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At least 1,711 records · Page 95Linked to original sources
PubMed2006

Caspase-dependent cell death involved in brain damage after acute subdural hematoma in rats.

Traumatic brain injury is associated with acute subdural hematoma (ASDH) that worsens outcome. Although early removal of blood can reduce mortality, patients still die or remain disabled after surgery and additional treatments are needed. The blood mass and extravasated blood induce pathomechanisms such as high intracranial pressure (ICP), ischemia, apoptosis and inflammation which lead to acute as well as delayed cell death. Only little is known about the basis of delayed cell death in this type of injury. Thus, the purpose of the study was to investigate to which extent caspase-dependent intracellular processes are involved in the lesion development after ASDH in rats. A volume of 300microL blood was infused into the subdural space under monitoring of ICP and tissue oxygen concentration. To asses delayed cell death mechanisms, DNA fragmentation was measured 1, 2, 4 and 7 days after ASDH by TUNEL staining, and the effect of the pan-caspase inhibitor zVADfmk on lesion volume was assessed 7 days post-ASDH. A peak of TUNEL-positive cells was found in the injured cortex at day 2 after blood infusion (53.4+/-11.6 cells/mm(2)). zVADfmk (160ng), applied by intracerebroventricular injection before ASDH, reduced lesion volume significantly by more than 50% (vehicle: 23.79+/-7.62mm(3); zVADfmk: 9.06+/-4.08). The data show for the first time that apoptotic processes are evident following ASDH and that caspase-dependent mechanisms play a crucial role in the lesion development caused by the blood effect on brain tissue.

Amino Acid Chloromethyl Ketones↗
PubMed2006

Catalpol modulates the expressions of Bcl-2 and Bax and attenuates apoptosis in gerbils after ischemic injury.

Our previous study described the neuroprotective effects of catalpol in gerbil ischemic model, in which catalpol was shown to prevent hippocampal neurons from death and ameliorate the cognitive ability of the animals. In the study, we focused on investigating the neuroprotective mechanism of catalpol. Animals were randomly assigned three groups as sham-operated, ischemia-treated with saline and ischemia-treated with catalpol. Transient global ischemia was produced by a 5 min occlusion of the bilateral common carotid arteries. Catalpol was intraperitoneally injected at the dose of 5 mg/kg immediately after reperfusion and repeatedly at 12, 24, 48 and 72 h. Histology as well as immunohistochemistry and TUNEL (the terminal deoxynucleotidyl transferase-mediated UTP nick end label) analysis were performed on serial slices through the dorsal hippocampus after gerbils were sacrificed. The results showed that 5 min transient global ischemia followed by 4 days reperfusion caused significant increases in TUNEL-positive and Bax-positive cells in hippocampal CA1 subfield. Catalpol not only significantly reduced TUNEL-positive and Bax-positive cells but also significantly increased Bcl-2-positive cells. All these suggested that catalpol could effectively inhibit apoptosis by modulating the expressions of Bcl-2 and Bax genes.

Animals↗
PubMed2005

Non-invasive quantification of lactate by proton MR spectroscopy and its clinical applications.

Lactate is an important metabolite in clinical cases indicating the status of metabolic impairment. We applied a clinically relevant simple method for lactate quantification using magnetic resonance spectroscopy (MRS). We used two long in-phase echo time (TE=272,544 ms) to calculate T2 relaxation time and the absolute concentration of lactate. This method was optimized using phantom study and applied to clinical cases. This technique does not require complicated processing and could be applied in daily clinical practice. Moreover, this technique enables lactate quantification in cases (e.g. tumor) where lipid peak is overlapped with the lactate peak at short echo times.

Adult↗
PubMed2004

Minocycline worsens hypoxic-ischemic brain injury in a neonatal mouse model.

Hypoxic-ischemic encephalopathy (HIE) is a leading cause of mortality and morbidity during the perinatal period, and currently no therapeutic drug is available. Minocycline, an antibiotic, has recently been shown to have neuroprotective effects distinct from its antimicrobial effect in several neurological disorders including ischemic brain injury. We examined the effect of minocycline on neonatal hypoxic-ischemic brain injury by using histologic scoring in both mouse and rat models. Mouse (C57Bl/6) and rat (SD) pups were exposed to a unilateral hypoxic-ischemic insult at 8 and 7 days of age, respectively. Minocycline hydrochloride was administered according to protocols that were reported to provide neuroprotection in adult or neonatal rats. Seven days after the insult, we examined brain injury in Nissl stained sections. Although minocycline ameliorated brain injury in the developing rat, it increased injury in the developing mouse. This detrimental effect in the mouse was consistent across different regions (cortex, striatum, and thalamus), with both single and multiple injection protocols and with both moderate and high-dose treatment (P < 0.05). The mechanism of the contrasting effects in mouse and rat is not clear and remains to be elucidated. Minocycline has been used as an antibiotic in the clinical setting for decades; therefore, it may be considered for use in infants with hypoxic-ischemic brain damage, based on prior reports of neuroprotection in the rat. However, it is important to examine this drug carefully before clinical use in human infants, taking our data in the mouse model into consideration.

Analysis of Variance↗
PubMed2005

Catalytically inactive heme oxygenase-2 mutant is cytoprotective.

Heme oxygenase (HO) catalyzes the rate-limiting step in heme degradation, producing iron, carbon monoxide, and bilirubin/biliverdin. HO consists of two isozymes: HO-1, which is an oxidative stress-response protein, and HO-2, which is constitutively expressed. HO-2 accounts for most HO activity within the nervous system. Its posttranslational modifications and/or interactions with other proteins make HO-2 a unique regulator of cellular homeostasis. Our previous results revealed that brain infarct volume was enlarged in HO-2 knockout mice. A similar neuroprotective role of HO-2 was shown using primary cortical neurons. To better understand the neuroprotective mechanism of HO-2, we used a catalytically inactive mutant, HO-2H45A, and investigated its cellular effects in response to hemin and hydrogen peroxide-induced cytotoxicity. We observed that HO-2WT overexpression in the HEK293 cell lines became less sensitive to hemin, whereas the inactive mutant HO-2H45A was more sensitive to hemin as compared to control. Interestingly, HO-2WT- and HO-2H45A-overexpressing cells were both protected against H2O2-induced oxidative stress and had less oxidatively modified proteins as compared to control cells. These data indicate that when HO-2 cannot metabolize the prooxidant heme, more cytotoxicity is found, whereas, interestingly, the catalytically inactive HO-2H45A was also able to protect cells against oxidative stress injury. These results suggest the multiplicity of action of the HO-2 protein itself.

Amino Acid Substitution↗
PubMed2005

Quantitative morphological study of microglial cells in the ischemic rat brain using principal component analysis.

Pathogenic stimuli induce alterations in the morphology of microglial cells. We analysed changes in lectin-stained cells on the 1st, 3rd, 7th or 14th day after transient global ischemia. Three areas differing in the degree of microglial reaction were selected for analysis: the upper cerebral cortex, the hippocampal CA1 area, and the hilus of the dentate gyrus. Nine morphological parameters, including fractal dimension, lacunarity, self-similarity range, solidity, convexity and form factor were determined. Then the resultant data were processed using principal component analysis (PCA). We found that the two first principal components together explained more than 73% of the observed variability, and may be sufficient both to describe the morphological diversity of the cells, and to determine the dynamics and direction of the changes. In both hippocampal areas, the transformation to hypertrophied and phagocytic cells was observed, but changes in the hilus were faster than in the CA1. In contrast, in the cortex, a microglial reaction was characterised by an increase in the complexity of processes. The results presented show that the quantitative morphological analysis can be an effective tool in research on the reactive behaviour of microglia and, particularly, in the detection of small and early changes in the cells.

Animals↗
PubMed2006

Spatiotemporal pH dynamics following insertion of neural microelectrode arrays.

Insertion trauma is a critical issue when assessing intracortical electrophysiological and neurochemical recordings. Previous reports document a wide variety of insertion techniques with speeds ranging from 10 microm/s to 10 m/s. We hypothesize that insertion speed has an effect on tissue trauma induced by implantation of a neural probe. In order to monitor the neural interface during and after probe insertion, we have developed a silicon-substrate array with hydrous iridium oxide microelectrodes for potentiometric recording of extracellular pH (pH(e)), a measure of brain homeostasis. Microelectrode sites were sensitive to pH in the super-Nernstian range (-85.9 mV/pH unit) and selective over other analytes including ascorbic acid, Na(+), K(+), Ca(2+), and Mg(2+). Following insertion, arrays recorded either triphasic or biphasic pH(e) responses, with a greater degree of prolonged acidosis for insertions at 50 microm/s than at 0.5 mm/s or 1.0 mm/s (p<0.05). Spatiotemporal analysis of the recordings also revealed micro-scale variability in the pH(e) response along the array, even when using the same insertion technique. Implants with more intense acidosis were often associated histologically with blood along the probe tract. The potentiometric microsensor array has implications not only as a useful tool to measure extracellular pH, but also as a feedback tool for delivery of pharmacological agents to treat surgical brain trauma.

Acidosis↗
PubMed2005

Continuous regional cerebral blood flow monitoring in the neurosurgical intensive care unit.

The aim of this study was to examine the intracranial pressure (ICP) and regional cerebral blood flow (rCoBF) changes during the acute stage of severe head injury and to improve outcome by modifying treatment modalities using real-time ICP and rCoBF data. Twenty patients with moderate or severe head injury that were monitored in our neurosurgical intensive care unit were included in this study. The changes in ICP, rCoBF and the relationship of ICP/rCoBF were observed. In patients with high ICP and low rCoBF, mannitol improves the rCoBF and decreases the ICP of these patients. When low rCoBF exists, hyperventilation may lead to a rapid further decline of rCoBF, however, some hyperemic brains respond well to hyperventilation treatment. Triple-H therapy is suitable for those with low rCoBF without significantly high ICP, which is an abnormal condition considered to be caused by vasospasm.

Adolescent↗
PubMed2006

Six-month follow-up study in patients with symptomatic intracranial arterial stenosis.

Ischaemic stroke due to intracranial atherosclerosis is estimated to comprise 8-12% of all ischaemic strokes. It is known that the risk of recurrence is extremely high in patients with ischaemic stroke caused by intracranial stenosis. In the present study we aimed to evaluate the clinical and radiological findings over a 6-month follow-up period in patients with intracranial atherosclerosis. Prospective data for the ischaemic stroke patients admitted to our clinic between 2001 and 2004 were collected. The localization of stenosis/occlusion detected by magnetic resonance angiography (MRA) was recorded and patients were divided into two groups according to the presence of one or more arterial stenoses on MRA. The patients were followed up for 6 months at regular intervals and stroke recurrence and deaths were noted. Of the 47 patients, 11 had posterior circulation stenosis and 36 had anterior circulation stenosis. Thirty-three patients had only one intracranial artery stenosis, whereas 14 had more than one intracranial artery stenosis. Of the 38 patients who completed the 6-month follow-up period, 13 had recurrent stroke, and 10 died. The rate of stroke recurrence in patients with intracranial artery stenosis may be higher than in patients with stroke due to other aetiologies, and stenosis of multiple intracranial arteries increases the rate of recurrence.

Aged↗
PubMed2006

Changes in amplitude-integrated electroencephalography in neonates treated with extracorporeal membrane oxygenation: a pilot study.

Neonates (n = 20) treated with extracorporeal membrane oxygenation were evaluated with serial amplitude-integrated electroencephalography (aEEG). There was no acute change in aEEG during extracorporeal membrane oxygenation cannulation, nor were there lateralizing effects. An abnormal aEEG predicted death or moderate to severe intracranial neuropathology with sensitivity = 1.0, specificity = 0.75, positive predictive value = 0.86, and negative predictive value = 1.0.

Brain Infarction↗
PubMed2004

Antioxidant effect of MCI-186, a new Free-Radical scavenger, on ischemia-reperfusion injury in a rat hindlimb amputation model.

BACKGROUND: A newly synthesized free-radical scavenger, MCI-186 (3-methyl-1-phenyl-2-pyrazolin-5-1), was recently approved in Japan for treating acute brain infarction. The purpose of this study was to investigate whether or not MCI-186 is effective in reducing ischemia-reperfusion injury in the extremities. MATERIALS AND METHODS: Warm ischemia was sustained for 4 hours. The animals were divided into 4 groups: (1) sham group, (2) control group (saline injection), (3) MCI group (MCI-186 injection), and (4) EPC group (EPC-K1 [(l-ascorbic acid 2-[3,4-dihydro-2, 5,7,8-tetramethyl-2-(4,8,12-trimethyltridecyl)-2H-1-benzopyran-6-yl hydrogen phosphate] potassium salt], a hydroxyl-radical scavenger, injection). Wet and dry (W/D) weights of the gastrocnemius and tibialis anterior muscles, muscle contractile function, and serum levels of creatine phosphokinase (CPK), lactate dehydrogenase (LDH), glutamic oxaloacetic transminase (GOT), and mitochondrial glutamic oxaloacetic transminase (GOT-m) were measured after 24 h of reperfusion. The cytotoxic aldehydes malondialdehyde and 4-hydroxy-2-nonenal as indices of lipid peroxidation (LPO), and neutrophil-specific enzyme myeloperoxidase (MPO) as an index of neutrophil infiltration, were measured in the gastrocnemius muscle. RESULTS: Contractile functions in the MCI and EPC groups were significantly better than in the control group. In the tibialis anterior muscle, the contractile function was better in the MCI group than in the EPC group. W/D ratios and serum levels of CPK, LDH, GOT, and GOT-m were lower in the sham and MCI groups than in the control group. Levels of LPO and MPO activity were significantly lower in the MCI and EPC groups than in the control group. Histological findings demonstrated that inflammatory tissue reactions rarely occurred in the MCI group. CONCLUSION: MCI-186 is effective in preventing ischemia-reperfusion injury in extremities. MCI-186 seems to have promise as a therapeutic agent, because it prevents ischemia-reperfusion injury even in the tibialis anterior muscle, which contains fast-twitch glycolytic fibers, known to be very susceptible to ischemic insult.

Amputation, Surgical↗
PubMed2003

Venous cavernoma at 8 Tesla MRI.

Cavernous angiomas or cavernomas are vascular malformations, which may be associated with risk of bleeding episodes. We present a case report comparing high resolution 8 Tesla gradient echo (GE) imaging with routine fast spin echo (FSE) at 1.5 Tesla in a patient with venous cavernoma. A 55-year-old male with a history of hemorrhagic stroke was studied using high-resolution 8 Tesla magnetic resonance imaging (MRI) system, which revealed venous cavernoma (9 x 8.6 mm) in the left parietal region and visualized adjacent microvascular supply. Signal loss was prominent in the cavernoma region compared to surrounding brain tissue, and signal intensity declined by factor 7.3 +/- 2.4 (679 +/- 62%) on GE images at 8 Tesla. Cavernoma was not apparent on routine T(2)-weighted FSE images at 1.5 Tesla MRI. This case report indicates that GE images at 8 Tesla can be useful for evaluation of vascular pathologies and microvasculature.

Brain Infarction↗
PubMedDate not supplied

Transplantation of embryonic stem cells overexpressing Bcl-2 promotes functional recovery after transient cerebral ischemia.

The study tested the hypothesis that transplantation of embryonic stem (ES) cells into rat cortex after a severe focal ischemia would promote structural repair and functional recovery. Overexpression of the human anti-apoptotic gene bcl-2 in ES cells was tested for increasing survival and differentiation of transplanted cells and promoting functional benefits. Mouse ES cells, pretreated with retinoic acid to induce differentiation down neural lineages, were transplanted into the post-infarct brain cavity of adult rats 7 days after 2-h occlusion of the middle cerebral artery (MCA). Over 1-8 weeks after transplantation, the lesion cavity filled with ES cell-derived cells that expressed markers for neurons, astrocytes, oligodendrocytes, and endothelial cells. ES cell-derived neurons exhibited dendrite outgrowth and formed a neuropil. ES cell-transplanted animals exhibited enhanced functional recovery on neurological and behavioral tests, compared to control animals injected with adult mouse cortical cells or vehicle. Furthermore, transplantation with ES cells overexpressing Bcl-2 further increased the survival of transplanted ES cells, neuronal differentiation, and functional outcome. This study supports that ES cell transplantation and gene modification may have values for enhancing recovery after stroke.

Animals↗
PubMed2005

Induction and redistribution of XAF1, a new antagonist of XIAP in the rat brain after transient focal ischemia.

Apoptotic cell death occurs in neurons after cerebral ischemia. To investigate the molecular basis of this mechanism of cell death, we explored the expression and localization of Smac/DIABLO, a newly identified mitochondrial apoptogenic molecule, and XAF1, a recently identified antagonist of XIAP anti-caspase activity in the rat brain following focal ischemia. Transient focal cerebral ischemia was produced for 90 min in rats. We observed changes in the expression of Smac, XAF1, and XIAP during reperfusion. The expression level of Smac/DIABLO was negligible under normal conditions and was moderately increased by 6-24 h reperfusion on both immunohistochemical and Western blotting levels. In opposition to the orthodox method of Western blotting employing electrophoretic analysis and homogenization, the immunohistochemical investigations of XIAP provided spatial information. Immunohistochemical analysis showed that the subcellular localization of XIAP became more extensive within cells during reperfusion, as compared with the normal state. Under normal conditions, XIAP was localized predominantly in the cytoplasm and the perinuclear region. However, at 6, 12, 24, and 48 h post-reperfusion, XIAP exhibited a diffuse distribution, including nuclear and cytoplasmic compartments. Interestingly, the expression of XAF1 exhibited significant changes during reperfusion. XAF1 expression was increased and there was a cellular redistribution with a nuclear localization in the post-ischemic phase by 6-24 h. XAF1 expression apparently enhances neuronal susceptibility to degeneration either by suppressing the ability of XIAP to complex with caspases or by sequestering XIAP in nuclear inclusions. These finding indicate that Smac/DIABLO, XAF1, and XIAP are implicated in the pathophysiological mechanisms of reperfusion injury.

Animals↗
PubMed2005

Decreased expression and impaired function of muscarinic acetylcholine receptors in the rat hippocampus following transient forebrain ischemia.

In this study, we investigated whether transient cerebral ischemia affects the function and molecular expression of specific muscarinic cholinergic receptors. Our results show that in contrast to the GABA-B and A1 adenosine receptor systems, the ability of muscarinic receptors to attenuate evoked excitatory responses at vulnerable CA1 synapses is significantly attenuated by 18 h following reperfusion. This attenuation in efficacy was restricted to the vulnerable CA1 subfield, as no significant change in muscarinic receptor-mediated attenuation of evoked responsiveness was observed within post-ischemic dentate granule cell synapses. Expression analysis revealed that the mRNA and immunoreactive protein levels for individual types of muscarinic receptors respond differently and uniquely to transient cerebral ischemia insult. Of particular interest is the m4 subtype of receptor, whose mRNA and protein expression levels were significantly diminished within the hippocampus by 12 and 24 h following reperfusion, respectively. As the m4 muscarinic receptor localizes to presynaptic terminals within the hippocampus, a decrease in its expression could account for the impaired functional responsiveness of the muscarinic receptor system following ischemic insult. Taken together, these results demonstrate that transient forebrain ischemia leads to dynamic alterations in the gene expression, protein prevalence, and functionality of muscarinic receptors in the post-ischemic hippocampus at times preceding the degeneration of the vulnerable neurons.

Acetylcholine↗
PubMed2006

Neuroprotection with the proteasome inhibitor MLN519 in focal ischemic brain injury: relation to nuclear factor kappaB (NF-kappaB), inflammatory gene expression, and leukocyte infiltration.

The ubiquitin proteasome system (UPS) is a major cellular protein degradation pathway that involves the modulation of key proteins controlling inflammation, cell cycle regulation and gene expression. Modulation of the UPS with proteasome inhibitors has indicated efficacy in the treatment of several disease states including cancer and neuro-inflammatory disorders. In particular, a series of recent reports have evaluated the pre-clinical efficacy of the proteasome inhibitor MLN519 for the treatment of focal ischemic/reperfusion brain injury in rats. Evidence from these studies indicate that the neuroprotection provided by MLN519 is related to an anti-inflammatory effect linked to the modulation of nuclear factor kappaB (NF-kappaB) activity, attenuation of cytokine (TNF-alpha, IL-1beta, and IL-6) and cellular adhesion molecule (ICAM-1 and E-selectin) expression, and reduction of neutrophil and macrophage infiltration into the injured rat brain. It is the aim of this paper to review the experimental neuroprotection data reported using MLN519 with a focus on the molecular and cellular mechanisms of anti-inflammatory action.

Acetylcysteine↗
PubMed2005

Post-ischemic administration of diazoxide attenuates long-term microglial activation in the rat brain after permanent carotid artery occlusion.

Diazoxide is a putative mitochondrial, ATP-sensitive potassium channel opener that has been implicated in neuroprotection in cerebral ischemia. Administered as pretreatment, diazoxide can attenuate ischemia-related neuronal injury, but little is known about the potential neuroprotective properties of the drug when it is given after the onset of an ischemic insult. In a previous study, we applied diazoxide after imposing chronic cerebral hypoperfusion by means of permanent, bilateral occlusion of the common carotid arteries (2VO) in rats. We observed that ischemia-induced learning impairment assessed in the Morris water maze, and microglial activation visualized by immunocytochemistry, were prevented by diazoxide as determined at 13 weeks after 2VO. However, dimethyl sulfoxide, the organic solvent of diazoxide also prevented memory deficits, without any effect on microglial activity. Therefore, we have repeated our experiments with the use of an inorganic solvent, aqueous NaOH solution in order to clarify the effect of diazoxide independent of dimethyl sulfoxide. The present results demonstrated that diazoxide alone did not improve learning performance, but it prevented microglial activation in the hippocampus 13 weeks after the onset of 2VO. These data provide evidence that post-treatment with diazoxide is not effective in impeding a long-term memory deficiency, but it can attenuate ischemia-induced microglial activation, independently of the solvent used.

Animals↗