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

1996 ◽  
Vol 80 (2) ◽  
pp. 680-684 ◽  
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.

scholarly journals Cerebral Ischemia Enhances Polyamine Oxidation: Identification of Enzymatically Formed 3-Aminopropanal as an Endogenous Mediator of Neuronal and Glial Cell Death

1998 ◽  
Vol 188 (2) ◽  
pp. 327-340 ◽  
Author(s):  
Svetlana Ivanova ◽  
Galina I. Botchkina ◽  
Yousef Al-Abed ◽  
Malcolm Meistrell ◽  
Franak Batliwalla ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Glial Cell ◽  
Oxidase Activity ◽  
Cell Damage ◽  
Polyamine Oxidase ◽  
Dependent Manner ◽  
Essential Information ◽  
Ischemic Brain

To elucidate endogenous mechanisms underlying cerebral damage during ischemia, brain polyamine oxidase activity was measured in rats subjected to permanent occlusion of the middle cerebral artery. Brain polyamine oxidase activity was increased significantly within 2 h after the onset of ischemia in brain homogenates (15.8 ± 0.9 nmol/h/mg protein) as compared with homogenates prepared from the normally perfused contralateral side (7.4 ± 0.5 nmol/h/mg protein) (P <0.05). The major catabolic products of polyamine oxidase are putrescine and 3-aminopropanal. Although 3-aminopropanal is a potent cytotoxin, essential information was previously lacking on whether 3-aminopropanal is produced during cerebral ischemia. We now report that 3-aminopropanal accumulates in the ischemic brain within 2 h after permanent forebrain ischemia in rats. Cytotoxic levels of 3-aminopropanal are achieved before the onset of significant cerebral cell damage, and increase in a time-dependent manner with spreading neuronal and glial cell death. Glial cell cultures exposed to 3-aminopropanal undergo apoptosis (LD50 = 160 μM), whereas neurons are killed by necrotic mechanisms (LD50 = 90 μM). The tetrapeptide caspase 1 inhibitor (Ac-YVAD-CMK) prevents 3-aminopropanal–mediated apoptosis in glial cells. Finally, treatment of rats with two structurally distinct inhibitors of polyamine oxidase (aminoguanidine and chloroquine) attenuates brain polyamine oxidase activity, prevents the production of 3-aminopropanal, and significantly protects against the development of ischemic brain damage in vivo. Considered together, these results indicate that polyamine oxidase–derived 3-aminopropanal is a mediator of the brain damaging sequelae of cerebral ischemia, which can be therapeutically modulated.

scholarly journals Interaction between XIAP and Smac/DIABLO in the Mouse Brain after Transient Focal Cerebral Ischemia

2003 ◽  
Vol 23 (9) ◽  
pp. 1010-1019 ◽  
Author(s):  
Atsushi Saito ◽  
Takeshi Hayashi ◽  
Shuzo Okuno ◽  
Michel Ferrand-Drake ◽  
Pak H. Chan
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Focal Cerebral Ischemia ◽  
Early Period ◽  
Neuronal Cell ◽  
Caspase 9 ◽  
Transient Focal Cerebral Ischemia ◽  
Apoptosis Protein ◽  
Caspase Cascade

The X chromosome–linked inhibitor-of-apoptosis protein (XIAP) contributes to apoptosis regulation after a variety of cell death stimuli. XIAP inhibits the caspase reaction via binding to caspases, and is inhibited via binding to the second mitochondria-derived activator of caspase (Smac)/DIABLO to tightly control apoptotic cell death. However, the interaction among XIAP, Smac/DIABLO, and caspases after in vivo cerebral ischemia is not well known. To clarify this issue, the authors examined time-dependent expression and interaction among XIAP, Smac/DIABLO, and activated caspase-9 by immunohistochemistry, Western blot analysis, and immunoprecipitation using an in vivo transient focal cerebral ischemia model. To examine the relationship of the XIAP pathway to the caspase cascade, a pan-caspase inhibitor was administered. XIAP increased concurrently with the release of Smac/DIABLO and the appearance of activated caspase-9 during the early period after reperfusion injury. The bindings of XIAP to Smac/DIABLO and to caspase-9 and the binding of Smac/DIABLO to caspase-9 reached a peak simultaneously after transient focal cerebral ischemia. Neither XIAP nor Smac/DIABLO expression was affected by caspase inhibition. These results suggest that the XIAP pathway was activated upstream of the caspase cascade and that interaction among XIAP, Smac/DIABLO, and caspase-9 plays an important role in the regulation of apoptotic neuronal cell death after transient focal cerebral ischemia.

Abstract P801: Impact of Oxidized Phospholipids on Outcomes From Cerebral Ischemia and Reperfusion Injury

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Jin Yu ◽  
Hong Zhu ◽  
Calvin Yeang ◽  
Joseph L Witztum ◽  
Sotirios Tsimikas ◽  
...  
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Ischemia And Reperfusion ◽  
Oxidized Phospholipids ◽  
Ischemia And Reperfusion Injury ◽  
Cerebral Ischemia And Reperfusion ◽  
The Brain

The mechanisms leading to oxidative stress and cellular dysfunction during stroke are not well understood. To test the hypothesis that transient cerebral artery occlusion (MCAo) in mice results in the generation of oxidized phospholipids (oxPLs) that contribute to neuronal cell death and glial activation. Both in vitro and in vivo cerebral ischemia and reperfusion injury (IRI) resulted in the elevation of specific oxPLs. Neuronal cell death was determined in the presence of oxPLs and the natural oxPL E06 antibody protected the cells from the toxic effects. IRI in mice gave rise to increased immunoreactivity of oxPLs in the brain. E06 reduced inflammatory markers in the brain following IRI, including iba-1, GFAP and inflammatory cytokines. In addition, oxPLs gave rise to M1 and Mox microglial phenotypes which was reversed in the presence of E06 and elicited a more M2 phenotype. Nrf2 deficient mice show increased infarct volumes and microglia from Nrf2 -/- mice show a reduction in Mox gene expression, and E06 protects both mice and cells from the Nrf2 deficit. Cerebral IRI generates oxPLs which triggers neuronal cell loss and inflammation and inactivation of oxPLs in vivo reduces infarct volume and improves outcomes.

scholarly journals Role of P2X7 Receptors in Ischemic and Excitotoxic Brain Injury In Vivo

2003 ◽  
Vol 23 (3) ◽  
pp. 381-384 ◽  
Author(s):  
Rosalind A. Le Feuvre ◽  
David Brough ◽  
Omar Touzani ◽  
Nancy J. Rothwell
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
P2x7 Receptors ◽  
Excitotoxic Cell Death ◽  
Experimentally Induced

Purinergic P2X7 receptors may affect neuronal cell death through their ability to regulate the processing and release of interleukin-1β (IL-1β), a key mediator in neurodegeneration. The authors tested the hypothesis that ATP, acting at P2X7 receptors, contributes to experimentally induced neuronal death in rodents in vivo. Deletion of P2X7 receptors (P2X7 knockout mice) did not affect cell death induced by temporary cerebral ischemia, which was reduced by treatment with IL-1 receptor antagonist (IL-1RA). Treatment of mice with P2X antagonists did not affect ischemic or excitotoxic cell death, suggesting that P2X7 receptors are not primary mediators of experimentally induced neuronal death.

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

Stroke ◽  
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.

scholarly journals miR-380-5p facilitates NRF2 and attenuates cerebral ischemia/reperfusion injury-induced neuronal cell death by directly targeting BACH1

2021 ◽  
Vol 12 (1) ◽  
pp. 210-217
Author(s):  
Yibiao Wang ◽  
Min Xu
Keyword(s):  
Cell Death ◽  
Cerebral Ischemia ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Neuronal Cell Death ◽  
Neuronal Cell ◽  
Luciferase Assay ◽  
Neuroprotective Effects ◽  
Cerebral Ischemia Reperfusion

Abstract Background This study aimed to explore the role of miR-380-5p in cerebral ischemia/reperfusion (CIR) injury-induced neuronal cell death and the potential signaling pathway involved. Methodology Human neuroblastoma cell line SH-SY5Y cells were used in this study. Oxygen and glucose deprivation/reperfusion (OGD/R) model was used to mimic ischemia/reperfusion injury. CCK-8 assay and flow cytometry were used to examine cell survival. Quantitative real time PCR (RT-qPCR) assay and Western blotting were used to measure the change of RNA and protein expression, respectively. TargetScan and Luciferase assay was used to confirm the target of miR-380-5p. Malondialdehyde (MDA) superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) were measured using commercial kits. Results miR-380-5p was downregulated in SH-SY5Y cells after OGD/R. Cell viability was increased by miR-380-5p, while cell apoptosis was reduced by miR-380-5p mimics. MDA was reduced by miR-380-5p mimics, while SOD and GSHPx were increased by miR-380-5p. Results of TargetScan and luciferase assay have showed that BACH1 is the direct target of miR-380-5p. Expression of NRF2 was upregulated after OGD/R, but was not affected by miR-380-5p. mRNA expression of HO-1 and NQO1 and ARE activity were increased by miR-380-5p. Overexpression of BACH1 reversed the antioxidant and neuroprotective effects of miR-380-5p. Conclusion miR-380-5p inhibited cell death induced by CIR injury through target BACH1 which also facilitated the activation of NRF2, indicating the antioxidant and neuroprotective effects of miR-380-5p.

scholarly journals The combination of Acalypha indica–Centella asiatica extracts decreases the neuronal damage in hypoxia-induced hippocampal injury animal model

2018 ◽  
Vol 27 (3) ◽  
pp. 137-44
Author(s):  
Siti Farida ◽  
Desak G.B. Krisnamurti ◽  
Ninik Mudjihartini ◽  
Erni H. Purwaningsih ◽  
Imelda M. Sianipar ◽  
...  
Keyword(s):  
Animal Model ◽  
Neuronal Damage ◽  
Cell Damage ◽  
Neuronal Cell ◽  
Centella Asiatica ◽  
Nerve Cells ◽  
Control Treatment ◽  
Control Group ◽  
Sprague Dawley ◽  
Acalypha Indica

Background: Approximately 80–85% of strokes are ischemic and lead to alterations in neuronal cell morphology and cell death. There is a lack of studies on the effect of the combination of Acalypha indica L. (AI) and Centella asiatica L. (CA) in terms of its neurotherapy property. This study was conducted to investigate the neurotherapeutic effect of the combination of AI–CA extracts in improving rat’s hippocampal neuron injury post-hypoxia.Methods: A total of 36 Sprague-Dawley rats were categorized into six groups and placed in a hypoxia chamber for 7 consecutive days. Then, they were moved to normoxia cages and treated for 7 consecutive days as follows: control group without treatment as a negative control; treatment groups were administered citicoline 50 mg/kgBW as a positive control; three different dose combinations of AI150–CA150, AI200–CA150, and AI250–CA150 mg/kgBW, respectively. Histological analyses were performed to assess the improvement in nerve cell damage in the hippocampus.Results: Treatment with citicoline significantly decreased the damage of nerve cells (30.8%); the combination of the AI–CA extracts of AI150–CA150, AI200–CA150, and AI250–CA150 also significantly decreased the damage of nerve cells (36%, 36.4%, and 30.4%, respectively) compared to the control rats (15.4%).Conclusion: The combination of AI–CA extracts decreased the neuronal damage in the hypoxia-induced hippocampal injury animal model. The improvement effect of the combination of AI–CA extracts was not significantly different to citicoline.

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