◽  
Ischemic Brain

Introduction: In central nervous system, progranulin (PGRN), a glycoprotein growth factor, is considered to play crucial roles in maintaining physiological functions, and mutations in PGRN gene cause TAR DNA-binding protein-43 (TDP-43)-positive frontotemporal lobar degeneration. Although several studies reported that PGRN plays protective roles against ischemic brain injury, it remains unknown the precise mechanisms by which PGRN exerts protective effects on the ischemic brain injury. Methods: We determined the temporal changes of expression and localization of PGRN after ischemia as well as therapeutic effects of PGRN on ischemic brain injury using in vitro and in vivo models. Results: First, we demonstrated a dynamic change of PGRN expression in ischemic Sprague-Dawley rats, including increased levels of PGRN expression in microglia within the ischemic core, and increased level of PGRN expression in survived neurons as well as induction of PGRN expression in endothelial cells within the ischemic penumbra. Second, we demonstrated that PGRN could protect against acute focal cerebral ischemia by variety of mechanisms including via attenuation of blood-brain barrier disruption, suppression of neuroinflammation, and neuroprotection: we found that PGRN may regulate vascular permeability via vascular endothelial growth factor (VEGF), that PGRN may suppress neuroinflammation after ischemia via anti-inflammatory interleukin-10 (IL-10) in microglia, and that neuroprotective effect of PGRN may be explained in part by inhibition of cytoplasmic redistribution of TDP-43 using PGRN knock-out mice (C57Bl/6 background). Finally, we demonstrated the therapeutic potential of PGRN against acute focal cerebral ischemia using a rat autologous thromboembolic model with delayed tissue plasminogen activator (tPA) treatment. Intravenously administered recombinant PGRN reduced volumes of cerebral infarct and edema, suppressed hemorrhagic transformation, and improved motor outcome (P = 0.007, 0.038, 0.007, and 0.004, respectively). Conclusions: PGRN may be a novel therapeutic target that provides vascular protection, anti-neuroinflammation, and neuroprotection related in part to VEGF, IL-10, and TDP-43, respectively.

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