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.

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 20-HETE synthesis inhibition promotes cerebral protection after intracerebral hemorrhage without inhibiting angiogenesis

2018 ◽  
Vol 39 (8) ◽  
pp. 1531-1543 ◽  
Author(s):  
Xiaoning Han ◽  
Xiaochun Zhao ◽  
Xi Lan ◽  
Qian Li ◽  
Yufeng Gao ◽  
...  
Keyword(s):  
Intracerebral Hemorrhage ◽  
Protective Effect ◽  
Brain Damage ◽  
Neuronal Death ◽  
Hippocampal Slices ◽  
Brain Lesion ◽  
Arachidonic Acid Metabolite ◽  
Lesion Volume ◽  
Synthesis Inhibitor ◽  
Neurologic Deficits

20-HETE, an arachidonic acid metabolite synthesized by cytochrome P450 4A, plays an important role in acute brain damage from ischemic stroke or subarachnoid hemorrhage. We tested the hypothesis that 20-HETE inhibition has a protective effect after intracerebral hemorrhage (ICH) and then investigated its effect on angiogenesis. We exposed hippocampal slice cultures to hemoglobin and induced ICH in mouse brains by intrastriatal collagenase injection to investigate the protective effect of 20-HETE synthesis inhibitor N-hydroxy-N′-(4- n-butyl-2-methylphenyl)-formamidine (HET0016). Hemoglobin-induced neuronal death was assessed by propidium iodide after 18 h in vitro. Lesion volume, neurologic deficits, cell death, reactive oxygen species (ROS), neuroinflammation, and angiogenesis were evaluated at different time points after ICH. In cultured mouse hippocampal slices, HET0016 attenuated hemoglobin-induced neuronal death and decreased levels of proinflammatory cytokines and ROS. In vivo, HET0016 reduced brain lesion volume and neurologic deficits, and decreased neuronal death, ROS production, gelatinolytic activity, and the inflammatory response at three days after ICH. However, HET0016 did not inhibit angiogenesis, as levels of CD31, VEGF, and VEGFR2 were unchanged on day 28. We conclude that 20-HETE is involved in ICH-induced brain damage. Inhibition of 20-HETE synthesis may provide a viable means to mitigate ICH injury without inhibition of angiogenesis.

scholarly journals Deferoxamine reduces intracerebral hemorrhage-induced white matter damage in aged rats

2015 ◽  
Vol 272 ◽  
pp. 128-134 ◽  
Author(s):  
Wei Ni ◽  
Masanobu Okauchi ◽  
Tetsuhiro Hatakeyama ◽  
Yuxiang Gu ◽  
Richard F. Keep ◽  
...  
Keyword(s):  
White Matter ◽  
Intracerebral Hemorrhage ◽  
Aged Rats ◽  
White Matter Damage

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.

scholarly journals Comprehensive Evaluation of White Matter Damage and Neuron Death and Whole-Transcriptome Analysis of Rats With Chronic Cerebral Hypoperfusion

2019 ◽  
Vol 13 ◽  
Author(s):  
Wenxian Li ◽  
Di Wei ◽  
Jianye Liang ◽  
Xiaomei Xie ◽  
Kangping Song ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
White Matter ◽  
Neuronal Death ◽  
Chronic Cerebral Hypoperfusion ◽  
Differentially Expressed ◽  
Cerebral Hypoperfusion ◽  
Neuron Death ◽  
White Matter Damage ◽  
Morris Water Maze Task ◽  
Whole Transcriptome

Background/AimsChronic cerebral hypoperfusion (CCH) is induced by chronic deficit of brain perfusion, contributes to a persistent or progressive cognitive dysfunction, which is characterized by diverse neuropathological manifestations. There are currently no effective medications available. White matter damage (WMD) and cortical neuron death may be caused by CCH, which are related to cognitive impairment, while the underlying molecular mechanisms remain unclear. In the study, a database of the transcriptome level was built to determine potential biomarkers in cortex of CCH.MethodsCCH was induced in male Sprague-Dawley rats by permanent occlusion of the bilateral common carotid arteries. Rats were randomly divided into three groups: Sham-operated group (n = 24), the 4th and 8th week of CCH groups (total = 56, n = 28 for each group). Cognitive function was evaluated using the Morris water maze task. WMD and neuron damage were detected using diffusion tensor imaging and histological analysis, respectively. Western blotting analysis of various markers was used to examine neuronal death. Whole-transcriptome microarray was performed to assess mRNA, circRNA, and lncRNA expression profiles at 4th and 8th weeks after CCH. Diversified bioinformatic tools were performed to analyze and predict the key biological processes and signaling pathways of differentially expressed RNAs and co-expressed potential target genes. Co-expression networks of mRNA–circRNA–miRNA and lncRNA–mRNA were constructed.ResultsCompared to the sham group, cognitive impairment, disintegration of white matter, blood-brain barrier damage and neuron death were induced by CCH. Neuron death including apoptosis and necroptosis might occur in the cortex of CCH. We constructed the regulatory networks of whole-transcriptomic including differentially expressed mRNAs, circRNAs, and lncRNAs, and related biological functions and pathways involved in neurological disease, cell death and survival, energy and metabolism, et al. Our results also indicated that Cyr61 mRNA may play a role in the CCH-related cortical neuronal death.ConclusionWMD and cortical neuronal death are worthy of attention in the pathogenesis of CCH. Additionally, the present results provide potential evidence at the whole-transcription level for CCH, offering candidate biomarkers and therapeutic targets.

scholarly journals Volume Changes After Traumatic Spinal Cord Injury in Animal Studies-A Systematic Review

2019 ◽  
Author(s):  
Mahdi Sharif-Alhoseini ◽  
Fariba Vahedi ◽  
Mahmoud Omidbeigi ◽  
Marzieh Sharifi ◽  
Zahra Hassannejad ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Animal Studies ◽  
Lesion Volume ◽  
Volume Changes ◽  
White Matter Damage ◽  
Electronic Search ◽  
Cord Injury ◽  
Over Time

Abstract- There are limited data on the lesion volume changes following spinal cord injury (SCI). In this study, a meta-analysis was performed to evaluate the volume size changes of the injured spinal cord over time among animal studies in traumatic SCI. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, we conducted a comprehensive electronic search of English literature of PubMed and EMBASE databases from 1946 to 2015 concerning the time-dependent changes in the volume of the spinal cord following mechanical traumatic SCI. A hand-search was also performed for non-interventional, non-molecular, and non-review studies. Quality appraisal, data extraction, qualitative and quantitative analyses were performed afterward. Of 11,561 articles yielded from electronic search, 49 articles were assessed for eligibility after reviewing of titles, abstracts, and references. Ultimately, 11 articles were eligible for quantitative synthesis. The ratio of lesion volume to spinal cord total volume increased over time. Avascularity appeared in spinal cord 4 hours after injury. During the first week, the spinal subarachnoid space decreased. The hemorrhagic lesion size peaked in 1 week and decreased thereafter. Significant loss of gray and white matter occurred from day 3 with a slower progression of white matter damage. Changes of lesion extent over time is critical in pathophysiologic processes after SCI. Early avascularity, rapid loss of gray matter, slow progression of white matter damage, and late cavitation are the pathophysiologic key points of SCI, which could be helpful in choosing the proper intervention on a timely basis.

scholarly journals Ambroxol Improves Neuronal Survival and Reduces White Matter Damage through Suppressing Endoplasmic Reticulum Stress in Microglia after Intracerebral Hemorrhage

2020 ◽  
Vol 2020 ◽  
pp. 1-12 ◽  
Author(s):  
Xuheng Jiang ◽  
Ji Zhang ◽  
Bojin Kou ◽  
Chao Zhang ◽  
Jun Zhong ◽  
...  
Keyword(s):  
Endoplasmic Reticulum ◽  
White Matter ◽  
Endoplasmic Reticulum Stress ◽  
Intracerebral Hemorrhage ◽  
Microglial Activation ◽  
Neuronal Survival ◽  
Public Health Problem ◽  
Additional Treatment ◽  
White Matter Damage ◽  
Overall Mortality

Intracerebral hemorrhage (ICH) has been becoming a serious public health problem. Pneumonia, occurring in 43% of all ICH patients, is a common complication heavily influencing outcome and accounting for more than 1/3 of the overall mortality in patients with ICH. Ambroxol may be an effective additional treatment for ICH patients with pneumonia. But its effect and potential mechanism on functional recovery post-ICH still remain elusive. In the present study, the results indicated that 35 mg/kg and 70 mg/kg ambroxol facilitated neuronal survival and reduced white matter fiber bundle damage due to mitigating microglial activation and reducing proinflammatory cytokine accumulation in mice with ICH. The possible mechanism might be due to suppressing endoplasmic reticulum stress involving the IRE1α/TRAF2 signaling pathway, which paves a new path for the treatment of ICH and opens a new window for the use of ambroxol in clinical practice.

1H MRSI of normal appearing white matter in multiple sclerosis

1997 ◽  
Vol 3 (4) ◽  
pp. 231-237 ◽  
Author(s):  
WD Rooney ◽  
DE Goodkin ◽  
N. Schuff ◽  
DJ Meyerhoff ◽  
D. Norman ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
White Matter ◽  
Magnetic Resonance ◽  
Proton Magnetic Resonance ◽  
Brain Lesion ◽  
Resonance Spectroscopy ◽  
Lesion Volume ◽  
Neuronal Marker ◽  
Control Subjects ◽  
Normal Appearing White Matter

The primary goal of this study was to determine if differences in proton magnetic resonance spectroscopy signals exist between normal appearing white matter (NAWM) of multiple sclerosis (MS) patients and white matter of control subjects. Water suppressed proton magnetic resonance spectroscopic imaging was used to determine the signal intensities of N-acetylated moieties (NA, predominantly N-acetylaspartate (NAA) the putative neuronal marker), creatine and phosphocreatine (Cr), and cholines (Ch) in 19 MS patients (15 relapsing-remitting and four secondary progressive) and 19 age matched control subjects. NA/Cr was significantly reduced (P < 0.00 1) in MS NAWM (1.8 ± 0.2; x ± s.d.) distant from MRI detected lesion areas compared to white matter of control subjects (2.1 ± 0.2). This reduction was due to an increase in Cr from 0.39 ± 0.04 (arbitrary units) in controls to 0.45 ± 0.05 in MS patients. There was no significant change in NA or Ch in MS NAWM compared to controls. NA/ Cr, distant from MRI lesion, was negatively correlated with total brain lesion volume as measured from T2-weighted MRI. We interpret the reduced NA/Cr in MS NAWM to indicate diffuse microscopic disease.

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