Blockade of the second messenger functions of the glutamate metabotropic receptor is associated with degenerative changes in the retina and brain of immature rodents.
Activation of metabotropic glutamate receptors (mGluR) by Glu or related mGluR agonists triggers phosphoinositide (PI) hydrolysis, intracellular Ca2+ mobilization and protein kinase C activation. These mGluR agonist-stimulated events are inhibited strongly by 2-amino-3-phosphono-L-propionic acid (L-AP3) and L-aspartate-beta-hydroxamate (L-A beta H), and much more weakly by D-AP3 and L-serine-O-phosphate (L-SOP). Daily s.c. administration of DL-AP3 subchronically to infant rodents causes the developing retina and optic nerves to degenerate. In the present study, we describe the evolution of the cytopathological reaction in the developing rodent retina following DL-AP3 treatment and show that DL-AP3 can induce similar cytopathological changes in several regions of the immature rodent brain. In addition, we show that the retinotoxic action of DL-AP3 is mimicked by L-A beta H but not by L-SOP, and that L-AP3 is a much stronger retinotoxin that D-AP3. These observations suggest a possible mechanistic link between the PI-hydrolysis blocking action and retinotoxic action. Our findings are consistent with the hypothesis that under normal physiological circumstances, the Glu metabotropic receptor through its PI-hydrolysis-linked second messenger functions provides vitally important support for developing neurons, and that disruption of this support can cause widespread neuronal degeneration.
Department of Psychiatry, Washington University School of Medicine, St Louis, MO 63110, USA.
M T
MT
Price
C
C
Romano
A S
AS
Fix
J P
JP
Tizzano
J W
JW
Olney
D000409:Alanine / Q000031:analogs & derivatives / Q000633:toxicity; D000818:Animals; D000831:Animals, Newborn; D001216:Asparagine / Q000031:analogs & derivatives / Q000494:pharmacology; D001927:Brain Diseases / Q000139:chemically induced* / Q000473:pathology; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D007536:Isomerism; D051379:Mice; D008813:Mice, Inbred ICR; D009410:Nerve Degeneration / Q000187:drug effects*; D009900:Optic Nerve / Q000473:pathology; D010768:Phosphoserine / Q000494:pharmacology; D051381:Rats; D018094:Receptors, Metabotropic Glutamate / Q000037:antagonists & inhibitors*; D012162:Retinal Degeneration / Q000139:chemically induced* / Q000473:pathology; D015290:Second Messenger Systems / Q000187:drug effects*
D018691:Excitatory Amino Acid Antagonists; D018094:Receptors, Metabotropic Glutamate; C000211:2-amino-3-phosphonopropionic acid; D010768:Phosphoserine; C024848:beta-aspartylhydroxamic acid; D001216:Asparagine; D000409:Alanine