scholarly journals The Effects of Atorvastatin on Global Cerebral Ischemia-Induced Neuronal Death

2021 ◽  
Vol 22 (9) ◽  
pp. 4385
Author(s):  
A Ra Kho ◽  
Dae Ki Hong ◽  
Beom Seok Kang ◽  
Woo-Jung Park ◽  
Kyung Chan Choi ◽  
...  
Keyword(s):  
Cognitive Function ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Therapeutic Option ◽  
Endothelial Damage ◽  
Global Cerebral Ischemia ◽  
Neuroprotective Effects ◽  
Hypoxic Brain ◽  
Fluoro Jade B ◽  
Neurologic Disability

(1) Background and Purpose: Global cerebral ischemia-induced severe hypoxic brain damage is one of the main causes of mortality and long-term neurologic disability even after receiving early blood reperfusion. This study aimed to test the hypothesis that atorvastatin potentially has neuroprotective effects in global cerebral ischemia (GCI). (2) Methods: We performed two sets of experiments, analyzing acute (1-week) and chronic (4-week) treatments. For the vehicle (Veh) and statin treatments, 1 mL of 0.9% saline and 5 mg/kg of atorvastatin (ATOR) were administered orally. For histological analysis, we used the following staining protocols: Fluoro-Jade B and NeuN, 4-hydroxynonenal, CD11b and GFAP, IgG, SMI71, and vWF. Finally, we evaluated the cognitive function with a battery of behavioral tests. (3) Results: The GCI-ATOR group showed significantly reduced neuronal death, oxidative stress, inflammation, and BBB disruption compared with the GCI-Veh group. Moreover, the GCI-ATOR group showed decreased endothelial damage and VV proliferation and had significantly improved cognitive function compared with the GCI-Veh group in both models. (4) Conclusions: ATOR has neuroprotective effects and helps recover the cognitive function after GCI in rats. Therefore, administration of atorvastatin may be a therapeutic option in managing GCI after CA.

scholarly journals Carvacrol Attenuates Hippocampal Neuronal Death after Global Cerebral Ischemia via Inhibition of Transient Receptor Potential Melastatin 7

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 231 ◽  
Author(s):  
Dae Hong ◽  
Bo Choi ◽  
A Kho ◽  
Song Lee ◽  
Jeong Jeong ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Transient Receptor Potential ◽  
Therapeutic Potential ◽  
Receptor Potential ◽  
Global Cerebral Ischemia ◽  
Neuroprotective Effects ◽  
Transient Receptor Potential Melastatin ◽  
Transient Receptor ◽  
Zinc Translocation

Over the last two decades, evidence supporting the concept of zinc-induced neuronal death has been introduced, and several intervention strategies have been investigated. Vesicular zinc is released into the synaptic cleft, where it then translocates to the cytoplasm, which leads to the production of reactive oxygen species and neurodegeneration. Carvacrol inhibits transient receptor potential melastatin 7 (TRPM7), which regulates the homeostasis of extracellular metal ions, such as calcium and zinc. In the present study, we test whether carvacrol displays any neuroprotective effects after global cerebral ischemia (GCI), via a blockade of zinc influx. To test our hypothesis, we used eight-week-old male Sprague–Dawley rats, and a GCI model was induced by bilateral common carotid artery occlusion (CCAO), accompanied by blood withdrawal from the femoral artery. Ischemic duration was defined as a seven-minute electroencephalographic (EEG) isoelectric period. Carvacrol (50 mg/kg) was injected into the intraperitoneal space once per day for three days after the onset of GCI. The present study found that administration of carvacrol significantly decreased the number of degenerating neurons, microglial activation, oxidative damage, and zinc translocation after GCI, via downregulation of TRPM7 channels. These findings suggest that carvacrol, a TRPM7 inhibitor, may have therapeutic potential after GCI by reducing intracellular zinc translocation.

scholarly journals DHEA-Neuroprotection and -Neurotoxicity after Transient Cerebral Ischemia in Rats

2008 ◽  
Vol 29 (2) ◽  
pp. 287-296 ◽  
Author(s):  
Zhen Li ◽  
Shengzhong Cui ◽  
Zhuo Zhang ◽  
Rong Zhou ◽  
Yingbin Ge ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Global Cerebral Ischemia ◽  
Neuroprotective Effects ◽  
Early Reperfusion ◽  
Transient Global Cerebral Ischemia ◽  
Sigma 1 ◽  
Therapeutic Opportunity ◽  
Learning Impairment ◽  
Administration Timing

Dehydroepiandrosterone (DHEA) has been implicated not only to prevent N-methyl-d-aspartate (NMDA)-induced neurotoxicity but also to enhance Ca2+ influx through NMDA receptor (NMDAr). However, these DHEA effects, which would produce inconsistent outcomes about neuronal damages, are not well studied in ischemia-induced cerebral damages. Herein, we report that a single administration of DHEA (20 mg/kg) during 3 to 48 h after transient global cerebral ischemia in rats exerted neuroprotective effects such as reduction of ischemia-induced neuronal death in the hippocampal CA1 and improvement of ischemia-induced deficits in spatial learning. By contrast, at 1 h before or after ischemia, the administration of DHEA exacerbated the ischemia-induced neuronal death and learning impairment. This DHEA neurotoxicity appeared to be caused by DHEA itself, but not through its metabolite testosterone, and was inhibited by a pretreatment with the NMDAr blocker MK801 or the sigma-1 (σ1) receptor antagonist NE100. However, the DHEA neuroprotection was blocked by NE100. These results show that DHEA not only provides robust ischemic neuroprotection with a long therapeutic opportunity but also exerts neurotoxicity when administered during ischemia and early reperfusion, which points to the importance of administration timing of DHEA in the clinical treatment of brain damages by the transient brain ischemia including stroke.

scholarly journals Fate of Astrocytes in The Gerbil Hippocampus After Transient Global Cerebral Ischemia

2019 ◽  
Vol 20 (4) ◽  
pp. 845 ◽  
Author(s):  
Hyeyoung Kim ◽  
Joon Park ◽  
Myoung Shin ◽  
Jun Cho ◽  
Tae-Kyeong Lee ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Pyramidal Neurons ◽  
Neuronal Degeneration ◽  
Global Cerebral Ischemia ◽  
Transient Global Cerebral Ischemia ◽  
Progressive Degeneration ◽  
Fluoro Jade B ◽  
Ca1 Area ◽  
Brain Tissue Damage

Neuronal death and reactive gliosis are major features of brain tissue damage following transient global cerebral ischemia (tgCI). This study investigated long-term changes in neuronal death and astrogliosis in the gerbil hippocampus for 180 days after 5 min of tgCI. A massive loss of pyramidal neurons was found in the hippocampal CA1 area (CA1) area between 5 and 30 days after tgCI by Fluoro-Jade B (FJB, a marker for neuronal degeneration) histofluorescence staining, but pyramidal neurons in the CA2/3 area did not die. The reaction of astrocytes (astrogliosis) was examined by glial fibrillary acidic protein (GFAP) immunohistochemistry. Morphological change or degeneration (death) of the astrocytes was found in the CA1 area after tgCI, but, in the CA2/3 area, astrogliosis was hardly shown. GFAP immunoreactive astrocytes in the CA1 area was significantly increased in number with time and peaked at 30 days after tgCI, and they began to be degenerated or dead from 40 days after tgCI. The effect was examined by double immunofluorescence staining for FJB and GFAP. The number of FJB/GFAP+ cells (degenerating astrocytes) was gradually increased with time after tgCI. At 180 days after tgCI, FJB/GFAP+ cells were significantly decreased, but FJB+ cells (dead astrocytes) were significantly increased. In brief, 5 min of tgCI induced a progressive degeneration of CA1 pyramidal neurons from 5 until 30 days with an increase of reactive astrocytes, and, thereafter, astrocytes were degenerated with time and dead at later times. This phenomenon might be shown due to the death of neurons.

scholarly journals Inhibition of MLKL-dependent necroptosis via downregulating interleukin-1R1 contributes to neuroprotection of hypoxic preconditioning in transient global cerebral ischemic rats

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lixuan Zhan ◽  
Xiaomei Lu ◽  
Wensheng Xu ◽  
Weiwen Sun ◽  
En Xu
Keyword(s):  
Plasma Membrane ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Interleukin 1 ◽  
Hypoxic Preconditioning ◽  
Global Cerebral Ischemia ◽  
Free Calcium ◽  
Membrane Translocation ◽  
Vessel Occlusion ◽  
Transient Global Cerebral Ischemia

Abstract Background Our previous study indicated that hypoxic preconditioning reduced receptor interacting protein (RIP) 3-mediated necroptotic neuronal death in hippocampal CA1 of adult rats after transient global cerebral ischemia (tGCI). Although mixed lineage kinase domain-like (MLKL) has emerged as a crucial molecule for necroptosis induction downstream of RIP3, how MLKL executes necroptosis is not yet well understood. In this study, we aim to elucidate the molecular mechanism underlying hypoxic preconditioning that inactivates MLKL-dependent neuronal necroptosis after tGCI. Methods Transient global cerebral ischemia was induced by the four-vessel occlusion method. Twenty-four hours before ischemia, rats were exposed to systemic hypoxia with 8% O2 for 30 min. Western blotting was used to detect the expression of MLKL and interleukin-1 type 1 receptor (IL-1R1) in CA1. Immunoprecipitation was used to assess the interactions among IL-1R1, RIP3, and phosphorylated MLKL (p-MLKL). The concentration of intracellular free calcium ion (Ca2+) was measured using Fluo-4 AM. Silencing and overexpression studies were used to study the role of p-MLKL in tGCI-induced neuronal death. Results Hypoxic preconditioning decreased the phosphorylation of MLKL both in neurons and microglia of CA1 after tGCI. The knockdown of MLKL with siRNA decreased the expression of p-MLKL and exerted neuroprotective effects after tGCI, whereas treatment with lentiviral delivery of MLKL showed opposite results. Mechanistically, hypoxic preconditioning or MLKL siRNA attenuated the RIP3-p-MLKL interaction, reduced the plasma membrane translocation of p-MLKL, and blocked Ca2+ influx after tGCI. Furthermore, hypoxic preconditioning downregulated the expression of IL-1R1 in CA1 after tGCI. Additionally, neutralizing IL-1R1 with its antagonist disrupted the interaction between IL-1R1 and the necrosome, attenuated the expression and the plasma membrane translocation of p-MLKL, thus alleviating neuronal death after tGCI. Conclusions These data support that the inhibition of MLKL-dependent neuronal necroptosis through downregulating IL-1R1 contributes to neuroprotection of hypoxic preconditioning against tGCI.

Improved Resuscitation after Cardiac Arrest in Rats Expressing the Baculovirus Caspase Inhibitor Protein p35 in Central Neurons

2003 ◽  
Vol 99 (1) ◽  
pp. 112-121 ◽  
Author(s):  
Peter Vogel ◽  
Herman v.d. Putten ◽  
Erik Popp ◽  
Jakub J. Krumnikl ◽  
Peter Teschendorf ◽  
...  
Keyword(s):  
Cardiac Arrest ◽  
Cerebral Ischemia ◽  
Neuronal Death ◽  
Neurologic Deficit ◽  
Global Cerebral Ischemia ◽  
Cardiac Massage ◽  
Caspase Inhibitor ◽  
Central Neurons ◽  
Cornu Ammonis ◽  
Baculovirus P35

Background Global cerebral ischemia is associated with delayed neuronal death. Given the role of caspases in apoptosis, caspase inhibitors may provide neuronal protection after cardiac arrest. To this end, the authors generated a transgenic rat line expressing baculovirus p35, a broad-spectrum caspase inhibitor, in central neurons. Its effects were evaluated on neuronal cell death and outcome after global cerebral ischemia. Methods Global cerebral ischemia was induced by cardiocirculatory arrest. After 6 min, animals were resuscitated by controlled ventilation, extrathoracic cardiac massage, epinephrine, and electrical countershocks. Neuronal death was assessed after 7 days by histologic evaluation of the hippocampal cornu ammonis 1 sector. Postischemic outcome was assessed by determination of overall survival and according to neurologic deficit scores 24 h, 3 days, and 7 days after resuscitation. Results The rate of 7-day survival after cardiac arrest for the transgenic rats (85%) was significantly higher than that for the nontransgenic controls (52%; P < 0.05). However, no differences were observed either in the number of terminal deoxynucleotidyltransferase-mediated d-uracil triphosphate-biotin nick end-labeling-positive cells or viable neurons in the cornu ammonis 1 sector or in the neurologic deficit score when comparing surviving transgenic and nontransgenic rats. These findings suggest that neuronal apoptosis after cardiac arrest is not primarily initiated by activation of caspases. Conclusion Expression of baculovirus p35 can improve survival after cardiac arrest in rats, but the mode and site of action remain to be elucidated.

scholarly journals Capsaicin exhibits neuroprotective effects in a model of transient global cerebral ischemia in Mongolian gerbils

2005 ◽  
Vol 144 (5) ◽  
pp. 727-735 ◽  
Author(s):  
Simona Pegorini ◽  
Daniela Braida ◽  
Chiara Verzoni ◽  
Chiara Guerini-Rocco ◽  
Gian Giacomo Consalez ◽  
...  
Keyword(s):  
Cerebral Ischemia ◽  
Global Cerebral Ischemia ◽  
Mongolian Gerbils ◽  
Neuroprotective Effects ◽  
Transient Global Cerebral Ischemia
Sign in / Sign up

Export Citation Format

Share Document