Synergistic protection of NMDA and AMPA antagonists against ischemic neuronal damage (2): Studies on in vivo cerebral ischemia model.

We examined whether Brazilian green propolis, a widely used folk medicine, has a neuroprotective functionin vitroand/orin vivo.In vitro, propolis significantly inhibited neurotoxicity induced in neuronally differentiated PC12 cell cultures by either 24 h hydrogen peroxide (H2O2) exposure or 48 h serum deprivation. Regarding the possible underlying mechanism, propolis protected against oxidative stress (lipid peroxidation) in mouse forebrain homogenates and scavenged free radicals [induced by diphenyl-p-picrylhydrazyl (DPPH). In micein vivo, propolis [30 or 100 mg/kg; intraperitoneally administered four times (at 2 days, 1 day and 60 min before, and at 4 h after induction of focal cerebral ischemia by permanent middle cerebral artery occlusion)] reduced brain infarction at 24 h after the occlusion. Thus, a propolis-induced inhibition of oxidative stress may be partly responsible for its neuroprotective function againstin vitrocell death andin vivofocal cerebral ischemia.

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Brain serotonin depletion attenuates heatstroke-induced cerebral ischemia and cell death in rats

Journal of Applied Physiology ◽

10.1152/jappl.1996.80.2.680 ◽

1996 ◽

Vol 80 (2) ◽

pp. 680-684 ◽

Cited By ~ 27

Author(s):

T. Y. Kao ◽

M. T. Lin

Keyword(s):

Cell Death ◽

Cerebral Ischemia ◽

Survival Time ◽

Neuronal Damage ◽

Cell Damage ◽

Neuronal Cell ◽

Serotonin Release ◽

Brain Serotonin ◽

Serotonin Depletion

To explore the importance of brain serotonin (5-hydroxytryptamine) in the heatstroke-induced cerebral ischemia and neuronal injury, we evaluated the effects of heatstroke on brain serotonin release, survival time, cerebral hemodynamic changes, and neuronal cell damage in rats with or without brain serotonin depletion produced by 5,7-dihydroxytryptamine. In vivo voltammetry was used to measure changes in extracellular concentrations of serotonin in the anterior hypothalamus, striatum, and frontal cortex. After the onset of heatstroke, rats without brain serotonin depletion displayed hyperthermia, decreased mean arterial pressure, increased intracranial pressure, decreased cerebral perfusion pressure, decreased cerebral blood flow, increased cerebral serotonin release, and increased cerebral neuronal damage compared with those of normothermic control rats. However, when the cerebral serotonin system was destroyed by 5,7-dihydroxytryptamine, the heatstroke-induced arterial hypotension, intracranial hypertension, ischemic damage to the brain, and elevated cerebral serotonin release were reduced. In addition, the survival time of the heatstroke rats was prolonged after the depletion of brain serotonin. The data indicate that brain serotonin depletion attenuates heatstroke-induced cerebral ischemia and cell death in rats.

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A Novel and Potent Poly(ADP-Ribose) Polymerase-1 Inhibitor, FR247304 (5-Chloro-2-[3-(4-phenyl-3,6-dihydro-1(2H)-pyridinyl)propyl]-4(3H)-quinazolinone), Attenuates Neuronal Damage in in Vitro and in Vivo Models of Cerebral Ischemia

Journal of Pharmacology and Experimental Therapeutics ◽

10.1124/jpet.104.066944 ◽

2004 ◽

Vol 310 (2) ◽

pp. 425-436 ◽

Cited By ~ 63

Author(s):

Akinori Iwashita ◽

Nobuteru Tojo ◽

Shigeru Matsuura ◽

Syunji Yamazaki ◽

Kazunori Kamijo ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Damage ◽

In Vivo Models

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Targeting Expression of hsp70i to Discrete Neuronal Populations Using the Lmo-1 Promoter: Assessment of the Neuroprotective Effects of hsp70i In vivo and In vitro

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200108000-00010 ◽

2001 ◽

Vol 21 (8) ◽

pp. 972-981 ◽

Cited By ~ 40

Author(s):

Stephen Kelly ◽

Alison Bieneman ◽

Karen Horsburgh ◽

David Hughes ◽

Michael V. Sofroniew ◽

...

Keyword(s):

Cerebral Ischemia ◽

Transgenic Mice ◽

Caudate Nucleus ◽

Neuronal Damage ◽

Global Cerebral Ischemia ◽

Specific Gene ◽

Wild Type ◽

Neuroprotective Effects ◽

Bilateral Carotid

Transgenic technology provides a powerful means of studying gene regulation and specific gene function with complex mammalian systems. In this study, the authors exploited the specific and discrete neuronal expression pattern mediated by promoter 1 of the Lmo-1 gene to study the neuroprotective effects of the inducible form of heat shock protein 70kD (hsp70i) in primary hippocampal cultures in a mouse model of global cerebral ischemia. Targeting expression of hsp70i to hippocampal neurons protected these cells significantly from toxic levels of glutamate and oxidative stress (for example, exposure to 10 μmol/L free iron produced a 26% increase in lactate dehydrogenase release from neurons cultured from wild-type mice, but a 7% increase in neurons cultured from hsp70i transgenic mice). Bilateral carotid occlusion (25 minutes) produced significantly less neuronal damage in the caudate nucleus and posterior thalamus in hsp70i transgenic mice than in wild-type littermates (for example, 21% ± 9.3% and 12.5% ± 9.0% neuronal damage in lateral caudate nucleus of wild-type and hsp70i transgenic mice, respectively, P < 0.05). The current study highlights the utility of targeted expression of transgenes of interest in cerebral ischemia and demonstrates that expression of hsp70i alone is sufficient to mediate the protection of primary neurons from denaturing stress and that expression of human hsp70i in vivo plays crucial role in determining the fate of neurons after ischemic challenge.

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CAPN1 (Calpain1)-Mediated Impairment of Autophagic Flux Contributes to Cerebral Ischemia-Induced Neuronal Damage

Stroke ◽

10.1161/strokeaha.120.032749 ◽

2021 ◽

Author(s):

Yueyang Liu ◽

Xiaohang Che ◽

Haotian Zhang ◽

Xiaoxiao Fu ◽

Yang Yao ◽

...

Keyword(s):

Cerebral Ischemia ◽

Kinase Inhibitor ◽

Neuronal Damage ◽

Neuronal Cell ◽

In Vivo Model ◽

Autophagic Flux ◽

Autophagosome Formation

Background and Purpose: CAPN1 (calpain1)—an intracellular Ca 2+ -regulated cysteine protease—can be activated under cerebral ischemia. However, the mechanisms by which CAPN1 activation promotes cerebral ischemic injury are not defined. Methods: In the present study, we used adeno-associated virus-mediated genetic knockdown and pharmacological blockade (MDL-28170) of CAPN1 to investigate the role of CAPN1 in the regulation of the autophagy-lysosomal pathway and neuronal damage in 2 models, rat permanent middle cerebral occlusion in vivo model and oxygen-glucose–deprived primary neuron in vitro model. Results: CAPN1 was activated in the cortex of permanent middle cerebral occlusion–operated rats and oxygen-glucose deprivation–exposed neurons. Genetic and pharmacological inhibition of CAPN1 significantly attenuated ischemia-induced lysosomal membrane permeabilization and subsequent accumulation of autophagic substrates in vivo and in vitro. Moreover, inhibition of CAPN1 increased autophagosome formation by decreasing the cleavage of the autophagy regulators BECN1 (Beclin1) and ATG (autophagy-related gene) 5. Importantly, the neuron-protective effect of MDL-28170 on ischemic insult was reversed by cotreatment with either class III-PI3K (phosphatidylinositol 3-kinase) inhibitor 3-methyladenine or lysosomal inhibitor chloroquine (chloroquine), suggesting that CAPN1 activation-mediated impairment of autophagic flux is crucial for cerebral ischemia-induced neuronal damage. Conclusions: The present study demonstrates for the first time that ischemia-induced CAPN1 activation impairs lysosomal function and suppresses autophagosome formation, which contribute to the accumulation of substrates and aggravate the ischemia-induced neuronal cell damage. Our work highlights the vital role of CAPN1 in the regulation of cerebral ischemia–mediated autophagy-lysosomal pathway defects and neuronal damage.

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Niosomes of Ascorbic Acid and α-Tocopherol in the Cerebral Ischemia-Reperfusion Model in Male Rats

BioMed Research International ◽

10.1155/2014/816103 ◽

2014 ◽

Vol 2014 ◽

pp. 1-9 ◽

Cited By ~ 11

Author(s):

Jaleh Varshosaz ◽

Somayeh Taymouri ◽

Abbas Pardakhty ◽

Majid Asadi-Shekaari ◽

Abodolreza Babaee

Keyword(s):

Ascorbic Acid ◽

Cerebral Ischemia ◽

Neuronal Damage ◽

Neuroprotective Effect ◽

Ischemia Reperfusion ◽

Male Rats ◽

Size Change ◽

Neuroprotective Effects

The objective of the present study was to prepare a stableivinjectable formulation of ascorbic acid and α-tocopherol in preventing the cerebral ischemia. Different niosomal formulations were prepared by Span and Tween mixed with cholesterol. The physicochemical characteristics of niosomal formulations were evaluatedin vitro. Forin vivoevaluation, the rats were made ischemic by middle cerebral artery occlusion model for 30 min and the selected formulation was used for determining its neuroprotective effect against cerebral ischemia. Neuronal damage was evaluated by optical microscopy and transmission electron microscopy. The encapsulation efficiency of ascorbic acid was increased to more than 84% by remote loading method. The cholesterol content of the niosomes, the hydrophilicity potential of the encapsulated compounds, and the preparation method of niosomes were the main factors affecting the mean volume diameter of the prepared vesicles. High physical stability of the niosomes prepared from Span 40 and Span 60 was demonstrated due to negligible size change of vesicles during 6 months storage at 4–8°C.In vivostudies showed that ST60/Chol 35 : 35 : 30 niosomes had more neuroprotective effects against cerebral ischemic injuries in male rats than free ascorbic acid.

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Protection after Transient Focal Cerebral Ischemia by the N-Methyl-d-Aspartate Antagonist Dextrorphan is Dependent upon Plasma and Brain Levels

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1991.169 ◽

1991 ◽

Vol 11 (6) ◽

pp. 1015-1024 ◽

Cited By ~ 30

Author(s):

Gary K. Steinberg ◽

David Kunis ◽

Jamshid Saleh ◽

Robert DeLaPaz

Keyword(s):

Cerebral Ischemia ◽

Side Effects ◽

Plasma Levels ◽

Neuronal Damage ◽

Focal Cerebral Ischemia ◽

Rabbit Model ◽

High Signal ◽

Brain Levels ◽

Transient Focal Cerebral Ischemia

Dextrorphan is a dextrorotatory morphinan and a noncompetitive N-methyl-d-aspartate (NMDA) receptor antagonist. We studied the dose response characteristics of dextrorphan's neuroprotective efficacy and side effects, correlating these beneficial and adverse responses with plasma and brain levels in a rabbit model of transient focal cerebral ischemia. Thirty-three rabbits, anesthetized with halothane, underwent occlusion of the left internal carotid and anterior cerebral arteries for 1 h, followed by 4.5 h of reperfusion. One hour after the onset of ischemia, they were treated with an i.v. infusion of varying dextrorphan doses or normal saline. After killing, the brains were analyzed for ischemic high signal intensity using magnetic resonance imaging (MRI) and for ischemic neuronal damage with histopathology. A separate group of 12 anesthetized ischemic rabbits received similar doses of dextrorphan, correlating plasma with brain dextrorphan levels. Twenty-six additional dextrorphan unanesthetized, nonischemic rabbits received infusions of dextrorphan to correlate behavioral side effects with dextrorphan dose and levels. Compared with controls, the dextrorphan 15 mg/kg group had significantly less cortical ischemic neuronal damage (5.3 versus 33.2%, p = 0.01) and a reduction in cortical MRI high signal area (9.1 versus 41.2%, p = 0.02). The dextrorphan 10 mg/kg rabbits showed less cortical ischemic neuronal damage (27.2%) and less MRI high signal (34.8%) but this was not statistically significant (p = 0.6). Dextrorphan 5 mg/kg had no benefit on either neocortical ischemic neuronal damage (35.8%) or MRI high signal (42.9%). The protective effect of dextrorphan was correlated with plasma free dextrorphan levels (r = −0.50, p < 0.02 for ischemic neuronal damage; r = −0.66, p < 0.001 for ischemic MRI high signal). All the rabbits with plasma levels > 2,000 ng/ml had < 12% cortical ischemic neuronal damage and < 34% MRI high signal. All rabbits with plasma levels > 3,000 ng/ml showed < 7% ischemic neuronal damage and < 11% MRI high signal. Plasma levels of ∼2,500 ng/ml correlated with brain dextrorphan levels of ∼6,000 ng/g. Unanesthetized rabbits with plasma levels of ∼2,500 ng/ml demonstrated loss of the righting reflex. These results demonstrate that systemic treatment with dextrorphan after 1 h focal ischemia can significantly protect against cerebral damage if adequate plasma and brain levels of dextrorphan are achieved. The brain levels necessary to obtain in vivo protection are similar to concentrations that prevent glutamate or NMDA-induced injury in neuronal culture.

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Dihydrolipoate Reduces Neuronal Injury after Cerebral Ischemia

Journal of Cerebral Blood Flow & Metabolism ◽

10.1038/jcbfm.1992.10 ◽

1992 ◽

Vol 12 (1) ◽

pp. 78-87 ◽

Cited By ~ 56

Author(s):

Jochen H. M. Prehn ◽

Chourouk Karkoutly ◽

Jörg Nuglisch ◽

Barbara Peruche ◽

Josef Krieglstein

Keyword(s):

Cerebral Ischemia ◽

Neuronal Damage ◽

Brain Infarction ◽

Neuronal Injury ◽

Artery Occlusion ◽

Neuroprotective Activity ◽

Neuronal Cultures ◽

Primary Neuronal Cultures

It has been shown in vitro that dihydrolipoate (dl-6,8-dithioloctanoic acid) has antioxidant activity against microsomal lipid peroxidation. We tested dihydrolipoate for its neuroprotective activity using models of hypoxic and excitotoxic neuronal damage in vitro and rodent models of cerebral ischemia in vivo. In vitro, neuronal damage was induced in primary neuronal cultures derived form 7-day-old chick embryo telencephalon by adding either 1 m M cyanide or 1 m M glutamate to the cultures. Cyanide-exposed and dihydrolipoate-treated (10−9–10−7 M) cultures showed an increased protein and ATP content compared with controls. The glutamate-exposed cultures treated with dihydrolipoate (10−7–10−5 M) showed a decreased number of damaged neurons. In vivo, dihydrolipoate treatment (50 and 100 mg/kg) reduced brain infarction after permanent middle cerebral artery occlusion in mice and rats. Dihydrolipoate treatment (50 and 100 mg/kg) could not ameliorate neuronal damage in the rat hippocampus or cortex caused by 10 min of forebrain ischemia. A comparable neuroprotection was obtained by using dimethylthiourea, both in vitro (10−7 and 10−6 M) and at a dose of 750 mg/kg in the focal ischemia models. Lipoate, the oxidized form of dihydrolipoate, failed to reduce neuronal injury in any model tested. We conclude that dihydrolipoate, similarly to dimethylthiourea, is able to protect neurons against ischemic damage by diminishing the accumulation of reactive oxygen species within the cerebral tissue.

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Deficiency of Myeloperoxidase Increases Infarct Volume and Nitrotyrosine Formation in Mouse Brain

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-200201000-00006 ◽

2002 ◽

Vol 22 (1) ◽

pp. 50-54 ◽

Cited By ~ 40

Author(s):

Shunya Takizawa ◽

Yasuaki Aratani ◽

Naoto Fukuyama ◽

Nobuyo Maeda ◽

Hisayuki Hirabayashi ◽

...

Keyword(s):

Cerebral Ischemia ◽

Neuronal Damage ◽

Infarct Volume ◽

Ischemia Reperfusion ◽

Enzyme Inactivation ◽

Wild Type ◽

Cerebral Ischemia Reperfusion ◽

Deficient Mice

Peroxynitrite is responsible for nitration in vivo, whereas myeloperoxidase can also catalyze protein nitration in the presence of high NO2− levels. Recent reports of myeloperoxidase-mediated enzyme inactivation or lipid peroxidation have suggested a role of myeloperoxidase in various pathological conditions. To clarify the role of myeloperoxidase in ischemic brain injury, the authors measured nitrotyrosine formation and infarct volume in myeloperoxidase-deficient or wild-type mice subjected to 2-hour focal cerebral ischemia-reperfusion. Twenty-four hours after reperfusion, infarct volume was significantly larger in myeloperoxidase-deficient mice than in wild-type mice (81 ± 20 mm3 vs. 52 ± 13 mm3, P < 0.01), and nitrotyrosine levels in the infarct region were higher in myeloperoxidase-deficient mice than in wild-type mice (13.4 ± 6.1 μg/mg vs. 9.8 ± 4.4 μg/mg, P = 0.13). Fourteen hours after reperfusion, the nitrotyrosine level was significantly higher in myeloperoxidase-deficient mice than in wild-type mice (3.3 ± 2.9 μg/mg vs. 1.4 ± 0.4 μg/mg, P < 0.05). The authors conclude that the absence of myeloperoxidase increases ischemic neuronal damage in vivo, and that the myeloperoxidase-mediated pathway is not responsible for the nitration reaction in cerebral ischemia-reperfusion.

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