Experimental studies of ischemic brain edema

Koizumi, Junzo; Yoshida, Yasuhiko; Nakazawa, Teiji; Ooneda, Genju

doi:10.3995/jstroke.8.1

Cited by 903 publications

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“…The internal carotid artery is followed rostrally, and the ptergopalatine branch is identified and divided. The 4-0 surgical thread coated by 5 mm silicone (a diameter of 0.25 mm) 4,5) at the distal is then introduced into the internal carotid artery and advanced 20 mm. In the sham-operated group, the external carotid artery was surgically prepared for insertion of the thread, but the thread was not inserted.…”

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confidence: 99%

Protective Effect of Ginsenoside-Re against Cerebral Ischemia/Reperfusion Damage in Rats

Zhou

Cao

Dou

2006

Biological & Pharmaceutical Bulletin

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Middle cerebral artery occlusion (MCAO) results in a cascade of events leading to a number of important cellular changes. These include calcium release from intracellular stores, the product of excessive free radicals, acidosis, 1) and so on. These changes are associated with mitochondrial dysfunction and rapid decreases in ATP.The fluidity of mitochondrial membranes is crucial to their function, especially the production of energy. The structure of neuron mitochondria membrane is destroyed and the fluidity of membrane decreased when there is 2 h of brain ischemia and 2 h reperfusion in rat. Free radicals directly damage neuron mitochondria membranes during reperfusion from cerebral ischemia, resulting in lipid peroxidation. 2)Panax ginseng is widely used in traditional Chinese medicine to enhance stamina and capacity to cope with fatigue as well as physical stress. The mechanisms of action of ginseng remain largely unclear. Nevertheless, the therapeutic effects of ginseng have been attributed to its active ingredients, ginsenosides, sugar conjugates of dihydroxyl or trihydroxyldammarane triterpenes. Ginsenosides are normally fractioned into two groups based on the types of aglycone, namely the panaxadiol group (e.g., Rb1 and Rc) and the panaxatriol group (e.g., Rg1 and Re). Re ( Fig. 1) is one of the ingredients with the highest content (0.15%) in Panax ginseng 3) and is responsible for many pharmacological effects of this plant, but protection of Re against cerebral ischemia-reperfusion injury has not been reported. In an attempt to elucidate the effect that Re prevents cerebral ischemia-reperfusion injury in the rat brain, we studied the membrane fluidity of brain mitochondria, MDA level, SOD and GSH-Px activities in rat brain. MATERIAL AND METHODS Animals and PrereatmentsMale Wistar rats weighing 250-300 g were purchased from the Experimental Animal Center of Shenyang Pharmaceutical University (Shenyang, China). Animals were housed in a room with temperature of 21-23°C, relative humidity of 30-70%, and a 12-h light/12-h dark cycle (lights on at 08:00 h). They had free access to food and water. All experimental procedures carried out in this study were performed in accordance with the Guidelines for the Care and Use of Laboratory Animals of Shenyang Pharmaceutical University in Shenyang.Animals were randomly divided into five groups. Rats in ginsenoside-Re pretreated groups (ischemia 2 h-reperfusion 2 hϩRe) were given p.o. ginsenoside-Re (5, 10, 20 mg kg Ϫ1 ) once a day, for 7 d prior to ischemia (IR+Re). Rats in shamoperated group (SAM) and ischemia 2 h-reperfusion 2 h group (IR) were given p.o. 0.5% CMC-saline. Re was suspended in a 0.5% carboxymethylcellulose (CMC)-saline reaching solution.Extraction of Ginsenoside Re Roots of Panax ginseng were collected from Fusong, Jilin province. The raw materials were ground into powder and passed through a 200 square mesh screen, then extracted by refluxing with MeOH. The MeOH extract was evaporated under vacuum to yield syrup that was suspended in H 2 O. Total sapon...

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confidence: 99%

Protective Effect of Ginsenoside-Re against Cerebral Ischemia/Reperfusion Damage in Rats

Zhou

Cao

Dou

2006

Biological & Pharmaceutical Bulletin

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“…Compound 4b was further evaluated for its neuroprotective activity in a rat transient middle cerebral artery (MCA) occlusion model. 35) Briefly, compound 4b was administered intraperitoneally immediately after both occlusion and reperfusion at a dose of 30 mg/kg each 23) further suggesting that 4b may block Na + channels with high use dependency.…”

Section: Resultsmentioning

confidence: 99%

“…They were then subjected to transient MCA occlusion for 90 min according to the modified method of Koizumi et al, 35) followed by reperfusion. Compound 4b was administered intraperitoneally immediately after both occlusion and reperfusion at a dose of 30 mg/kg (salt form) each time.…”

Section: Effect Of Compound 4b On Ischemic Brain Damage In a Rat Tranmentioning

confidence: 99%

Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke

Seki

Takahashi

Aoyama

et al. 2012

CHEMICAL & PHARMACEUTICAL BULLETIN

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In investigating potent sodium (Na ) channel blockers for the treatment of ischemic stroke, we synthesized a novel series of 3-amino-1-(5-indanyloxy)-2-propanol derivatives and evaluated their inhibitory effects on neuronal Na channels. The 3-amino-1-(5-indanyloxy)-2-propanol derivatives exhibited potent blocking activity for Na channels and a significantly low affinity for dopamine D 2 receptors, which demonstrates a minimal clinical risk for extrapyramidal side effects. In particular, compound 4b, a 3-amino-1-(5-indanyloxy)-2-propanol derivative bearing a benzimidazole moiety, showed desirable neuroprotective activity in a rat transient middle cerebral artery occlusion model. Furthermore, compound 4b displayed a high binding affinity for neurotoxin receptor site 2 of the Na channels, which suggests that 4b would act as a use-dependent Na channel blocker in sustained depolarization during ischemic stroke.Key words sodium channel blocker; ischemic stroke; neuroprotection; neurotoxin receptor site 2Despite their many efforts and the promising neuroprotective action of some drug candidates, such as N-methyl- and a persistent tendency for depolarization by blocking Na + channel inactivation and shifting activation to a more negative membrane potential. 13,14) Furthermore, compounds that bind to neurotoxin receptor site 2 are thought to block Na + channels in a use-dependent manner. [15][16][17] The concept of use dependency can be further explained by the modulated receptor hypothesis, 18) which proposes that drug binding is tighter to open or inactivated channels than to resting states. These observations suggest that site 2 Na + channel blockers may have a minimal effect on normal neuronal signaling but may act more effectively during ischemic conditions, where the membrane potential is persistently depolarized. In contrast, clinical trials of other neuroprotective agents, particularly NMDA receptor antagonists, have been discontinued because of their dose-limiting side effects. 19) Thus, Na + channel blockers are promising agents for the treatment of stroke because of their mechanism of action, and they have been in clinical development (Fig. 1). [20][21][22][23] In this paper, we report the synthesis, modification, and pharmacological evaluation of 3-amino-1-(5-indanyloxy)-2-propanol derivatives as Na + channel blockers. ChemistryWe previously discovered compound 1, which had a potent binding affinity for the BTX binding site on Na + channels (Fig. 2), using high-throughput screening (HTS). However, this compound also showed a high affinity for dopamine D 2 receptors, which indicates a high clinical risk for extrapyramidal side effects. 24) Thus, we initiated a search for Na + channel blockers with high in vivo neuroprotective activity and a low affinity for dopamine D 2 receptors. SUN N8075 bearing a 1-phenoxy-3-piperazinyl-2-propanol moiety is a Na + channel blocker that lacks binding affinity to dopamine D 2 receptors. 23)Compound 1 has a 3-amino-1-(5-indanyloxy)-2-propanol moiRegular Article

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“…The right middle cerebral artery was transiently occluded, according to the method of Koizumi et al 22) Briefly, rats (280-330 g) were anesthetized by intraperitoneal injection of urethane (600 mg/kg) and a-chloralose (60 mg/kg), and body temperature was controlled by using isothermal pads (Braintree Scientific, Braintree, MA, U.S.A.). The right carotid artery bifurcation was exposed and a silicon-coated embolizer (filament size 4-0, Ø: 0.37 mm; Doccol Corp., Redlands, CA, U.S.A.) was inserted from the common carotid artery into the internal carotid artery to a distance of 18 mm.…”

Section: Transient Middle Cerebral Artery Occlusion (Mcao)mentioning

confidence: 99%

Cyanine Dyes Attenuate Cerebral Ischemia and Reperfusion Injury in Rats

Koya‐Miyata

Ohta

Akita

et al. 2010

Biological & Pharmaceutical Bulletin

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Ischemic stroke is a leading cause of death and long-lasting disability. However, therapeutic options for acute ischemic stroke remain very limited.1) Ischemic stroke triggers a cascade of pathophysiological events including excitotoxicity, ionic imbalance, oxidative stress, and apoptosis-like cell death ending in destructive neurodegeneration.2-4) The cumulative evidence suggests involvement of reactive oxygen species (ROS) in the pathogenesis of ischemic injury.5) Several components of ROS including superoxides ( · O 2 Ϫ ), hydroxyl radicals ( · OH), and hydrogen peroxide (H 2 O 2 ) are generated by post-ischemia/reperfusion injury. They are known to induce DNA damage, lipid peroxidation, disruption of blood brain-barrier (BBB), and microglial activation in the ischemic tissue. The rat middle cerebral artery occlusion (MCAO) model mimics the pathophysiological consequences induced by ischemic stroke in humans and thus has been frequently employed.Cyanine photosensitizing dyes have been shown to have various biological activities, such as antimicrobial, antioxidant, macrophage activation, and oxidative phosphorylation uncoupling activities.6-9) Some of those dyes have been used as immunomodulators to treat allergy and rheumatoid arthritis, and to promote wound-healing. [10][11][12][13] It was reported that platonin, a kind of cyanine dye, suppressed acute endotoxemia in rats by inhibiting inflammatory cytokine release from lipopolysaccharide (LPS)-stimulated lymphocytes.14,15) Recent studies suggested that neutrophil infiltration and release of inflammatory cytokines (i.e., interleukin (IL)-1b, IL-6, IL-17, IL-23, and tumor necrosis factor-a) participate in a secondary mechanism of brain injury following ischemia and reperfusion. [16][17][18] Because there is substantial evidence showing that immune responses play crucial roles in mediating neuronal damage in the animal model of stroke, 16) it is reasonable to expect that cyanine dyes with anti-inflammatory properties could protect against neuroinflammatory events. To our knowledge, little is not known whether these dyes are pharmacologically active against ischemia-induced brain injury or neurodegenerative disorders. To explore this potential of cyanine dyes, it would be of interest to examine their effects in the MCAO model, an animal model of ischemic stroke. Prior to the in vivo evaluation, we screened more than 250 cyanine dyes for their neurotrophin-like activity (such as potentiation of neurite outgrowth in neural cells) and found that NK-4 (Fig. 1A), NK-150 (Fig. 1B), and some other related compounds showed remarkable neurite outgrowth-promoting activity in PC12 neural cells. NK-4 and NK-150 are thought to be safe compounds since they showed no acute toxicity when orally-administrated to mice at a dose of 2000 mg/kg (our unpublished observation). In the present report, we further examined NK-4 and NK-150 for their ability to promote nerve growth factor (NGF)-primed neurite outgrowth and for free radical scavenging activity in vitro. We also examined the...

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Experimental studies of ischemic brain edema

Cited by 903 publications

References 0 publications

Protective Effect of Ginsenoside-Re against Cerebral Ischemia/Reperfusion Damage in Rats

Protective Effect of Ginsenoside-Re against Cerebral Ischemia/Reperfusion Damage in Rats

Synthesis and Pharmacological Evaluation of 3-Amino-1-(5-indanyloxy)-2-propanol Derivatives as Potent Sodium Channel Blockers for the Treatment of Stroke

Cyanine Dyes Attenuate Cerebral Ischemia and Reperfusion Injury in Rats

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