scholarly journals Defective Neuropeptide Processing and Ischemic Brain Injury: A Study on Proprotein Convertase 2 and its Substrate Neuropeptide in Ischemic Brains

2009 ◽  
Vol 29 (4) ◽  
pp. 698-706 ◽  
Author(s):  
Shuqin Zhan ◽  
Hongbo Zhao ◽  
Aaron J White ◽  
Manabu Minami ◽  
Giuseppe Pignataro ◽  
...  
Keyword(s):  
Brain Injury ◽  
Brain Ischemia ◽  
Focal Cerebral Ischemia ◽  
Protein Biosynthesis ◽  
Mrna Level ◽  
Proteolytic Processing ◽  
Ischemic Brain Injury ◽  
Proprotein Convertase ◽  
Early Reperfusion ◽  
Ischemic Brain

Using a focal cerebral ischemia model in rats, brain ischemia-induced changes in expression levels of mRNA and protein, and activities of proprotein convertase 2 (PC2) in the cortex were examined. In situ hybridization analyses revealed a transient upregulation of the mRNA level for PC2 at an early reperfusion hour, at which the level of PC2 protein was also high as determined by immunocytochemistry and western blotting. When enzymatic activities of PC2 were analyzed using a synthetic substrate, a significant decrease was observed at early reperfusion hours at which levels of PC2 protein were still high. Also decreased at these reperfusion hours were tissue levels of dynorphin-A(1-8) (DYN-A(1-8)), a PC2 substrate, as determined by radioimmunoassay. Further examination of PC2 protein biosynthesis by metabolic labeling in cultured neuronal cells showed that in ischemic cells, the proteolytic processing of PC2 was greatly attenuated. Finally, in mice, an intracerebroventricular administration of synthetic DYN-A(1-8) significantly reduced the extent of ischemic brain injury. In mice those lack an active PC2, exacerbated brain injury was observed after an otherwise non-lethal focal ischemia. We conclude that brain ischemia attenuates PC2 and PC2-mediated neuropeptide processing. This attenuation may play a role in the pathology of ischemic brain injury.

scholarly journals AMP-Dependent Hypothermia Affords Protection from Ischemic Brain Injury

2012 ◽  
Vol 33 (2) ◽  
pp. 171-174 ◽  
Author(s):  
Mirko Muzzi ◽  
Francesco Blasi ◽  
Alberto Chiarugi
Keyword(s):  
Brain Injury ◽  
Brain Ischemia ◽  
Adenosine Monophosphate ◽  
Artery Occlusion ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Stroke Treatment ◽  
Adenosine A1 ◽  
A1 Receptor ◽  
Cerebral Artery Occlusion

In light of the relevance of therapeutic hypothermia to stroke treatment, we investigated whether 5′-adenosine monophosphate (AMP)-dependent cooling affords protection from ischemic brain injury. We show that hypothermia by AMP is because of adenosine A1 receptor (A1R) activation and is not invariantly associated with hypotension. Inhibition of ecto-5′-nucleotidase-dependent constitutive degradation of brain extracellular AMP by methylene-ADP (AMPCP) also suffices to prompt A1R-dependent hypothermia without hypotension. Both intraischemic and postischemic hypothermia by AMP or AMPCP reduce infarct volumes and mortality of mice subjected to transient middle cerebral artery occlusion. Data disclose that AMP-dependent hypothermia is of therapeutic relevance to treatment of brain ischemia.

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 Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity

2016 ◽  
Vol 114 (3) ◽  
pp. E396-E405 ◽  
Author(s):  
Minshu Li ◽  
Zhiguo Li ◽  
Yang Yao ◽  
Wei-Na Jin ◽  
Kristofer Wood ◽  
...  
Keyword(s):  
Brain Injury ◽  
Nk Cells ◽  
Brain Ischemia ◽  
Postmortem Brain ◽  
Cell Contact ◽  
Target Cells ◽  
Cell Mediated Immunity ◽  
Ischemic Brain Injury ◽  
Ischemic Brain ◽  
Interleukin 15

Astrocytes are believed to bridge interactions between infiltrating lymphocytes and neurons during brain ischemia, but the mechanisms for this action are poorly understood. Here we found that interleukin-15 (IL-15) is dramatically up-regulated in astrocytes of postmortem brain tissues from patients with ischemic stroke and in a mouse model of transient focal brain ischemia. We generated a glial fibrillary acidic protein (GFAP) promoter-controlled IL-15–expressing transgenic mouse (GFAP–IL-15tg) line and found enlarged brain infarcts, exacerbated neurodeficits after the induction of brain ischemia. In addition, knockdown of IL-15 in astrocytes attenuated ischemic brain injury. Interestingly, the accumulation of CD8+ T and natural killer (NK) cells was augmented in these GFAP–IL-15tg mice after brain ischemia. Of note, depletion of CD8+ T or NK cells attenuated ischemic brain injury in GFAP–IL-15tg mice. Furthermore, knockdown of the IL-15 receptor α or blockade of cell-to-cell contact diminished the activation and effector function of CD8+ T and NK cells in GFAP–IL-15tg mice, suggesting that astrocytic IL-15 is delivered in trans to target cells. Collectively, these findings indicate that astrocytic IL-15 could aggravate postischemic brain damage via propagation of CD8+ T and NK cell-mediated immunity.

scholarly journals Effect of 3-Aminobenzamide on the Ultrastructure of Astrocytes and Microvessels After Focal Cerebral Ischemia in Rats

Dose-Response ◽  
2020 ◽  
Vol 18 (1) ◽  
pp. 155932581990124 ◽  
Author(s):  
Jinqiao Wang ◽  
Chunyan Ma ◽  
Jing Zhu ◽  
Gaofeng Rao ◽  
Hongjuan Li
Keyword(s):  
Brain Injury ◽  
Focal Cerebral Ischemia ◽  
Ischemia Reperfusion ◽  
Parp Inhibition ◽  
Ultrastructural Changes ◽  
Critical Event ◽  
Ischemic Brain Injury ◽  
Sprague Dawley ◽  
Ischemic Brain ◽  
Perivascular Edema

The disruption of blood–brain barrier (BBB) is a critical event in the formation of brain edema during early phases of ischemic brain injury. Poly(ADP-ribose) polymerase (PARP) activation, which contributes to BBB damage, has been reported in ischemia–reperfusion and traumatic brain injury. Here, we investigated the effect of 3-aminobenzamide (3-AB), a PARP-1 inhibitor, on the ultrastructure of BBB. Male Sprague Dawley rats were suffered from 90 minutes of middle cerebral artery occlusion, followed by 4.5 hours or 22.5 hours of reperfusion (R). The vehicle or 3-AB (10 mg/kg) was administered intraperitoneally (ip) 60 minutes after lacking of blood. Tissue Evans Blue (EB) levels, ultrastructures of astrocytes and microvessels, and areas of perivascular edema were examined in penumbra and core, at I 1.5 hours /R 4.5 hours and I 1.5 hours /R 22.5 hours, respectively. The severity of ultrastructural changes was graded with a scoring system in each group. We showed that 3-AB treatment significantly decreased tissue EB levels and ultrastructural scores, attenuated damages in astrocytes and microvessels, and reduced areas of perivascular edema. In conclusion, PARP inhibition may provide a novel therapeutic approach to ischemic brain injury.

scholarly journals Progesterone Administration during Reperfusion, but not Preischemia Alone, Reduces Injury in Ovariectomized Rats

2002 ◽  
Vol 22 (10) ◽  
pp. 1181-1188 ◽  
Author(s):  
Stephanie J. Murphy ◽  
Marguerite T. Littleton-Kearney ◽  
Patricia D. Hurn
Keyword(s):  
Brain Injury ◽  
Artery Occlusion ◽  
Ovariectomized Rats ◽  
Ischemic Brain Injury ◽  
Regional Cerebral Blood ◽  
Triphenyltetrazolium Chloride ◽  
Caudate Putamen ◽  
Early Reperfusion ◽  
Ischemic Brain ◽  
Cerebral Artery Occlusion

Although progesterone is neuroprotective in traumatic brain injury, its efficacy in stroke is unclear. The authors determined whether there are infarction differences after middle cerebral artery occlusion (MCAO) in ovariectomized rats treated acutely with progesterone before MCAO or both pre- and postischemia. Rats received vehicle, 5 (P5), 10 (P10), or 20 (P20) mg/kg progesterone intraperitoneally 30 minutes before MCAO. In another cohort, animals received vehicle or 5 (P5R) mg/kg progesterone intraperitoneally 30 minutes before MCAO, at reperfusion initiation, and at 6-hour reperfusion. Animals underwent 2-hour MCAO by the intraluminal filament technique, followed by 22-hour reperfusion. Cortical (CTX) and caudate-putamen (CP) infarctions were determined by 2,3,5-triphenyltetrazolium chloride staining and digital image analysis. End-ischemic and early reperfusion regional cerebral blood flow (CBF) was measured by [14C]-iodoantipyrine quantitative autoradiography in vehicle- or progesterone (5 mg/kg)-treated rats. Cortical infarction (% contralateral CTX) was 31 ± 30% (vehicle), 39 ± 23% (P5), 41 ± 14% (P10), and 28 ± 20% (P20). Caudate-putamen infarction (% contralateral CP) was 45 ± 37% (vehicle), 62 ± 34% (P5), 75 ± 17% (P10), and 52 ± 30% (P20). In vehicle and P5R groups, CTX infarction was 37 ± 20% and *20 ± 17%, respectively (* P < 0.05 from vehicle). In vehicle and P5R groups, CP infarction was 63 ± 26% and 43 ± 29%, respectively. End-ischemic regional CBF and CBF recovery during initial reperfusion was unaffected by progesterone treatment. These data suggest that progesterone administration both before MCAO and during reperfusion decreases ischemic brain injury.

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.

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