DNA microarray analysis of the contused spinal cord: effect of NMDA receptor inhibition.
Spinal cord injury (SCI)-induced neurodegeneration leads to irreversible and devastating motor and sensory dysfunction. Post-traumatic outcomes are determined by events occurring during the first 24 hours after SCI. An increase in extracellular glutamate concentration to neurotoxic levels is one of the earliest events after SCI. We used Affymetrix DNA oligonucleotide microarrays (with 1,322 DNA probes) analysis to measure gene expression in order to test the hypothesis that SCI-induced N-methyl-D-aspartate (NMDA) receptor activation triggers significant postinjury transcriptional changes. Here we report that SCI, 1 hour after trauma, induced change in mRNA levels of 165 genes and expression sequence tags (ESTs). SCI affected mRNA levels of those genes that regulate predominantly transcription factors, inflammation, cell survival, and membrane excitability. We also report that NMDA receptor inhibition (with -(+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]-cyclohepten-5,10-imine hydrogen maleate [MK-801]) reversed the effect of SCI on about 50% of the SCI-affected mRNAs. Especially interesting is the finding that NMDA receptor activation participates in the up-regulation of inflammatory factors. Therefore, SCI-induced NMDA receptor activation is one of the dominant, early signals after trauma that leads to changes in mRNA levels of a number of genes relevant to recovery processes. The majority of MK-801 effects on the SCI-induced mRNA changes reported here are novel. Additionally, we found that the MK-801 treatment also changed the mRNA levels of 168 genes and ESTs that had not been affected by SCI alone, and that some of their gene products could have harmful effects on SCI outcome.
Nesic
O
O
Department of Human Biological Chemistry and Genetics, University of Texas Medical Branch, Galveston, Texas 77555-0652, USA. Olnesic@utmb.edu
Svrakic
N M
NM
Xu
G-Y
GY
McAdoo
D
D
Westlund
K N
KN
Hulsebosch
C E
CE
Ye
Zeiming
Z
Galante
A
A
Soteropoulos
P
P
Tolias
P
P
Young
W
W
Hart
R P
RP
Perez-Polo
J R
JR
D000818:Animals; D016000:Cluster Analysis; D003288:Contusions; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology; D005455:Fluorescent Antibody Technique; D020869:Gene Expression Profiling; D007278:Injections, Spinal; D008297:Male; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D013119:Spinal Cord Injuries / Q000235:genetics / Q000378:metabolism*
D018691:Excitatory Amino Acid Antagonists; D018696:Neuroprotective Agents; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate