The Neuroprotective Effect of the Novel AMPA Receptor Antagonist PD152247 (PNQX) in Temporary Focal Ischemia in the Rat

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.

Download Full-text

Therapeutic window of opportunity for the neuroprotective effect of valproate versus the competitive AMPA receptor antagonist NS1209 following status epilepticus in rats

Neuropharmacology ◽

10.1016/j.neuropharm.2011.06.015 ◽

2011 ◽

Vol 61 (5-6) ◽

pp. 1033-1047 ◽

Cited By ~ 28

Author(s):

Melanie Langer ◽

Claudia Brandt ◽

Christina Zellinger ◽

Wolfgang Löscher

Keyword(s):

Status Epilepticus ◽

Receptor Antagonist ◽

Ampa Receptor ◽

Neuroprotective Effect ◽

Therapeutic Window ◽

Window Of Opportunity ◽

Ampa Receptor Antagonist

Download Full-text

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

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/00004647-199702000-00003 ◽

1997 ◽

Vol 17 (2) ◽

pp. 147-152 ◽

Cited By ~ 9

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.

Download Full-text