AMPA receptor downregulation induced by ischaemia/reperfusion is attenuated by age and blocked by meloxicam.
OBJECTIVE
Stroke prevalence increases with age, while alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) and inflammation have been related to ischaemia-induced damage. This study shows how age and treatment with an anti-inflammatory agent (meloxicam) modify the levels of AMPAR subunits GluR1 and GluR2, as well as the mRNA levels of the GluR2-editing enzyme, ADAR2, in a global brain ischaemia/reperfusion (I/R) model.


METHODS
Two days after global ischaemia CA1, CA3, dentate gyrus and cerebral cortex were obtained from sham-operated and I/R-injured 3- and 18-month-old Sprague-Dawley rats. Real time polymerase chain reaction, Western blotting and immunohistochemical assays were performed. Meloxicam treatment was assayed on young animals.


RESULTS
Data showed that age attenuates the downregulation induced by I/R in the AMPAR subunits GluR1 and GluR2 and modifies the GluR1/GluR2 mRNA level ratio in a structure-dependent way. The study of the ADAR2 mRNA levels showed more downregulation in older animals than young ones. Meloxicam treatment prevented the transcriptional arrest induced by I/R.


CONCLUSIONS
Our data suggest that changes in the AMPAR isoforms could be associated with ageing in the different structures studied. Although GluR2 editing seems to be involved in age-dependent vulnerability to ischaemia supporting the 'GluR2 hypothesis', this alone does not explain the differential vulnerability in the different brain regions. Finally, inflammation could play a role in protection from I/R-induced injury.
Montori
S
S
Area de Biología Celular, Instituto de Biomedicina. Universidad de León, 24071 León, Spain.
Dos Anjos
S
S
Ríos-Granja
M A
MA
Pérez-García
C C
CC
Fernández-López
A
A
Martínez-Villayandre
B
B
D000243:Adenosine Deaminase / Q000235:genetics; D000375:Aging / Q000502:physiology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D015415:Biomarkers / Q000378:metabolism; D039481:CD11b Antigen / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D015870:Gene Expression / Q000187:drug effects; D008297:Male; D000077239:Meloxicam; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D018091:Receptors, AMPA / Q000235:genetics / Q000378:metabolism*; D015427:Reperfusion Injury / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D020521:Stroke / Q000188:drug therapy / Q000276:immunology / Q000378:metabolism; D013843:Thiazines / Q000494:pharmacology*; D013844:Thiazoles / Q000494:pharmacology*
D000243:Adenosine Deaminase; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D039481:CD11b Antigen; D000077239:Meloxicam; D012333:RNA, Messenger; D018091:Receptors, AMPA; D013843:Thiazines; D013844:Thiazoles; C104722:glutamate receptor ionotropic, AMPA 2