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1.
Neurochem Int ; 56(8): 878-85, 2010 Jul.
Article in English | MEDLINE | ID: mdl-20350575

ABSTRACT

This study describes the effect of global brain ischemia followed by 48 h reperfusion, when delayed neuronal death can be already observed. We quantified the mRNA levels of the N-methyl-D-aspartate receptor (NMDAR) subunits and those of the astroglia (glial fibrilar acidic protein, GFAP) and microglia (CD11b) markers using real time PCR on the cerebral cortex and hippocampus of 3- and 18-month-old Sprague-Dawley rats. Data show an ischemia/reperfusion-induced decrease in the mRNA levels of the NMDAR NR1, NR2A and NR2B subunits genes, which contrasts with the increase in the CD11b and GFAP mRNA levels. These effects are attenuated in all the genes studied in 18-month-old animals, suggesting that this mechanism of response is less efficient in aged animals. Western blot assays of NR1, NR2A and NR2B show parallels with the real time PCR data, indicating that the down-regulation of these genes is controlled at the transcriptional level. We suggest that a decrease in the efficiency in the control of the NMDAR transcription could account for the higher vulnerability in aged animals, but it cannot explain by itself differences in the vulnerability to ischemia in different areas of the brain. In the assays of ischemia/reperfusion followed by a treatment with the anti-inflammatory agent meloxicam, we observed that ischemic insult was unable to elicit changes in the NMDAR transcription, thus suggesting that inflammation plays a crucial role in the transcriptional control of these genes.


Subject(s)
Aging/physiology , Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Brain Ischemia/metabolism , Down-Regulation/drug effects , Receptors, N-Methyl-D-Aspartate/antagonists & inhibitors , Receptors, N-Methyl-D-Aspartate/biosynthesis , Reperfusion Injury/metabolism , Thiazines/pharmacology , Thiazoles/pharmacology , Aging/drug effects , Animals , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Brain Ischemia/drug therapy , Brain Ischemia/pathology , Disease Models, Animal , Down-Regulation/genetics , Male , Meloxicam , RNA, Messenger/drug effects , RNA, Messenger/metabolism , Random Allocation , Rats , Rats, Sprague-Dawley , Receptors, N-Methyl-D-Aspartate/genetics , Reperfusion Injury/drug therapy , Thiazines/therapeutic use , Thiazoles/therapeutic use , Treatment Outcome
2.
Brain Res ; 1287: 20-7, 2009 Sep 01.
Article in English | MEDLINE | ID: mdl-19563786

ABSTRACT

Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR) and inflammatory processes have been related to ischemia-induced damage, but there are few studies addressing their response in different brain areas. Here we compare AMPAR expression after ischemia in several brain areas (hippocampus, cerebral cortex and caudate-putamen) in an attempt to correlate it with their different vulnerabilities. We found outstanding decreases in GluR1 and GluR2 mRNA levels after global ischemia and 48 h reperfusion (I/R) in all the areas studied, however, protein levels maintained in some areas such as CA3, suggesting different post-transcriptional control in different areas of the brain. To characterize the inflammatory response in these areas, we measured the mRNA levels of CD11b/CD18 membrane integrin (a reactive microglia marker), which showed an important but similar up-regulation in all brain areas studied, which was confirmed by immunohistochemistry. We conclude that the down-regulation of AMPAR gene expression following I/R does not explain differences in the vulnerability of different areas. Additionally, our data indicate that the level of inflammation is independent of the vulnerability of the different brain areas and does not explain differences in the AMPAR expression observed in the brain areas studied.


Subject(s)
Brain Ischemia/metabolism , Brain Ischemia/pathology , Inflammation Mediators/metabolism , Receptors, AMPA/biosynthesis , Animals , Caudate Nucleus/metabolism , Caudate Nucleus/pathology , Down-Regulation/genetics , Gene Expression Regulation/physiology , Hippocampus/metabolism , Hippocampus/pathology , Inflammation Mediators/physiology , Male , Putamen/metabolism , Putamen/pathology , RNA, Messenger/antagonists & inhibitors , RNA, Messenger/biosynthesis , Rats , Rats, Sprague-Dawley , Receptors, AMPA/genetics , Receptors, AMPA/physiology
3.
Neurochem Int ; 54(3-4): 180-5, 2009.
Article in English | MEDLINE | ID: mdl-19103243

ABSTRACT

The mRNA expression of the major subunits of N-methyl-d-aspartate receptors (NR1, NR2A and NR2B) following ischemia-reperfusion was studied in structures with different vulnerabilities to ischemic insult in the rat brain. The study was performed using quantitative real-time PCR on samples from 3-month-old male Sprague-Dawley rats after global transient forebrain ischemia followed by 48h of reperfusion. Expression of NMDA receptor subunits mRNAs decreased significantly in all structures studied in the injured animals as compared to the sham-operated ones. The hippocampal subfields (CA1, CA3 and dentate gyrus) as well as the caudate-putamen, both reported to be highly ischemic-vulnerable structures, showed outstandingly lower mRNA levels of NMDA receptor subunits than the cerebral cortex, which is considered a more ischemic-resistant structure. The ratios of the mRNA levels of the different subunits were analyzed as a measure of the NMDA receptor expression pattern for each structure studied. Hippocampal areas showed changes in NMDA receptor expression after the insult, with significant decreases in the NR2A with respect to the NR1 and NR2B subunits. Thus, the NR1:NR2A:NR2B (1:1:2) ratios observed in the sham-operated animals became (2:1:4) in insulted animals. This modified expression pattern was similar in CA1, CA3 and the dentate gyrus, in spite of the different vulnerabilities reported for these hippocampal areas. In contrast, no significant differences in the expression pattern were observed in the caudate-putamen or cerebral cortex on comparing the sham-operated animals with the ischemia-reperfused rats. Our results support the notion that the regulation of NMDA receptor gene expression is dependent on the brain structure rather than on the higher or lower vulnerability of the area studied.


Subject(s)
Brain/metabolism , Glutamic Acid/metabolism , Hypoxia-Ischemia, Brain/metabolism , Receptors, N-Methyl-D-Aspartate/genetics , Animals , Brain/anatomy & histology , Brain/physiopathology , Cerebral Cortex/anatomy & histology , Cerebral Cortex/metabolism , Cerebral Cortex/physiopathology , Disease Models, Animal , Down-Regulation/genetics , Gene Expression Regulation/genetics , Hippocampus/anatomy & histology , Hippocampus/metabolism , Hippocampus/physiopathology , Hypoxia-Ischemia, Brain/physiopathology , Male , Neostriatum/anatomy & histology , Neostriatum/metabolism , Neostriatum/physiopathology , Protein Subunits/genetics , RNA, Messenger/metabolism , Rats , Rats, Sprague-Dawley
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