scholarly journals Iron Toxicity in Mice with Collagenase-Induced Intracerebral Hemorrhage

2010 ◽  
Vol 31 (5) ◽  
pp. 1243-1250 ◽  
Author(s):  
He Wu ◽  
Tao Wu ◽  
Xueying Xu ◽  
Jessica Wang ◽  
Jian Wang
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Neuronal Death ◽  
Neutrophil Infiltration ◽  
Iron Chelator ◽  
Iron Toxicity ◽  
Iron Accumulation ◽  
Neurologic Function ◽  
Old Mice ◽  
Intrastriatal Injection

Intracerebral hemorrhage (ICH) is a devastating form of stroke. In this study, we examined the efficacy of deferoxamine (DFX), an iron chelator, after collagenase-induced ICH in 12-month-old mice. Intracerebral hemorrhage was induced by intrastriatal injection of collagenase. Deferoxamine (200 mg/kg, intraperitoneal) or vehicle was administrated 6 hours after ICH and then every 12 hours for up to 3 days. Neurologic deficits were examined on days 1 and 3 after ICH. Mice were killed after 1 or 3 days of DFX treatment for examination of iron deposition, neuronal death, oxidative stress, microglia/astrocyte activation, neutrophil infiltration, brain injury volume, and brain edema and swelling. Collagenase-induced ICH resulted in iron overload in the perihematomal region on day 3. Systemic administration of DFX decreased iron accumulation and neuronal death, attenuated production of reactive oxygen species, and reduced microglial activation and neutrophil infiltration without affecting astrocytes. Although DFX did not reduce brain injury volume, edema, or swelling, it improved neurologic function. Results of our study indicate that iron toxicity contributes to collagenase-induced hemorrhagic brain injury and that reducing iron accumulation can reduce neuronal death and modestly improve functional outcome after ICH in mice.

scholarly journals Minocycline-Induced Attenuation of Iron Overload and Brain Injury After Experimental Intracerebral Hemorrhage

Stroke ◽  
2011 ◽  
Vol 42 (12) ◽  
pp. 3587-3593 ◽  
Author(s):  
Fan Zhao ◽  
Ya Hua ◽  
Yangdong He ◽  
Richard F. Keep ◽  
Guohua Xi
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Iron Overload ◽  
Brain Edema ◽  
Neuronal Death ◽  
Iron Chelator ◽  
Total Iron ◽  
Brain Iron

Background and Purpose— Brain iron overload plays a detrimental role in brain injury after intracerebral hemorrhage (ICH). A recent study found that minocycline acts as an iron chelator and reduces iron-induced neuronal death in vitro. The present study investigated if minocycline reduces iron overload after ICH and iron-induced brain injury in vivo. Methods— This study was divided into 4 parts: (1) rats with different sizes of ICH were euthanized 3 days later for serum total iron and brain edema determination; (2) rats had an ICH treated with minocycline or vehicle. Serum iron, brain iron, and brain iron handling proteins were measured; (3) rats had an intracaudate injection of saline, iron, iron+minocycline, or iron+macrophage/microglia inhibitory factor and were used for brain edema and neuronal death measurements; and (4) rats had an intracaudate injection of iron and were treated with minocycline. The brains were used for edema measurement. Results— After ICH, serum total iron and brain nonheme iron increased and these changes were reduced by minocycline treatment. Minocycline also reduced ICH-induced upregulation of brain iron handling proteins and neuronal death. Intracaudate injection of iron caused brain edema, blood–brain barrier leakage, and brain cell death, all of which were significantly reduced by coinjection with minocycline. Conclusions— The current study found that minocycline reduces iron overload after ICH and iron-induced brain injury. It is also well known minocycline is an inhibitor of microglial activation. Minocycline may be very useful for patients with ICH because both iron accumulation and microglia activation contribute to brain damage after ICH.

Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage

2003 ◽  
Vol 15 (4) ◽  
pp. 1-7 ◽  
Author(s):  
Takehiro Nakamura ◽  
Richard F. Keep ◽  
Ya Hua ◽  
Timothy Schallert ◽  
Julian T. Hoff ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Iron Chelator ◽  
Iron Accumulation ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Autologous Whole Blood ◽  
The Right

Object In the authors' previous studies they found that brain iron accumulation and oxidative stress contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study they investigated whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury. Methods Male Sprague–Dawley rats received an infusion of 100 μl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days thereafter. Iron distribution was examined histochemically (enhanced Perl reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Apurinic/apyrimidinic endonuclease/redox effector factor–1 (APE/Ref-1), a repair mechanism for DNA oxidative damage, was quantitated by Western blot analysis. Iron accumulation was observed in the perihematoma zone beginning 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in APE/Ref-1. Conclusions Deferoxamine and other iron chelators may be potential therapeutic agents for treating ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.

Abstract TMP80: A Lipid-soluble Iron Chelator Protects Against Intracerebral Hemorrhage In Mice

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
HE WU ◽  
Tao Wu ◽  
Mingchang Li ◽  
Jian Wang
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Neuronal Death ◽  
Ferrous Iron ◽  
Brain Lesion ◽  
Neutrophil Infiltration ◽  
Iron Chelator ◽  
Post Treatment ◽  
Lesion Volume ◽  
White Matter Damage

Background and purpose: Intracerebral hemorrhage (ICH) is a devastating form of stroke with no clinically proven treatment. Previous studies have indicated that 2,2’-dipyridyl, a lipid-soluble ferrous iron chelator, can reduce brain injury after cerebral ischemia and reduce cerebral vasospasm after subarachnoid hemorrhage. In this study, we examined the efficacy of 2,2’-dipyridyl after ICH in middle-aged mice (12 months old). Methods: ICH was modeled by intrastriatal injection of collagenase or autologous whole blood. 2,2’-Dipyridyl or vehicle was administered intraperitoneally 2 h before ICH (pretreatment) or 6 h after ICH (post-treatment) and then once daily for up to 3 days. Mice in the pretreatment group were sacrificed 1 or 3 days after ICH and examined for iron deposition, neuronal death, oxidative stress, microglial/astrocyte activation, neutrophil infiltration, and white matter damage. Mice in the post-treatment group were examined for brain lesion volume and edema on day 3 and for neurologic deficits on days 1, 3, and 28 after ICH. Results: Pretreatment with 2,2’-dipyridyl decreased iron accumulation and neuronal death, attenuated production of reactive oxygen species, reduced microglial activation without affecting astrocytes or neutrophil infiltration, and attenuated white matter damage (n=5 mice/group, all p <0.01). Post-treatment reduced brain lesion volume by 40.5%, lessened edema, and improved neurologic function (n=6-8 mice/group, all p <0.05) but did not affect body weight loss or mortality rate. Conclusions: The lipid-soluble ferrous iron chelator 2,2’-dipyridyl can reduce brain injury and improve functional recovery after ICH.

Abstract 2156: Minocycline-induced Attenuation Of Iron Overload And Brain Injury Following Experimental Intracerebral Hemorrhage

Stroke ◽  
2012 ◽  
Vol 43 (suppl_1) ◽  
Author(s):  
Fan Zhao ◽  
Ya Hua ◽  
Richard F Keep ◽  
Guohua Xi
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Iron Overload ◽  
Brain Edema ◽  
Blood Brain Barrier ◽  
Neuronal Death ◽  
Total Iron ◽  
Brain Barrier ◽  
Brain Iron ◽  
Blood Brain

Background and Purpose: Brain iron overload plays a detrimental role in brain injury after intracerebral hemorrhage (ICH). A recent study found that minocycline acts as an iron chelator and reduces iron-induced neuronal death in vitro. The present study investigated if minocycline reduces iron overload after ICH and iron-induced brain injury in vivo. Methods: This study was divided into three parts. (1) Male Sprague-Dawley rats with different sizes of ICH were euthanized 3 days later for serum total iron and brain edema determination. (2) Rats had an ICH treated with minocycline or vehicle. Rats were euthanized 1, 3 and 7 days later for serum iron, brain iron, and brain iron handling protein measurements. (3) Rats had a 50µl intracaudate injection of either saline, FeCl2, FeCl2+minocycline or FeCl2+macrophage/microglia inhibitory factor and were euthanized at one day later for measurements of brain edema, blood-brain barrier disruption and neuronal death. Results: After ICH, serum total iron and brain non-heme iron increased and these changes were reduced by minocycline treatment (e.g. serum total iron at day 3: 158±36 vs. 245±22 µg/dL in the vehicle-treated group, p<0.01). Minocycline also reduced ICH-induced upregulation of brain iron handling proteins and neuronal death. Intracaudate injection of iron caused brain edema, blood-brain barrier leakage and brain cell death, all of which were significantly reduced by co-injection with minocycline (p<0.05). Conclusions: The current study found that minocycline reduces iron overload after ICH and iron-induced brain injury. It is also well known minocycline is an inhibitor of microglial activation. Minocycline may be very useful for ICH patients because both iron accumulation and microglia activation contribute to brain damage following ICH.

scholarly journals Brain injury after intracerebral hemorrhage in spontaneously hypertensive rats

2011 ◽  
Vol 114 (6) ◽  
pp. 1805-1811 ◽  
Author(s):  
Gang Wu ◽  
Xuhui Bao ◽  
Guohua Xi ◽  
Richard F. Keep ◽  
B. Gregory Thompson ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Neuronal Death ◽  
Spontaneously Hypertensive Rats ◽  
Neurological Deficits ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Autologous Whole Blood

Object Hypertension is the main cause of spontaneous intracerebral hemorrhages (ICHs), but the effects of hypertension on ICH-induced brain injury have not been well studied. In this study, the authors examined ICH-induced brain injury in spontaneously hypertensive rats (SHRs). Methods This 2-part study was performed in 12-week-old male SHRs and Wistar Kyoto (WKY) rats. First, the rats received an intracaudate injection of 0.3 U collagenase, and hematoma sizes were determined at 24 hours. Second, rats were injected with 100 μl autologous whole blood into the right basal ganglia. Brain edema, neuronal death, ferritin expression, microglia activation, and neurological deficits were examined. Results Hematoma sizes were the same in SHR and WKY rats 24 hours after collagenase injection. The SHRs had greater neuronal death and neurological deficits after blood injection. Intracerebral hemorrhage also resulted in higher brain ferritin levels and stronger activation of microglia in SHRs. However, perihematomal brain edema was the same in the SHRs and WKY rats. Conclusions Moderate chronic hypertension resulted in more severe ICH-induced neuronal death and neurological deficits, but did not exaggerate hematoma enlargement and perihematomal brain edema in the rat ICH models.

scholarly journals PGE2-EP3 signaling exacerbates intracerebral hemorrhage outcomes in 24-mo-old mice

2016 ◽  
Vol 310 (11) ◽  
pp. H1725-H1734 ◽  
Author(s):  
Jenna L. Leclerc ◽  
Andrew S. Lampert ◽  
Matthew A. Diller ◽  
Sylvain Doré
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Functional Recovery ◽  
Fine Motor ◽  
Prostaglandin E ◽  
Receptor Subtype ◽  
Ep Receptor ◽  
Ep3 Receptor ◽  
Old Mice ◽  
Young Mice

With the population aging at an accelerated rate, the prevalence of stroke and financial burden of stroke-related health care costs are expected to continue to increase. Intracerebral hemorrhage (ICH) is a devastating stroke subtype more commonly affecting the elderly population, who display increased mortality and worse functional outcomes compared with younger patients. This study aimed to investigate the contribution of the prostaglandin E2 (PGE2) E prostanoid (EP) receptor subtype 3 in modulating anatomical outcomes and functional recovery following ICH in 24-mo-old mice. EP3 is the most abundant EP receptor in the brain and we have previously shown that signaling through the PGE2-EP3 axis exacerbates ICH outcomes in young mice. Here, we show that EP3 receptor deletion results in 17.9 ± 6.1% less ICH-induced brain injury ( P < 0.05) and improves neurological functional recovery ( P < 0.01), as identified by lower neurological deficit scores, decreased resting time, and more gross and fine motor movements. Immunohistological staining was performed to investigate possible mechanisms of EP3-mediated neurotoxicity. Identified mechanisms include reduced blood accumulation and modulation of angiogenic and astroglial responses. Using this aged cohort of mice, we have confirmed and extended our previous results in young mice demonstrating the deleterious role of the PGE2-EP3 signaling axis in modulating brain injury and functional recovery after ICH, further supporting the notion of the EP3 receptor as a putative therapeutic avenue for the treatment of ICH.

scholarly journals Treatment of secondary brain injury by perturbing postsynaptic density protein-95-NMDA receptor interaction after intracerebral hemorrhage in rats

2018 ◽  
Vol 39 (8) ◽  
pp. 1588-1601 ◽  
Author(s):  
Zhifeng Wang ◽  
Zhouqing Chen ◽  
Junjie Yang ◽  
Ziying Yang ◽  
Jia Yin ◽  
...  
Keyword(s):  
Brain Injury ◽  
Nmda Receptor ◽  
Intracerebral Hemorrhage ◽  
Neuronal Death ◽  
Postsynaptic Density ◽  
Synaptic Function ◽  
Learning Ability ◽  
Receptor Interaction ◽  
Secondary Brain Injury ◽  
Postsynaptic Density Protein

Postsynaptic density protein-95 (PSD95) plays important roles in the formation, differentiation, remodeling, and maturation of neuronal synapses. This study is to estimate the potential role of PSD95 in cognitive dysfunction and synaptic injury following intracerebral hemorrhage (ICH). The interaction between PSD95 and NMDA receptor subunit NR2B-neurotransmitter nitric oxide synthase (nNOS) could form a signal protein complex mediating excitatory signaling. Besides NR2B-nNOS, PSD95 also can bind to neurexin-1–neuroligin-1 to form a complex and participates in maintaining synaptic function. In this study, we found that there were an increase in the formation of PSD95-NR2B-nNOS complex and a decrease in the formation of neurexin-1–neuroligin-1-PSD95 complex after ICH, and this was accompanied by increased neuronal death and degeneration, and behavior dysfunction. PSD95 inhibitor Tat-NR2B9c effectively inhibited the interaction between PSD95 and NR2B-nNOS, and promoted the formation of neurexin-1–nueuroligin-1-PSD95 complex. In addition, Tat-NR2B9c treatment significantly reduced neuronal death and degeneration and matrix metalloproteinase 9 activity, alleviated inflammatory response and neurobehavioral disorders, and improved the cognitive and learning ability of ICH rats. Inhibition of the formation of PSD95-NR2B-nNOS complex can rescue secondary brain injury and behavioral cognitive impairment after ICH. PSD95 is expected to be a target for improving the prognosis of patients with ICH.

scholarly journals Albumin Reduces Oxidative Stress and Neuronal Apoptosis via the ERK/Nrf2/HO-1 Pathway after Intracerebral Hemorrhage in Rats

2021 ◽  
Vol 2021 ◽  
pp. 1-14
Author(s):  
Shuixiang Deng ◽  
Shengpeng Liu ◽  
Peng Jin ◽  
Shengjie Feng ◽  
Mi Tian ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Neuronal Death ◽  
Neuronal Apoptosis ◽  
Heme Oxygenase 1 ◽  
Related Factor ◽  
Endogenous Expression ◽  
Short And Long Term

Background. Albumin has been regarded as a potent antioxidant with free radical scavenging activities. Oxidative stress and neuronal apoptosis are responsible for its highly damaging effects on brain injury after intracerebral hemorrhage (ICH). Here, the present study investigated the neuroprotective effect of albumin against early brain injury after ICH and the potential underlying mechanisms. Methods. Adult male Sprague-Dawley rats were subjected to intrastriatal injection of autologous blood to induce ICH. Human serum albumin was given by intravenous injection 1 h after ICH. U0126, an inhibitor of extracellular signal-regulated kinase (ERK1/2), and ML385, an inhibitor of nuclear factor-E2-related factor 2 (Nrf2), were intraperitoneally administered 1 h before ICH induction. Short- and long-term neurobehavioral tests, western blotting, immunofluorescence staining, oxidative stress evaluations, and apoptosis measurements were performed. Results. Endogenous expression of albumin (peaked at 5 days) and heme oxygenase 1 (HO-1, peaked at 24 h) was increased after ICH compared with the sham group. Albumin and HO-1 were colocalized with neurons. Compared with vehicle, albumin treatment significantly improved short- and long-term neurobehavioral deficits and reduced oxidative stress and neuronal death at 72 h after ICH. Moreover, albumin treatment significantly promoted the phosphorylation of ERK1/2; increased the expression of Nrf2, HO-1, and Bcl-2; and downregulated the expression of Romo1 and Bax. U0126 and ML385 abolished the treatment effects of albumin on behavior and protein levels after ICH. Conclusions. Albumin attenuated oxidative stress-related neuronal death may in part via the ERK/Nrf2/HO-1 signaling pathway after ICH in rats. Our study suggests that albumin may be a novel therapeutic method to ameliorate brain injury after ICH.

Deferoxamine-induced attenuation of brain edema and neurological deficits in a rat model of intracerebral hemorrhage

2004 ◽  
Vol 100 (4) ◽  
pp. 672-678 ◽  
Author(s):  
Takehiro Nakamura ◽  
Richard F. Keep ◽  
Ya Hua ◽  
Timothy Schallert ◽  
Julian T. Hoff ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Oxidative Dna Damage ◽  
Iron Accumulation ◽  
Neurological Deficits ◽  
Content Type ◽  
Autologous Whole Blood ◽  
Fine Print

Object. Previous studies undertaken by the authors have indicated that iron accumulation and oxidative stress in the brain contribute to secondary brain damage after intracerebral hemorrhage (ICH). In the present study the authors investigate whether deferoxamine, an iron chelator, can reduce ICH-induced brain injury. Methods. Male Sprague—Dawley rats each received an infusion of 100 µl of autologous whole blood into the right basal ganglia and were killed 1, 3, or 7 days later. Iron distribution was examined histochemically (enhanced Perls reaction). The effects of deferoxamine on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Immunohistochemical analysis was performed to investigate 8-hydroxyl-2′-deoxyguanosine (8-OHdG), a marker of oxidative DNA damage, and Western blot analysis was performed to measure the amount of apurinic/apyrimidinic endonuclease/redox effector factor—1 (APE/Ref-1), a repair mechanism for DNA oxidative damage. Iron accumulation was observed in the perihematomal zone from 1 day after ICH. Deferoxamine attenuated brain edema, neurological deficits, and ICH-induced changes in 8-OHdG and APE/Ref-1. Conclusions. Deferoxamine and other iron chelators may be potential therapeutic agents for ICH. They may act by reducing the oxidative stress caused by the release of iron from the hematoma.

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