scholarly journals Neuroprotective Effect of YM9OK, an AMPA-Receptor Antagonist,against Delayed Neuronal Death Induced by Transient Global Cerebral Ischemia in Gerbils and Rats.

1997 ◽  
Vol 74 (3) ◽  
pp. 253-260 ◽  
Author(s):  
Sachiko Kawasaki-Yatsugi ◽  
Shin-ichi Yatsugi ◽  
Kazuo Koshiya ◽  
Masao Shimizu-Sasamata
Keyword(s):  
Cerebral Ischemia ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Neuronal Death ◽  
Neuroprotective Effect ◽  
Delayed Neuronal Death ◽  
Global Cerebral Ischemia ◽  
Ampa Receptor Antagonist ◽  
Transient Global Cerebral Ischemia

scholarly journals Neuroprotective Effect of the AMPA Receptor Antagonist LY-293558 in Focal Cerebral Ischemia in the Cat

1994 ◽  
Vol 14 (3) ◽  
pp. 466-471 ◽  
Author(s):  
R. Bullock ◽  
D. I. Graham ◽  
S. Swanson ◽  
J. McCulloch
Keyword(s):  
Cerebral Ischemia ◽  
Middle Cerebral Artery ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Cerebral Artery ◽  
Focal Cerebral Ischemia ◽  
Neuroprotective Effect ◽  
Ischemic Damage ◽  
Physiological Variables ◽  
Ampa Receptor Antagonist

The effects of the glutamate α-amino-3-hydroxy 5-methyl-4-isoxazole propionate (AMPA) receptor antagonist LY-293558 in reducing ischemic brain damage have been assessed in halothane-anesthetized cats. Focal cerebral ischemia was produced by permanent occlusion of one middle cerebral artery, and the animals were killed 6 h later. The amount of early irreversible ischemic damage was assessed at 16 predetermined stereotactic planes by an observer blinded to treatment paradigm employed. Treatment with LY-293558 (15 mg/kg i.v., plus infusion of 7 mg/kg/h) initiated 30 min prior to middle cerebral artery occlusion reduced significantly (p < 0.02) the volume of ischemic damage (from 3,423 ± 212 mm3 of the cerebral hemisphere in vehicle-treated cats to 2,822 ± 569 mm3 in LY-293558-treated cats). The present data demonstrate that an AMPA receptor antagonist can reduce focal ischemic damage in a gyrencephalic species in which key physiological variables have been controlled and monitored throughout the postischemic period. These data provide additional support for the clinical evaluation of AMPA receptor antagonists in focal cerebral ischemia in humans.

scholarly journals Effects of the AMPA-Receptor Antagonist, NBQX, on Neuron Loss in Dentate Hilus of the Hippocampal Formation after 8, 10, or 12 Min of Cerebral Ischemia in the Rat

1997 ◽  
Vol 17 (2) ◽  
pp. 147-152 ◽  
Author(s):  
Ping Hu ◽  
Nils Henrik Diemer ◽  
Torben Bruhn ◽  
Flemming Fryd Johansen
Keyword(s):  
Cerebral Ischemia ◽  
Receptor Antagonist ◽  
Ampa Receptor ◽  
Hippocampal Formation ◽  
Neuroprotective Effect ◽  
Pyramidal Cells ◽  
Ca1 Pyramidal Cells ◽  
Ampa Receptor Antagonist ◽  
Hippocampal Ca1 ◽  
Dentate Hilus

The α-amino-3-hydroxy-5-methyl-4-isoxazole (AMPA) receptor antagonist, 2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo( F)quinoxaline (NBQX), offers protection to hippocampal CA1 pyramidal cells after short episodes of transient cerebral ischemia. Besides CA1 pyramidal cells, neurons containing somatostatin (SS) and located in the dentate hilus of the hippocampal formation are lost after cerebral ischemia. We studied the protective effects of NBQX on SS neurons in the hilus and on hippocampal CA1 pyramidal cells following 8, 10, or 12 min of four-vessel occlusion ischemia during systemic hypotension. NBQX was administered 3 × 30 mg/kg at 0, 10, and 25 after induction of ischemia or sham, and all rats survived for 7 days. NBQX given to control rats without ischemia had no influence on number or morphology of hilar SS neurons and CA1 pyramidal cells. After 8 min of ischemia, NBQX prevented loss of hilar SS neurons. After 10 and 12 min of ischemia, NBQX had no significant effects on loss of SS neurons in the dentate hilus. However, in all ischemic groups, NBQX significantly reduced loss of CA1 pyramidal cells as compared to control rats. This neuroprotective effect decreased gradually and significantly as the time of ischemia increased. Our results support the observation that SS neurons in hilus are among the most ischemia-vulnerable neurons in the brain. We found that administration of NBQX in generally accepted dosages can protect the rapidly dying SS neurons in hilus from only brief episodes of ischemia.

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.

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