Polyamine metabolism and glutamate receptor agonists-mediated excitotoxicity in the rat brain

by Selleckchem | Jan 28 2024

Putrescine (PUT) increases have been seen in a range of models of neuropathological disturbances. The present study was designed to compare the ability of various types of glutamate receptor agonist to promote excitotoxic brain damage and to examine whether a PUT increase is a general marker of excitotoxic brain damage. To that end, we evaluated features of brain damage associated with the excitotoxicity induced by both ionotropic glutamate receptor (iGluR) and metabotropic glutamate receptor (mGluR) agonists in the conscious rat and the changes produced in the regulation of polyamine metabolism. Intracerebroventricular infusion of N-methyl-D-aspartate (NMDA; 80 nmol), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA; 15 nmol), kainic acid (KA; 2.3 nmol), (R,S)-3,5-dihydroxyphenylglycine (3,5-DHPG; 1.5 micromol), and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD; 2 micromol) produced similar seizure incidences (76-84%) in the rat. The convulsant episodes appeared sooner after iGluR (13-22 min) than after mGluR agonists (50-179 min). Histological analysis of the hippocampus 24 hr after seizures indicated several degrees of excitotoxic injury after equiconvulsive doses of the iGluR and mGluR agonists assayed. The agonists can be placed in the following order, according to the degree of damage they produce: AMPA > 3,5-DHPG approximately KA > NMDA > 1S,3R-ACPD. In the frontal cortex, moderate to low levels of damage were observed after all GluR agonists. Both iGluR- and mGluR-induced seizures produced an overshoot in the hippocampal and cortical PUT concentration, whereas spermidine and spermine levels were similar to control. Moreover, a concurrence of increased PUT levels and brain damage was observed, indicating that PUT is a general marker of excitotoxic brain damage.

Comments:

This study seems to delve into the effects of various glutamate receptor agonists on brain damage in rats and their impact on polyamine metabolism, particularly focusing on putrescine (PUT) levels.

They compared the impact of both ionotropic glutamate receptor (iGluR) and metabotropic glutamate receptor (mGluR) agonists on inducing excitotoxic brain damage. The researchers used different agonists—N-methyl-D-aspartate (NMDA), alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), kainic acid (KA), (R,S)-3,5-dihydroxyphenylglycine (3,5-DHPG), and (1S,3R)-1-aminocyclopentane-1,3-dicarboxylic acid (1S,3R-ACPD)—via intracerebroventricular infusion in conscious rats.

The key findings include:
- Similar seizure incidences were induced by both iGluR and mGluR agonists, although the onset of convulsions was faster with iGluR agonists compared to mGluR agonists.
- Histological analysis after 24 hours revealed varying degrees of excitotoxic injury in the hippocampus and frontal cortex after exposure to the different agonists.
- The order of damage produced by the agonists was AMPA > 3,5-DHPG approximately KA > NMDA > 1S,3R-ACPD in terms of severity.
- Both iGluR and mGluR agonists increased PUT concentration in the hippocampus and frontal cortex, while spermidine and spermine levels remained similar to control.
- The simultaneous increase in PUT levels and brain damage suggests PUT as a general marker of excitotoxic brain damage.

This study not only compares the effects of different glutamate receptor agonists on brain damage but also highlights PUT as a potential marker for such damage. The findings could contribute to understanding the mechanisms underlying excitotoxicity and aid in identifying markers for brain damage in various neuropathological conditions.