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.

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.

Estrogen therapy for experimental intracerebral hemorrhage in rats

2005 ◽  
Vol 103 (1) ◽  
pp. 97-103 ◽  
Author(s):  
Takehiro Nakamura ◽  
Ya Hua ◽  
Richard F. Keep ◽  
Jung-Weon Park ◽  
Guohua Xi ◽  
...  
Keyword(s):  
Brain Injury ◽  
Intracerebral Hemorrhage ◽  
Brain Edema ◽  
Estrogen Therapy ◽  
Female Rats ◽  
Male Rats ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Autologous Whole Blood ◽  
17Β Estradiol

Object The aims of this study were to determine the following: whether there are sex differences in intracerebral hemorrhage (ICH) induced brain injury in rats, whether delayed administration of 17β-estradiol can reduce ICH-induced brain damage, and whether these effects are estrogen receptor (ER)-dependent. Methods Male and female Sprague—Dawley rats received an infusion of 100 µl autologous whole blood into the right basal ganglia. Twenty-four hours later the rats were killed. The effects of 17β-estradiol on ICH-induced brain injury were examined by measuring brain edema and neurological deficits. Both ER-α and hemeoxygenase (HO)-1 were investigated through Western blot and immunohistochemical analysis. Brain edema was significantly less severe in female compared with that in male rats. The ER antagonist ICI 182,780 exacerbated ICH-induced brain edema in female but not in male rats, indicating that ER-α activation during ICH is protective in female rats. Administration of exogenous 17β-estradiol in male, but not in female, rats significantly attenuated brain edema, neurological deficits, and ICH-induced changes in HO-1 when given 2 hours after hemorrhage. The effects of exogenous 17β-estradiol occurred through an ER-independent mechanism. Conclusions Results in this study indicate that 17β-estradiol could be a potential therapeutic agent for ICH.

scholarly journals 17β-Estradiol Attenuates Intracerebral Hemorrhage-Induced Blood–Brain Barrier Injury and Oxidative Stress Through SRC3-Mediated PI3K/Akt Signaling Pathway in a Mouse Model

ASN NEURO ◽  
2021 ◽  
Vol 13 ◽  
pp. 175909142110384
Author(s):  
Han Xiao ◽  
Jianyang Liu ◽  
Jialin He ◽  
Ziwei Lan ◽  
Mingyang Deng ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Mouse Model ◽  
Intracerebral Hemorrhage ◽  
Signaling Pathway ◽  
Brain Edema ◽  
Akt Signaling ◽  
Neurological Deficits ◽  
Akt Signaling Pathway ◽  
And Oxidative Stress

Estrogen is neuroprotective in brain injury models, and steroid receptor cofactor 3 (SRC3) mediates estrogen signaling. We aimed to investigate whether and how SRC3 is involved in the neuroprotective effects of 17ß-estradiol (E2) in a mouse model of intracerebral hemorrhage (ICH). Ovariectomized female mice were treated with E2 after autologous blood injection-induced ICH. Brain damage was assessed by neurological deficit score, brain water content, and oxidative stress levels. Blood–brain barrier (BBB) integrity was evaluated by Evan's blue extravasation and claudin-5, ZO-1, and occludin levels. SRC3 expression and PI3K/Akt signaling pathway were examined in ICH mice treated with E2. The effect of SRC3 on E2-mediated neuroprotection was determined by examining neurological outcomes in SRC3-deficient mice undergone ICH and E2 treatment. We found that E2 alleviated ICH-induced brain edema and neurological deficits, protected BBB integrity, and suppressed oxidative stress. E2 enhanced SRC3 expression and PI3K-/Akt signaling pathway. SRC3 deficiency abolished the protective effects of E2 on ICH-induced neurological deficits, brain edema, and BBB integrity. Our results suggest that E2 suppresses ICH-induced brain injury and SRC3 plays a critical role in E2-mediated neuroprotection.

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.

Role of AT1 receptors and NAD(P)H oxidase in diabetes-aggravated ischemic brain injury

2004 ◽  
Vol 286 (6) ◽  
pp. H2442-H2451 ◽  
Author(s):  
Ikuyo Kusaka ◽  
Gen Kusaka ◽  
Changman Zhou ◽  
Mami Ishikawa ◽  
Anil Nanda ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Lipid Peroxidation ◽  
Brain Injury ◽  
Cerebral Ischemia ◽  
Cerebral Infarction ◽  
Focal Cerebral Ischemia ◽  
Lipid Hydroperoxide ◽  
Neurological Deficits ◽  
Sprague Dawley

The objective of the present study was to examine the role of the angiotensin II type 1 receptor (AT1-R) in the diabetes-aggravated oxidative stress and brain injury observed in a rat model of combined diabetes and focal cerebral ischemia. Diabetes was induced by an injection of streptozotoxin (STZ; 55 mg/kg iv) at 8 wk of age. Two weeks after the induction of diabetes, some animals received continuous subcutaneous infusion of the AT1-R antagonist candesartan (0.5 mg·kg−1·day−1) for 14 days. Focal cerebral ischemia, induced by middle cerebral artery occlusion/reperfusion (MCAO), was conducted at 4 wk after STZ injection. Male Sprague-Dawley rats ( n = 189) were divided into five groups: normal control, diabetes, MCAO, diabetes + MCAO, and diabetes + MCAO + candesartan. The major observations were that 1) MCAO produced typical cerebral infarction and neurological deficits at 24 h that were accompanied by elevation of NAD(P)H oxidase gp91phox and p22phox mRNAs, and lipid hydroperoxide production in the ipsilateral hemisphere; 2) diabetes enhanced NAD(P)H oxidase gp91phox and p22phox mRNA expression, potentiated lipid peroxidation, aggravated neurological deficits, and enlarged cerebral infarction; and 3) candesartan reduced the expression of gp91phox and p22phox, decreased lipid peroxidation, lessened cerebral infarction, and improved the neurological outcome. We conclude that diabetes exaggerates the oxidative stress, NAD(P)H oxidase induction, and brain injury induced by focal cerebral ischemia. The diabetes-aggravated brain injury involves AT1-Rs. We have shown for the first time that candesartan reduces brain injury in a combined model of diabetes and cerebral ischemia.

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.

Long-term effects of experimental intracerebral hemorrhage: the role of iron

2006 ◽  
Vol 104 (2) ◽  
pp. 305-312 ◽  
Author(s):  
Ya Hua ◽  
Takehiro Nakamura ◽  
Richard F. Keep ◽  
Jimin Wu ◽  
Timothy Schallert ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Brain Atrophy ◽  
Iron Chelation ◽  
Tissue Loss ◽  
Neurological Deficits ◽  
Sprague Dawley ◽  
Long Term Effects ◽  
Autologous Whole Blood ◽  
Hemoglobin Degradation

Object Intracerebral hemorrhage (ICH) causes brain atrophy and neurological deficits. The mechanisms of brain atrophy after ICH are poorly understood, although recent evidence suggests that some ICH-induced brain injury results from the products of hemoglobin degradation, including iron. In this study the authors examine the role of iron in brain atrophy and neurological deficits following ICH. Methods Male Sprague–Dawley rats received an infusion of either 100 μl autologous whole blood or saline into the right caudate. Hematoxylin and eosin staining was used for histological examination, and iron levels and ferritin immunoreactivities were also examined. Deferoxamine was used as an iron chelator. Over the duration of the experiment, the rats underwent behavioral testing (forelimb placing, forelimb use asymmetry, and corner turn tests). Brain atrophy in the caudate with prolonged neurological deficits occurred after ICH. Although partial functional recovery occurred with time, residual neurological deficits were still detectable at 3 months postprocedure. Iron accumulation and ferritin upregulation were present in the ipsilateral caudate. Deferoxamine reduced brain atrophy and improved behavioral outcomes, and it also reduced brain ferritin immunoreactivity. Conclusions An ICH results in an accumulation of iron in the brain that is not cleared within 3 months and that contributes to brain tissue loss and neurological deficits posthemorrhage. Iron chelation may be a useful therapy for patients with ICH.

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 RNF34 overexpression exacerbates neurological deficits and brain injury in a mouse model of intracerebral hemorrhage by potentiating mitochondrial dysfunction-mediated oxidative stress

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Xin Qu ◽  
Ning Wang ◽  
Wenjin Chen ◽  
Meng Qi ◽  
Yueqiao Xue ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Brain Injury ◽  
Transgenic Mice ◽  
Intracerebral Hemorrhage ◽  
Mitochondrial Dysfunction ◽  
Neuronal Activity ◽  
Neurological Deficits ◽  
Protein Ubiquitination ◽  
Stress Levels ◽  
And Oxidative Stress

Abstract Intracerebral hemorrhage (ICH) is a common neurological condition associated with high disability and mortality. Alterations in protein ubiquitination have emerged as a key mechanism in the pathogenesis of neurological diseases. Here, we investigated the effects of the E3 ubiquitin ligase ring finger protein 34 (RNF34) on neurological deficits and brain injury in ICH mice. An ICH model was established via intracerebral injection of autologous blood into wild-type and RNF34 transgenic mice. Brain injury, neurological function, neuronal activity, and oxidative stress levels were measured, respectively. The underlying mechanisms were explored by molecular and cellular approaches. Our results showed that RNF34 overexpression in mice significantly aggravated the ICH-induced memory impairment, brain edema, infarction, hematoma volume, and loss of neuronal activity. RNF34 and oxidative stress levels gradually increased from 6 to 48 h after the ICH challenge and were positively correlated. The ICH-induced increase in intracellular ROS, superoxide anion, and mROS generation and the decrease in adenosine triphosphate production were exacerbated in RNF34 transgenic mice, but NADPH oxidase activity was unaffected. Moreover, RNF34 upregulation potentiated the ICH-induced decrease in PGC-1α, UCP2, and MnSOD expressions. RNF34 interacted with PGC-1α and targeted it for ubiquitin-dependent degradation. This study reveals that RNF34 exacerbates neurological deficits and brain injury by facilitating PGC-1α protein degradation and promoting mitochondrial dysfunction-mediated oxidative stress.

scholarly journals Autophagy after Experimental Intracerebral Hemorrhage

2007 ◽  
Vol 28 (5) ◽  
pp. 897-905 ◽  
Author(s):  
Yangdong He ◽  
Shu Wan ◽  
Ya Hua ◽  
Richard F Keep ◽  
Guohua Xi
Keyword(s):  
Cell Death ◽  
Brain Injury ◽  
Basal Ganglia ◽  
Intracerebral Hemorrhage ◽  
Cathepsin D ◽  
Cell Types ◽  
Sprague Dawley ◽  
Male Adult ◽  
Double Labeling ◽  
Autologous Whole Blood

Autophagy contributes to ischemic brain injury, but it is not clear if autophagy occurs after intracerebral hemorrhage (ICH). This study examined whether ICH-induced cell death is partly autophagic. It then examined the role of iron in inducing this form of cell death after ICH. Male, adult Sprague-Dawley rats received an infusion of autologous whole blood or ferrous iron into the right basal ganglia. Control rats (sham) had a needle insertion. The rats were killed at 1, 3, 7, or 28 days later. Some rats were treated with either deferoxamine or vehicle after ICH. Microtubule-associated protein light chain-3 (LC3), a biomarker of autophagosome, and cathepsin D, a lysosomal biomarker, were measured by Western blot analysis and immunohistochemistry. Immunofluorescent double-labeling was used to identify the cell types expressing cathepsin D. Electron microscopy was performed to examine the cellular ultrastructure changes after ICH. We found that conversion of LC3-I to LC3-II, cathepsin D expression, and vacuole formation are increased in the ipsilateral basal ganglia after ICH. Intracerebral infusion of iron also resulted in enhanced conversion of LC3-I to LC3-II and increased cathepsin D levels. Deferoxamine (an iron chelator) treatment significantly reduced the conversion of LC3-I to LC3-II and cathepsin D levels after ICH. Our results demonstrated that autophagy occurs after ICH, and iron has a key role in ICH-induced autophagy. This also suggests that iron-induced autophagy may play a role in brain injury in other diseases associated with iron overload.

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