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Cerebral protection by AMPA- and NMDA-receptor antagonists administered after severe insulin-induced hypoglycemia
1Laboratory for Experimental Brain Research, Lund University Hospital, Sweden.
Abstract:
Excitatory amino acids are implicated in the development of neuronal cell damage following periods of reversible cerebral ischemia or insulin-induced hypoglycemic coma. To explore the importance of glutamate receptor activation in the posthypoglycemic phase, we exposed rats to 20 min of insulin-induced severe hypoglycemia. The rats were treated immediately after the hypoglycemic insult with four regimes of glutamate receptor antagonists: (1) the AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazole propriate)-receptor antagonist NBQX [2.3-dihydroxy-6-nitro-7-sulfamoyl-benzo (F) quinoxaline] given as a bolus dose of 30 mg.kg-1 i.p., followed by an i.v. infusion of 225 micrograms.kg-1.min-1 for 6 h; (2) the non-competitive NMDA-receptor antagonist, dizocilpine (MK-801) 1 mg.kg-1 given i.v.; (3) a combined NBQX treatment, (a bolus dose of 10 mg.kg-1 i.p., followed by an i.v. infusion of 225 micrograms.kg-1.min-1 for 6 h), with dizocilpine 0.33 mg.kg-1 given twice i.p. at 0 and 15 min after recovery and (4) the competitive NMDA-receptor blocker CGP 40,116 [D-(E)-2-amino-4-methyl-5-phosphono-3- pentenoic acid] 10 mg.kg-1 given i.p. In the striatum, all glutamate receptor blockers significantly decreased neuronal damage by approximately 30%. An approximately 50% decrease in neuronal damage was demonstrated in neocortex and hippocampus following the combined treatment with NBQX and dizocilpine, while protection was variable following the treatment with a single glutamate-receptor antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)
Insights
Glutamate receptor antagonists, including NBQX and dizocilpine, reduced neuronal damage after hypoglycemia. Combined treatment offered the most significant neuroprotection in rat models.
Area of Science:
- Neuroscience
- Pharmacology
Background:
- Excitatory amino acids contribute to neuronal damage after cerebral ischemia and hypoglycemia.
- Glutamate receptor activation plays a role in posthypoglycemic neuronal injury.
Purpose of the Study:
- To investigate the neuroprotective effects of glutamate receptor antagonists in a rat model of insulin-induced hypoglycemia.
- To evaluate the efficacy of AMPA and NMDA receptor antagonists, individually and in combination, in reducing posthypoglycemic neuronal damage.
Main Methods:
- Rats were subjected to 20 minutes of severe insulin-induced hypoglycemia.
- Treatment regimens included NBQX (AMPA antagonist), dizocilpine (NMDA antagonist), CGP 40,116 (NMDA antagonist), and combinations thereof.
- Neuronal damage was assessed in the striatum, neocortex, and hippocampus.
Main Results:
- All tested glutamate receptor antagonists significantly reduced neuronal damage in the striatum by approximately 30%.
- Combined treatment with NBQX and dizocilpine achieved a ~50% reduction in neuronal damage in the neocortex and hippocampus.
- Neuroprotection varied when single glutamate receptor antagonists were administered.
Conclusions:
- Glutamate receptor antagonism confers significant neuroprotection against hypoglycemia-induced neuronal damage.
- Combined blockade of AMPA and NMDA receptors demonstrates superior efficacy in protecting vulnerable brain regions.
- Targeting glutamate receptors is a promising therapeutic strategy for managing posthypoglycemic brain injury.