scholarly journals Heme–Hemopexin Complex Attenuates Neuronal Cell Death and Stroke Damage

2009 ◽  
Vol 29 (5) ◽  
pp. 953-964 ◽  
Author(s):  
Rung-chi Li ◽  
Sofiyan Saleem ◽  
Gehua Zhen ◽  
Wangsen Cao ◽  
Hean Zhuang ◽  
...  
Keyword(s):  
Cortical Neurons ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Neuronal Cultures ◽  
Tert Butyl Hydroperoxide ◽  
Primary Mouse ◽  
Free Heme ◽  
Cerebral Artery Occlusion ◽  
The Brain

Hemoproteins undergo degradation during hypoxic/ischemic conditions, but the prooxidant free heme that is released cannot be recycled and must be degraded. The extracellular heme associates with its high-affinity binding protein, hemopexin (HPX). Hemopexin is shown here to be expressed by cortical neurons and it is present in mouse cerebellum, cortex, hippocampus, and striatum. Using the transient ischemia model (90-min middle cerebral artery occlusion followed by 96-h survival), we provide evidence that HPX is protective in the brain, as neurologic deficits and infarct volumes were significantly greater in HPX−/− than in wild-type mice. Addressing the potential protective HPX cellular pathway, we observed that exogenous free heme decreased cell survival in primary mouse cortical neuron cultures, whereas the heme bound to HPX was not toxic. Heme-HPX complexes induce HO1 and, consequently, protect primary neurons against the toxicity of both heme and prooxidant tert-butyl hydroperoxide; such protection was decreased in HO1−/− neuronal cultures. Taken together, these data show that HPX protects against heme-induced toxicity and oxidative stress and that HO1 is required. We propose that the heme-HPX system protects against stroke-related damage by maintaining a tight balance between free and bound heme. Thus, regulating extracellular free heme levels, such as with HPX, could be neuroprotective.

scholarly journals A novel indication of platonin, a therapeutic immunomodulating medicine, on neuroprotection against ischemic stroke in mice

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Joen-Rong Sheu ◽  
Zhih-Cherng Chen ◽  
Thanasekaran Jayakumar ◽  
Duen-Suey Chou ◽  
Ting-Lin Yen ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Ischemic Stroke ◽  
Infarct Volume ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Neuroprotective Effects ◽  
Occlusion Time ◽  
Oxide Synthase ◽  
Cerebral Artery Occlusion

Abstract Thrombosis and stroke are major causes of disability and death worldwide. However, the regular antithrombotic drugs may have unsatisfactory results and side effects. Platonin, a cyanine photosensitizing dye, has been used to treat trauma, ulcers and some acute inflammation. Here, we explored the neuroprotective effects of platonin against middle cerebral artery occlusion (MCAO)-induced ischemic stroke in mice. Platonin(200 μg/kg) substantially reduced cerebral infarct volume, brain edema, neuronal cell death and neurological deficit scores, and improved the MCAO-reduced locomotor activity and rotarod performance. Platonin(5–10 μM) potently inhibited platelet aggregation and c-Jun NH2-terminal kinase (JNK) phosphorylation in collagen-activated platelets. The antiaggregation effect did not affect bleeding time but increased occlusion time in platonin(100 and 200 μg/kg)-treated mice. Platonin(2–10 μM) was potent in diminishing collagen- and Fenton reaction-induced ∙OH formation. Platonin(5–10 μM) also suppressed the expression of nitric oxide, inducible nitric oxide synthase, cyclooxygenase-2, interleukin-1β, and JNK phosphorylation in lipopolysaccharide-stimulated macrophages. MCAO-induced expression of 3-nitrotyrosine and Iba1 was apparently attenuated in platonin(200 μg/kg)-treated mice. In conclusion, platonin exhibited remarkable neuroprotective properties against MCAO-induced ischemia in a mouse model through its antiaggregation, antiinflammatory and antiradical properties. The observed therapeutic efficacy of platonin may consider being a novel medcine against ischemic stroke.

scholarly journals Inhibition of the glutamine transporter SNAT1 confers neuroprotection in mice by modulating the mTOR-autophagy system

2019 ◽  
Vol 2 (1) ◽  
Author(s):  
Daisuke Yamada ◽  
Kenji Kawabe ◽  
Ikue Tosa ◽  
Shunpei Tsukamoto ◽  
Ryota Nakazato ◽  
...  
Keyword(s):  
Infarct Size ◽  
Neuronal Cell Death ◽  
Mammalian Target Of Rapamycin ◽  
Neuronal Cell ◽  
Suppressive Effect ◽  
Artery Occlusion ◽  
Culture Conditions ◽  
Triphenyltetrazolium Chloride ◽  
Cerebral Artery Occlusion

Abstract The pathophysiological role of mammalian target of rapamycin complex 1 (mTORC1) in neurodegenerative diseases is established, but possible therapeutic targets responsible for its activation in neurons must be explored. Here we identified solute carrier family 38a member 1 (SNAT1, Slc38a1) as a positive regulator of mTORC1 in neurons. Slc38a1flox/flox and Synapsin I-Cre mice were crossed to generate mutant mice in which Slc38a1 was selectively deleted in neurons. Measurement of 2,3,5-triphenyltetrazolium chloride (TTC) or the MAP2-negative area in a mouse model of middle cerebral artery occlusion (MCAO) revealed that Slc38a1 deficiency decreased infarct size. We found a transient increase in the phosphorylation of p70S6k1 (pp70S6k1) and a suppressive effect of rapamycin on infarct size in MCAO mice. Autophagy inhibitors completely mitigated the suppressive effect of SNAT1 deficiency on neuronal cell death under in vitro stroke culture conditions. These results demonstrate that SNAT1 promoted ischemic brain damage via mTOR-autophagy system.

Acupuncture attenuates neuronal cell death in middle cerebral artery occlusion model of focal ischemia

2010 ◽  
Vol 32 (sup1) ◽  
pp. 84-87 ◽  
Author(s):  
Kyoung Ah Kang ◽  
Eun Sim Shin ◽  
Jinyoung Hur ◽  
Mohmmad Rakibul Hasan ◽  
Hyejung Lee ◽  
...  
Keyword(s):  
Cell Death ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Focal Ischemia ◽  
Artery Occlusion ◽  
Occlusion Model ◽  
Cerebral Artery Occlusion

scholarly journals Resveratrol modulates the Akt/GSK-3β signaling pathway in a middle cerebral artery occlusion animal model

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Dong-Ju Park ◽  
Ju-Bin Kang ◽  
Fawad-Ali Shah ◽  
Phil-Ok Koh
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Signaling Pathway ◽  
Neuroprotective Effect ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Gsk 3Β ◽  
Cerebral Artery Occlusion

Abstract Cerebral ischemia is a major cause of neurodegenerative disease. It induces neuronal vulnerability and susceptibility, and leads to neuronal cell death. Resveratrol is a polyphenolic compound that acts as an anti-oxidant. It exerts a neuroprotective effect against focal cerebral ischemic injury. Akt signaling pathway is accepted as a representative cell survival pathway, including proliferation, growth, and glycogen synthesis. This study investigated whether resveratrol regulates Akt/glycogen synthase kinase-3β (GSK-3β) pathway in a middle cerebral artery occlusion (MCAO)-induced ischemic brain injury. Adult male rats were intraperitoneally injected with vehicle or resveratrol (30 mg/kg) and cerebral cortices were isolated 24 h after MCAO. Neurological behavior test, corner test, brain edema measurment, and 2,3,5-triphenyltetrazolium chloride staining were performed to elucidate the neuroprotective effects of resveratrol. Phospho-Akt and phospho-GSK-3β expression levels were measured using Western blot analysis. MCAO injury led to severe neurobehavioral deficit, infraction, and histopathological changes in cerebral cortex. However, resveratrol treatment alleviated these changes caused by MCAO injury. Moreover, MCAO injury induced decreases in phospho-Akt and phospho-GSK-3β protein levels, whereas resveratrol attenuated these decreases. Phosphorylations of Akt and GSK-3β act as a critical role for the suppression of apoptotic cell death. Thus, our finding suggests that resveratrol attenuates neuronal cell death in MCAO-induced cerebral ischemia and Akt/GSK-3β signaling pathway contributes to the neuroprotective effect of resveratrol.

scholarly journals Quercetin attenuates the reduction of parvalbumin in middle cerebral artery occlusion animal model

2021 ◽  
Vol 37 (1) ◽  
Author(s):  
Dong-Ju Park ◽  
Ju-Bin Kang ◽  
Fawad-Ali Shah ◽  
Phil-Ok Koh
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Neuroprotective Effect ◽  
Neuronal Cell ◽  
Artery Occlusion ◽  
Male Rats ◽  
Neurological Deficits ◽  
Glutamate Toxicity ◽  
Cerebral Artery Occlusion

Abstract Background Calcium is a critical factor involved in modulation of essential cellular functions. Parvalbumin is a calcium buffering protein that regulates intracellular calcium concentrations. It prevents rises in calcium concentrations and inhibits apoptotic processes during ischemic injury. Quercetin exerts potent antioxidant and anti-apoptotic effects during brain ischemia. We investigated whether quercetin can regulate parvalbumin expression in cerebral ischemia and glutamate toxicity-induced neuronal cell death. Adult male rats were treated with vehicle or quercetin (10 mg/kg) 30 min prior to middle cerebral artery occlusion (MCAO) and cerebral cortical tissues were collected 24 h after MCAO. We used various techniques including Western blot, reverse transcription-PCR, and immunohistochemical staining to elucidate the changes of parvalbumin expression. Results Quercetin ameliorated MCAO-induced neurological deficits and behavioral changes. Moreover, quercetin prevented MCAO-induced a decrease in parvalbumin expression. Conclusions These findings suggest that quercetin exerts a neuroprotective effect through regulation of parvalbumin expression.

Activation of astroglial CB1R mediates cerebral ischemic tolerance induced by electroacupuncture

2021 ◽  
pp. 0271678X2199439
Author(s):  
Cen Yang ◽  
Jingjing Liu ◽  
Jingyi Wang ◽  
Anqi Yin ◽  
Zhenhua Jiang ◽  
...  
Keyword(s):  
Endocannabinoid System ◽  
Artery Occlusion ◽  
Ischemic Tolerance ◽  
Protective Mechanisms ◽  
Promising Therapeutic Approach ◽  
Subsequent Activation ◽  
Cerebral Ischemic ◽  
Cerebral Artery Occlusion ◽  
The Brain

There are no effective treatments for stroke. The activation of endogenous protective mechanisms is a promising therapeutic approach, which evokes the intrinsic ability of the brain to protect itself. Accumulated evidence strongly suggests that electroacupuncture (EA) pretreatment induces rapid tolerance to cerebral ischemia. With regard to mechanisms underlying ischemic tolerance induced by EA, many molecules and signaling pathways are involved, such as the endocannabinoid system, although the exact mechanisms have not been fully elucidated. In the current study, we employed mutant mice, neuropharmacology, microdialysis, and virus transfection techniques in a middle cerebral artery occlusion (MCAO) model to explore the cell-specific and brain region-specific mechanisms of EA-induced neuroprotection. EA pretreatment resulted in increased ambient endocannabinoid (eCB) levels and subsequent activation of ischemic penumbral astroglial cannabinoid type 1 receptors (CB1R) which led to moderate upregulation of extracellular glutamate that protected neurons from cerebral ischemic injury. These findings provide a novel cellular mechanism of EA and a potential therapeutic target for ischemic stroke.

Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain

2007 ◽  
Vol 412 (2) ◽  
pp. 114-117 ◽  
Author(s):  
John C. Ashton ◽  
Rosanna M.A. Rahman ◽  
Shiva M. Nair ◽  
Brad A. Sutherland ◽  
Michelle Glass ◽  
...  
Keyword(s):  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Artery Occlusion ◽  
Cerebral Hypoxia ◽  
Cb2 Receptor ◽  
Hypoxia Ischemia ◽  
Cerebral Artery Occlusion ◽  
The Brain

Abstract 91: Remodeling After Stroke: The Recovering Brain Is Vulnerable To Lipoxygenase-dependent Semaphorin Signaling

Stroke ◽  
2013 ◽  
Vol 44 (suppl_1) ◽  
Author(s):  
Anton Pekcec ◽  
Kazim Yigitkanli ◽  
Joo Eun Jung ◽  
Hulya Karatas ◽  
Eng H Lo ◽  
...  
Keyword(s):  
Knockout Mice ◽  
Cortical Neurons ◽  
Second Messengers ◽  
Artery Occlusion ◽  
Tube Formation ◽  
Stroke Recovery ◽  
Experimental Stroke ◽  
Axon Extension ◽  
Cultured Cortical Neurons ◽  
Cerebral Artery Occlusion

Background and Purpose— Recovery from stroke is limited in part by an inhibitory environment in the post-ischemic brain, but factors preventing successful remodeling are not well known. We sought to investigate if signaling from the axon guidance molecule semaphorin 3A (Sema3A) via eicosanoid second messengers can contribute to this inhibitory environment, and if blocking the Sema3A pathway can provide a benefit following experimental stroke. Methods— Cultured cortical neurons from mice were treated with recombinant Sema3A, or with the eicosanoids 12-HETE and 12-HPETE. Neurons from ALOX15 knockout mice, and a human brain endothelial cell line, were treated similarly. The filament model of MCAO was used to induce experimental stroke in mice, in some of which Sema3A was injected stereotactically into the striatum. The 12/15-LOX inhibitor LOXBlock-1 was injected intraperitoneally one week after MCAO. Results— Expression levels of 12/15-lipoxygenase (12/15-LOX) were increased within two hours after exposure of primary neurons to 90nM recombinant Sema3A. Either Sema3A, or the 12/15-lipoxygenase (12/15-LOX) metabolites 12-HETE and 12-HPETE at 300nM, blocked axon extension in neurons compared to solvent controls, and decreased tube formation in endothelial cells. The Sema3A effect was reversed by inhibiting 12/15-LOX, and neurons derived from 12/15-LOX knockout mice were insensitive to Sema3A. Following middle cerebral artery occlusion to induce stroke in mice, immunohistochemistry showed both Sema3A and 12/15-LOX are increased in the cortex up to two weeks. To determine if a Sema3A-dependent damage pathway is activated following ischemia, we injected recombinant Sema3A into the striatum. Sema3A alone did not cause injury in normal brains. But when injected into post-ischemic brains, Sema3A increased cortical damage by 79%, and again this effect was reversed by 12/15-LOX inhibition. Administration of the 12/15-LOX inhibitor LOXBlock-1 7 days after transient MCAO increased vascularization in the infarcted and peri-infarct area one week later. Conclusions— Our findings suggest that blocking the semaphorin pathway may provide a novel therapeutic strategy to improve stroke recovery.

Abstract 166: Endothelial Overexpression of LOX-1 Increases Stroke Size in vivo

2013 ◽  
Vol 113 (suppl_1) ◽  
Author(s):  
Alexander Akhmedov ◽  
Remo D Spescha ◽  
Francesco Paneni ◽  
Giovani G Camici ◽  
Thomas F Luescher
Keyword(s):  
Endothelial Cells ◽  
Ischemic Stroke ◽  
Endothelial Dysfunction ◽  
Middle Cerebral Artery ◽  
Middle Cerebral Artery Occlusion ◽  
Cerebral Artery ◽  
Oxidized Ldl ◽  
Artery Occlusion ◽  
Cerebral Artery Occlusion ◽  
The Brain

Background— Stroke is one of the most common causes of death and long term disability worldwide primarily affecting the elderly population. Lectin-like oxidized LDL receptor 1 (LOX-1) is the receptor for oxidized LDL identified in endothelial cells. Binding of OxLDL to LOX-1 induces several cellular events in endothelial cells, such as activation of transcription factor NF-kB, upregulation of MCP-1, and reduction in intracellular NO. Accumulating evidence suggests that LOX-1 is involved in endothelial dysfunction, inflammation, atherogenesis, myocardial infarction, and intimal thickening after balloon catheter injury. Interestingly, a recent study demonstrated that acetylsalicylic acid (aspirin), which could prevent ischemic stroke, inhibited Ox-LDL-mediated LOX-1 expression in human coronary endothelial cells. The expression of LOX-1 was increased at a transient ischemic core site in the rat middle cerebral artery occlusion model. These data suggest that LOX-1 expression induces atherosclerosis in the brain and is the precipitating cause of ischemic stroke. Therefore, the goal of the present study was to investigate the role of endothelial LOX-1 in stroke using experimental mouse model. Methods and Results— 12-week-old male LOX-1TG generated recently in our group and wild-type (WT) mice were applied for a transient middle cerebral artery occlusion (MCAO) model to induce ischemia/reperfusion (I/R) brain injury. LOX-1TG mice developed 24h post-MCAO significantly larger infarcts in the brain compared to WT (81.51±8.84 vs. 46.41±10.13, n=7, p < 0.05) as assessed morphologically using Triphenyltetrazolium chloride (TTC) staining. Moreover, LOX-1TG showed higher neurological deficit in RotaRod (35.57±8.92 vs. 66.14±10.63, n=7, p < 0.05) and Bederson tests (2.22±0.14 vs. 1.25±0.30, n=9-12, p < 0.05) - two experimental physiological tests for neurological function. Conclusions— Thus, our data suggest that LOX-1 plays a critical role in the ischemic stroke when expressed at unphysiological levels. Such LOX-1 -associated phenotype could be due to the endothelial dysfunction. Therefore, LOX-1 may represent novel therapeutic targets for preventing ischemic stroke.

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