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ABSTRACT: Neural and mesenchymal stem cells have extensive tropism for malignant glioma. The tumor tropism of induced pluripotent stem (iPS) cells was tested using the Matrigel invasion assay. Mouse iPS cells showed a significant tropism to the conditioned media prepared from six rodent and human glioma cell lines and this tropism to the glioma conditioned media was partially blocked by the neutralizing antibodies for four major tumor-associated growth factors [stem cell factor (SCF), platelet-derived growth factor BB (PDGF-BB), stromal-derived factor-1α (SDF-1α) and vascular endothelial growth factor (VEGF)], which are secreted from the malignant gliomas. The tropism of the iPS cells was enhanced by the growth factors in a concentration-dependent manner from 0.1 to 100 ng/ml. The receptors for those growth factors (c-Kit, ICAM-1, CXCR4 and VEGFR2), measured by reverse transcriptase-polymerase chain reaction, were highly up-regulated in the mouse iPS cells compared to the mouse fibroblasts. The results showed that the specific growth factors secreted from the gliomas strongly attracted the iPS cells. Therefore, gene therapies using iPS cells as vectors to deliver anti-tumor agents are novel strategies for the treatment of malignant gliomas that deeply infiltrate the brain.
Oncology letters 03/2011; 2(2):283-288. · 0.11 Impact Factor
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ABSTRACT: We examined reactive oxygen species (ROS) generation on cerebral ischemia/reperfusion by intravital fluorescence imaging.
In anesthetized adult rats, a fluorescent dye (5 microL), MitoSOX (5 micromol/L) for superoxide radical (.O2-), and hydroxyphenyl fluorescein (20 micromol/L) for hydroxyl radical (.OH), was injected into cortices by a pressurized bolus. Through a closed cranial window, fluorescent images were taken with a confocal microscope on 10-minute forebrain ischemia. Because hemoglobin absorbs excitation and emission lights, ischemia may affect the change in fluorescence intensity (FI) inside the brain. To examine the effects of ischemia on the FI change, fluoromicrospheres (0.2-microm diameter) were used to mimic a dye and FI was analyzed in the same manner as when using ROS indicators. Their FI increased to 129% during ischemia (n=3/mimicking each dye), and based on the results, FI of ROS indicators was corrected.
After correcting the FI of MitoSOX and hydroxyphenyl fluorescein, they showed no change during ischemia, whereas the raw data showed the increase. In the early period of reperfusion, FI significantly (n=5/each, P<.01) increased (to 183% in MitoSOX and to 189% in hydroxyphenyl fluorescein), and these increases were significant in the areas adjacent to the arteries. To test the feasibility of our imaging, edaravone (3.0 mg/kg) was used. The treatment completely scavenged .OH, but did not do so in .O2- generation.
ROS production increased in the early period of reperfusion but not during ischemia, which was location selective, being significant in the areas adjacent to the arteries. Our method was useful for investigating intracellular in situ ROS production.
Neurosurgery 07/2010; 67(1):118-27; discussion 127-8. · 2.79 Impact Factor
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ABSTRACT: To develop an effective neuroprotective strategy against ischemic injury, it is important to identify the key molecules involved in the progression of injury. Direct molecular analysis of tissue using mass spectrometry (MS) is a subject of much interest in the field of metabolomics. Most notably, imaging mass spectrometry (IMS) allows visualization of molecular distributions on the tissue surface. To understand lipid dynamics during ischemic injury, we performed IMS analysis on rat brain tissue sections with focal cerebral ischemia. Sprague-Dawley rats were sacrificed at 24 h after middle cerebral artery occlusion, and brain sections were prepared. IMS analyses were conducted using matrix-assisted laser desorption/ionization time-of-flight mass spectrometer (MALDI-TOF MS) in positive ion mode. To determine the molecular structures, the detected ions were subjected to tandem MS. The intensity counts of the ion signals of m/z 798.5 and m/z 760.5 that are revealed to be a phosphatidylcholine, PC (16:0/18:1) are reduced in the area of focal cerebral ischemia as compared to the normal cerebral area. In contrast, the signal of m/z 496.3, identified as a lyso-phosphatidylcholine, LPC (16:0), was clearly increased in the area of focal cerebral ischemia. In IMS analyses, changes of PC (16:0/18:1) and LPC (16:0) are observed beyond the border of the injured area. Together with previous reports--that PCs are hydrolyzed by phospholipase A(2) (PLA(2)) and produce LPCs,--our present results suggest that LPC (16:0) is generated during the injury process after cerebral ischemia, presumably via PLA(2) activation, and that PC (16:0/18:1) is one of its precursor molecules.
Neuroscience 03/2010; 168(1):219-25. · 3.38 Impact Factor
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ABSTRACT: In our previous study, we successfully treated an established C6 brain tumor using neural stem cells transduced with the herpes simplex virus-thymidine kinase gene (HSVtk) and ganciclovir in the rat. In the present study, we investigated the use of mesenchymal stem cells (MSCs), obtained from adult rats and transduced with HSVtk (MSCtk cells), instead of neural stem cells because MSCs are much easier to obtain from the adult subjects. Those cells were used for in vitro co-culture study and in vivo co-implantation study with C6 rat glioma cells to examine bystander tumoricidal effect, which revealed a sufficient bystander effect and only 1/32 MSCtk cells were needed for complete tumor eradication. In vitro bystander effect was also observed in a real-time fashion using a culture microscope and it was shown that only tumor cells that had contact with MSCtk cells died. In vivo treatment study of an established C6 brain tumor with an intratumoral injection of MSCtk cells followed by systemic ganciclovir administration demonstrated a significant reduction of the tumor size and a significant survival prolongation. The treatment strategy using MSCtk and ganciclovir (MSCtk therapy) is more feasible and practical for clinical application than the method using neural stem cells.
International Journal of Oncology 12/2009; 35(6):1265-70. · 2.40 Impact Factor
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ABSTRACT: The neuroprotective effects and mechanism of action of GIF-0173, a Delta12-prostaglandin J analogue, were investigated in the early phase of cerebral ischemia. GIF-0173 was administered intravenously immediately following middle cerebral artery occlusion (MCAO) in photochemically induced thrombosis model of rat. Neurological scores and infarct sizes were examined at 24 h after MCAO. Cerebral blood flow (CBF) was monitored by laser-Doppler flowmetry for 1 h after MCAO. In cultured cortical neurons obtained from 1-day-old rats, the effects of GIF-0173 on the excitotoxicity induced by glutamate were examined. Morphological changes, neuronal death, and changes in intracellular calcium concentration ([Ca(2+)](i)) were also examined. GIF-0173 improved neurological scores and reduced the infarct size in a dose-dependent manner following MCAO. But GIF-0173 did not improve CBF after MCAO. GIF-0173 also prevented glutamate-induced neuronal death and acute cellular swelling in primary cultures in a dose-dependent manner, indicating that it inhibited neuronal necrosis. GIF-0173 dose-dependently suppressed the glutamate-induced increase in [Ca(2+)](i), but could not inhibit NMDA-induced calcium influx. The effects of GIF-0173 against glutamate-induced [Ca(2+)](i) increase were reversed by addition of non-specific prostaglandin D (PGD(2)) receptor antagonist and were comparable to the effects of PGD(2) DP1 receptor agonist, which prevented [Ca(2+)](i) increase and neuronal death. We conclude that GIF-0173 reduces cerebral infarction and protects cultured neurons against glutamate-induced excitotoxicity by inhibiting [Ca(2+)](i) increase through DP1 receptor activation.
Experimental Neurology 08/2009; 219(2):481-91. · 4.70 Impact Factor
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ABSTRACT: Our previous study demonstrated successful treatment of an established rat brain tumor through the bystander effect by intra-tumoral injection of neural stem cells transduced with herpes simplex virus-thymidine kinase gene (NSCtk) followed by systemic ganciclovir (GCV) administration (NSCtk therapy). Since glioma has a strong tendency to infiltrate into surrounding brain tissue and that is one of the main causes of local treatment failure, we, in the present study, injected NSCtk cells at distant sites of rat brain tumors and evaluated migratory potential of NSCtk toward the tumor and anti-tumor effects of the NSCtk therapy of this experimental setting. NSCtk cells were intracranially implanted either at 2mm medial in the ipsilateral hemisphere or at the mirror point in the contralateral hemisphere to the C6 rat glioma cell implantation. Active migration of NSCtk cells toward C6 cells was observed even when NSCtk cells were implanted in the contralateral hemisphere. When GCV was systemically administered, growth of intracranial tumor was markedly inhibited and the survival was significantly prolonged through the bystander effect by NSCtk cells migrated from distant injection sites of the tumor. The results of the present study suggest that NSCtk therapy is still effective in the area far from the NSCtk injection site and, therefore, suitable for treatment of malignant gliomas that deeply infiltrate and widely disseminate in the brain.
Cancer Letters 07/2007; 251(2):220-7. · 4.24 Impact Factor
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Takayasu Suzuki,
Teruhisa Kazui, Seiji Yamamoto,
Naoki Washiyama,
Kazuhiro Ohkura,
Kentaro Ohishi,
Abul Hasan Muhammad Bashar,
Katsushi Yamashita,
Hitoshi Terada,
Kazuchika Suzuki,
Satoshi Akuzawa,
Michio Fujie
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ABSTRACT: Reactive free radical species are thought to be involved in postoperative neurologic dysfunction after antegrade selective cerebral perfusion in brains with old infarction. We assessed the brain protective effect of prophylactically administered edaravone, a free radical scavenger, for antegrade selective cerebral perfusion in brains with or without old infarction in a canine model.
A canine model of old cerebral infarction was created by injecting cylindric silicone embolus into the middle cerebral artery. Animals showing obvious neurologic deficits and surviving 4 weeks or longer were included in the model. Deep hypothermia with antegrade selective cerebral perfusion was performed in both intact (non-edaravone, group A; edaravone-treated, group B) and infarcted animals (non-edaravone, group C; edaravone-treated, group D). Serum concentrations of malondialdehyde, hexanoyl-lysine, glutamate, and venous-arterial lactate difference were measured, and central conduction time and amplitude of somatosensory evoked potentials were assessed during the operation.
Compared with the intact groups, serum concentrations of malondialdehyde and hexanoyl-lysine in group C significantly increased at the end of antegrade selective cerebral perfusion, whereas that of glutamate did so in the rewarming phase. Increases in all these biochemical parameters were suppressed in group D. In group C, the venous-arterial lactate difference was significantly greater in the rewarming phase at 28 degrees C compared with intact groups. A significant prolongation of postoperative central conduction time and decrease in neuronal activity were detected in group C, both of which recovered in group D.
Prophylactic administration of edaravone exerted a significant protective effect against postoperative neurologic dysfunction after antegrade selective cerebral perfusion in a canine model with old cerebral infarction.
The Journal of thoracic and cardiovascular surgery 04/2007; 133(3):710-6. · 3.41 Impact Factor
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Junkoh Yamamoto, Seiji Yamamoto,
Toru Hirano,
Shaoyi Li,
Masayo Koide,
Eiji Kohno,
Mitsuo Okada,
Chikanori Inenaga,
Tsutomu Tokuyama,
Naoki Yokota,
Susumu Terakawa,
Hiroki Namba
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ABSTRACT: Singlet oxygen ((1)O(2)) generated in photodynamic therapy (PDT) plays a very important role in killing tumor cells. Using a new near-IR photomultiplier tube system, we monitored the real-time production of (1)O(2) during PDT and thus investigated the relationship between the (1)O(2) production and photodynamic effects.
We did PDT in 9L gliosarcoma cells in vitro and in an experimental tumor model in vivo using 5-aminolevulinic acid and nanosecond-pulsed dye laser. During this time, we monitored (1)O(2) using this system. Moreover, based on the (1)O(2) monitoring, we set the different conditions of laser exposure and investigated whether they could affect the tumor cell death.
We could observe the temporal changes of (1)O(2) production during PDT in detail. At a low fluence rate the (1)O(2) signal gradually decreased with a low peak, whereas at a high fluence rate it decreased immediately with a high peak. Consequently, the cumulative (1)O(2) at a low fluence rate was higher, which thus induced a strong photodynamic effect. The proportion of apoptosis to necrosis might therefore be dependent on the peak and duration of the (1)O(2) signal. A low fluence rate tended to induce apoptotic change, whereas a high fluence rate tended to induce necrotic change.
The results of this study suggested that the monitoring of (1)O(2) enables us to predict the photodynamic effect, allowing us to select the optimal laser conditions for each patient.
Clinical Cancer Research 01/2007; 12(23):7132-9. · 7.74 Impact Factor
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12/2006: pages 15-23;
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ABSTRACT: The significance of the extent of surgical resection on the prognosis of glioma still remains controversial even at the present
time with modern computerized surgical facilities. Low-grade tumors are in general relatively slow-growing and most tumors
remain stable for a quite long period even after partial resection with/without radiotherapy. Glioblastoma multiforme, the
most malignant histological type of gliomas, on the other hand, is highly invasive and virtually incurable even after removal
of the whole tumor mass with contrast-enhancement on MRI. The median survival of the patients with glioblastoma is generally
less than one year from the time of diagnosis and this has not significantly improved for more than three decades despite
continuous refinement of treatment strategies. Since the tumor recurrence usually occurs from the resection border where some
residual tumor cells have been left behind and distant metastasis is seldom observed in gliomas, local tumor control would
prolong the survival of those patients. Continuous efforts have been paid to develop novel strategies and some promising experimental
data have been demonstrated. Therefore, when the effective adjuvant therapies after surgical removal become available, the
extent of surgical removal would become one of the most important prognostic factors, which is already the case in medulloblastoma.
In the present paper, current standard therapies for gliomas are reviewed and newly developed methods to improve extent of
tumor removal are introduced.
12/2005: pages 22-28;
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ABSTRACT: Long-term administration of a histamine H2 receptor (H2R) antagonist (inverse agonist) induces upregulation of H2R in parietal cells, which may be relevant to the rebound hypersecretion of gastric acid that occurs after withdrawal of treatment. The mechanisms underlying this effect are unknown. We hypothesized that the H2R upregulation could be related to receptor trafficking and used H2R-green fluorescent protein (H2R-GFP) to test the hypothesis. Human H2R-GFP was generated and functionally expressed in HEK-293 cells. Binding of the H2R antagonist [3H]tiotidine was performed to quantify H2R expression, and H2R-GFP was imaged in living cells by confocal and evanescent wave microscopy. The binding affinity of [3H]tiotidine was not significantly different between H2R-GFP- and wild-type H2R-expressing HEK-293 cells, both of which had constitutive activity of adenylate cyclase. Visualization of H2R-GFP revealed that the agonist-induced H2R internalization and the antagonist-induced recycling of the internalized H2R from the recycling endosome within 2 h. Long exposure to the antagonist increased GFP fluorescence in the plasma membrane and also induced upregulation of H2R-GFP estimated by the binding assay, whereas long exposure to the agonist enhanced degradative trafficking of H2R-GFP. We examined whether the upregulation reflected an increase in receptor synthesis. Treatment with antagonist did not augment H2R mRNA, and subsequent inhibition of protein synthesis by cycloheximide had no effect on H2R upregulation. These findings suggested that upon exposure to an antagonist (inverse agonist), the equilibrium between receptor endocytosis and recycling is altered before H2R upregulation, probably via suppressing H2R degradation.
AJP Gastrointestinal and Liver Physiology 12/2005; 289(5):G880-9. · 3.43 Impact Factor
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Junkoh Yamamoto,
Toru Hirano,
Shaoyi Li,
Masayo Koide,
Eiji Kohno,
Chikanori Inenaga,
Tsutomu Tokuyama,
Naoki Yokota, Seiji Yamamoto,
Susumu Terakawa,
Hiroki Namba
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ABSTRACT: We investigated the feasibility of a novel photosensitizer, ATX-S10.Na (II), in photodynamic therapy (PDT) for glioma. First, PDT was performed in various brain tumor cell lines in vitro. Cytotoxicity depended upon both drug concentration and laser energy and the 50% inhibitory concentration ranged from 3.5 to 20 microg/ml. Next, PDT was performed in the subcutaneous and intracranial 9L tumor models in Fischer rats using ATX-S10.Na (II) and light from a 670-nm diode laser delivered by intratumoral insertion of an optical fiber. The effect of PDT on brain tumors was evaluated using magnetic resonance imaging. Sequential changes of the ATX-S10.Na (II) concentrations were also measured quantitatively by fluorospectrometry up to 12 h after intravenous administration in rats with intracranial and subcutaneous tumors. The concentration of ATX-S10.Na (II) in the brain tumor reached a maximum at 2 h after administration and the tumor/normal brain concentration ratio was as high as 131 at 8 h. Intratumoral PDT for intracranial tumors irradiated at this timing showed an obvious anti-tumor effect without severe side effects. The present study demonstrated the highly selective accumulation of ATX-S10.Na (II) in tumor tissue and its potent photodynamic effect in an experimental malignant glioma model.
International Journal of Oncology 12/2005; 27(5):1207-13. · 2.40 Impact Factor
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ABSTRACT: Phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) is a minor component of the lipid bilayer but plays an important role in various cellular functions, including exocytosis and endocytosis. Recently, PI(4,5)P2 was shown to form microdomains in the plasma membrane. In this study, we investigated the relationship between the spatial organization of PI(4,5)P2 microdomains and exocytotic machineries in clonal rat pheochromocytoma PC12 cells. Both PI(4,5)P2 and syntaxin, a soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein essential for exocytosis, exhibited punctate clusters in isolated plasma membranes. The number of PI(4,5)P2 microdomains colocalizing with syntaxin clusters and large dense core vesicles (LDCVs) was decreased after catecholamine release. Alternatively, the expression of type I phosphatidylinositol-4-phosphate 5-kinase (PIP5KI) increased the number of PI(4,5)P2 microdomains at syntaxin clusters with docked LDCVs and enhanced exocytotic activity, possibly by increasing the number of release sites. About half of the PI(4,5)P2 microdomains were not colocalized with Thy-1, a specific marker of lipid rafts, and the colocalization of transfected PIP5KI with syntaxin clusters was observed. These results suggest that the formation of PI(4,5)P2 microdomains at syntaxin clusters with docked LDCVs is essential for Ca2+-dependent exocytosis.
Journal of Biological Chemistry 05/2005; 280(17):17346-52. · 4.77 Impact Factor
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ABSTRACT: Cigarette smoking is a significant risk factor in the incidence of cerebrovascular disorders. Among the many compounds in cigarette smoke, nicotine is considered to most significantly affect cerebral arterial tone. The purpose of this study is to investigate precise pharmacological effects of nicotine on the regulation of cerebral arterial tone. To mimic smoking, a low concentration of nicotine (10(-6) mol/L), which is equivalent to the serum level of habitual smokers, was treated for 1 hour in an isometric tension study and for 24 hours in a study using cultured vascular endothelial cells (VECs). Using the canine basilar artery, the effect of nicotine on uridine 5'-triphosphate (UTP)-induced vasoconstriction was examined in the isometric tension study. Protein kinase C (PKC) activity in the canine basilar artery was measured by enzyme immunoassay. Endothelial function was assessed by endothelium-dependent vasodilatation and endogenous nitric oxide (NO) synthesis in VECs using a fluorescent indicator, diaminofluorescein-FM diacetate (DAF-FM/DA). Nicotine significantly enhanced UTP-induced contraction and PKC activity in the artery, and attenuated endothelium-dependent vasodilatation and NO synthesis in VECs. Because PKC activity was increased by de-endothelialization itself, endothelial dysfunction by nicotine enhances PKC activity. Because PKC was further activated by nicotine even in the de-endothelialized artery, nicotine directly affects PKC activities in smooth muscle. These results indicate that nicotine potentiates contractile response through direct and indirect PKC activation in the canine basilar artery.
Journal of Cerebral Blood Flow & Metabolism 04/2005; 25(3):292-301. · 5.01 Impact Factor
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ABSTRACT: We sought to examine the influence on the brain, with or without old infarction, of pH management during antegrade selective cerebral perfusion in a canine model.
A cerebral infarct canine model was created by injecting a cylindrical silicone embolus. Dogs that had obvious neurologic deficits and had survived for 4 weeks or more were included in the model. Deep hypothermia with antegrade selective cerebral perfusion was performed in intact mongrel dogs (alpha-stat: group A, n = 6; pH-stat: group B, n = 6) and mongrel dogs with infarctions (alpha-stat: group C, n = 6; pH-stat: group D, n = 6). Maxillary vein saturation of oxygen, venous-arterial lactate difference, and serum concentrations of malondialdehyde and glutamate were measured and central conduction times and amplitude in somatosensory evoked potentials were assessed during the operation.
During the experimental procedure, the maxillary vein saturation of oxygen was significantly less (P <.05), whereas the venous-arterial lactate difference was significantly greater (P <.05) in the cooling phase to 28 degrees C in group C than in the other groups. The pH-stat group showed significantly greater arterial Paco(2) and lower pH than the alpha-stat group during the period between the cooling to 28 degrees C and the rewarming to 28 degrees C (P <.05). Other intraoperative parameters did not show any difference among the groups. In group C the serum concentrations of malondialdehyde and glutamate significantly increased, as did the central conduction time, whereas in both groups C and D the amplitude ratio decreased significantly.
This experiment suggests that pH-stat management during antegrade selective cerebral perfusion provides more effective protection for a brain with old infarction than alpha-stat management.
Journal of Thoracic and Cardiovascular Surgery 09/2004; 128(3):378-85. · 3.41 Impact Factor
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ABSTRACT: Recently, it has been reported that Na+/H+ exchanger (NHE) inhibitors demonstrated protective effects on ischemia/reperfusion brain injury in animal models. However, the mechanisms by which the neurons were protected against ischemic insult remain unclear. To reveal the cellular mechanism of the NHE inhibitor on the neuronal death, we examined the effects of a selective NHE inhibitor, SM-20220 (N-[aminoiminomethyl]-1-methyl-1H-indole-2-carboxamide methanesulfonate), on glutamate-induced neuronal death in rat cortical culture.
Cortical neurons were prepared from 1-day old rats, and cultured on the glass-based dishes. Glutamate-induced neuronal death was assessed by staining the cells with propidium iodide. Morphological changes in the neurons were observed with a video-enhanced contrast-differential interference contrast microscope. The intracellular calcium concentration ([Ca2+]i) and the intracellular pH (pHi) were measured by fluorescence imaging with a confocal laser microscope using fluo-3/acetoxymethylester (AM) and 2', 7'-bis-2-carboxy-ethyl-5(6)-carboxyfluorescein (BCECF)/AM as a fluorescent dye, respectively.
SM-20220 (0.3 to 30 nmol/L) dose-dependently attenuated glutamate (300 micromol/L)-induced neuronal death over a period of 6 hours, and inhibited the acute cellular swelling following glutamate (500 micromol/L) exposure. Dual peaks of [Ca2+]i rise were observed at 5 and 12 minutes after glutamate (500 micromol/L) exposure, followed by a persistent rise. SM-20220 suppressed the persistent [Ca2+]i increase. SM-20220 inhibited intracellular acidification following glutamate (500 micromol/L) exposure. All of the events induced by glutamate were also inhibited by the N-methyl-d-aspartate receptor antagonist, MK-801, indicating the death process was excitotoxicity.
NHE inhibitor is neuroprotective through inhibition of both persistent [Ca2+]i increase and acidification in excitotoxicity.
Stroke 02/2004; 35(1):185-90. · 5.73 Impact Factor
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ABSTRACT: We sought to determine whether chronic vasospasm following subarachnoid hemorrhage (SAH) would abolish the cerebral blood flow (CBF) autoregulation in anesthetized Sprague–Dawley rats. SAH was induced by intracisternal injection of autologous blood; in control animals saline was injected instead. CBF was measured 48 h after SAH, that is during chronic vasospasm, by laser-Doppler flowmetry over the frontal cortex under condition of hypertension (SAH, n=6; control, n=8) or hypotension (SAH, n=6; control, n=6). Hyper- and hypotension were induced by increasing mean arterial blood pressure (MABP) stepwise from 90 to 180 mmHg with phenylephrine (0.1–10 μg/min i.v.), or by decreasing it from 90 to 40 mmHg by controlled hemorrhage. An autoregulatory index (AI) expressed as delta CBF (%) per 10 mmHg increase or decrease in MABP was employed to analyze CBF response. CBF remained constant (−7<AI<7) at MABPs ranging from 60 to 130 mmHg in the control group and from 70 to 140 mmHg in the SAH group, showing CBF autoregulation. In the SAH group, that is, the upper and the lower limits of autoregulatory range were increased by 10 mmHg (p<0.05). SAH did not increase intracranial pressure significantly (control 9.2±0.67 vs. SAH 10.0±1.05 mmHg, n=5) 48 h after SAH was induced. These results indicate that, during chronic vasospasm, SAH does not abolish the autoregulation process but raises its lower and upper blood pressure limits. The capacity of spastic cerebral arteries to dilate in case of hypotension decreased, while their tolerance to hypertension increased.
Brain Research 02/1998; · 2.73 Impact Factor
