NMDA and AMPA receptor expression and cortical neuronal death are associated with p38 in glutamate-induced excitotoxicity in vivo.
Early overstimulation of ionotropic glutamate receptors (iGluRs), such as the N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionate (AMPA) receptors, produces excitotoxicity in several brain regions. The molecular composition of those receptors and their regulation by intracellular signaling systems could be determinants in the development of progressive neurodegenerative mechanisms in the central nervous system (CNS). Studies of p38 mitogen-activated protein kinase (MAPK) activation, morphologic changes including cell number, and the expression of the NR1 and GluR2 subunits, by reverse transcriptase-PCR were evaluated at early postnatal ages (postnatal day [PD]8-14) in cerebral cortex of rats treated with monosodium glutamate (MSG; 4 mg/g body weight) administered subcutaneously on PD1, 3, 5, and 7. An important increase in p38 activity at PD8 and loss of cortical cell number were observed from PD8-14 in animals treated with MSG, together with significant morphologic changes characterized by cell shrinkage, nuclear hyperchromatism, and cytoplasmic vacuolation. These morphologic changes were prevented by SB203580, an inhibitor of p38 signaling, at PD8-14. No change in cerebral cortex thickness was observed among experimental or control rats. A significant increase in NR1 subunit expression was observed in response to MSG from PD8-14. GluR2 expression increased from PD8-12, but at PD14, its expression was reduced to 54% with respect to controls. SB203580 prevented alone the decreased in GluR2 expression induced by MSG. These results suggest that initial neuronal death (at PD8 and 10) in cerebral cortex may be due to an excessive Ca2+ influx through NMDA receptors, whereas the further damage process could be mediated by AMPA receptors through p38 signaling. This could represent a determinant mechanism to decide whether nerve cells survive or die.
Rivera-Cervantes
M C
MC
Laboratorio de Neurobiología Celular y Molecular, Departamento de Biología Celular y Molecular, Centro Universitario de Ciencias Biológicas y Agropecuarias, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico.
Torres
J Segura
JS
Feria-Velasco
A
A
Armendariz-Borunda
J
J
Beas-Zárate
C
C
D051698:Activating Transcription Factor 2; D000367:Age Factors; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D002352:Carrier Proteins; D016923:Cell Death / Q000187:drug effects*; D002470:Cell Survival; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000254:growth & development; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D003720:Densitometry / Q000379:methods; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D018698:Glutamic Acid / Q000633:toxicity*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D020287:In Situ Nick-End Labeling / Q000379:methods; D008297:Male; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000502:physiology*; D009474:Neurons / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D011247:Pregnancy; D021122:Protein Subunits / Q000235:genetics / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D014157:Transcription Factors / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases
D051698:Activating Transcription Factor 2; C087299:C1QBP protein, human; C490195:C1qbp protein, rat; D002352:Carrier Proteins; D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018960:Hyaluronan Receptors; D007093:Imidazoles; D024101:Mitochondrial Proteins; D021122:Protein Subunits; D011725:Pyridines; D012333:RNA, Messenger; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D014157:Transcription Factors; D018698:Glutamic Acid; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580