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Published on: January 10, 2025
AMPA receptor downregulation induced by ischaemia/reperfusion is attenuated by age and blocked by meloxicam
S Montori1, S Dos Anjos, M A Ríos-Granja
1Area de Biología Celular, Instituto de Biomedicina. Universidad de León, 24071 León, Spain.
Aim:
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.
Conclusion:
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.
Insights
Ageing affects alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor (AMPAR) subunits and editing enzyme ADAR2 levels after brain ischemia. Meloxicam treatment offers protection, suggesting inflammation
Area of Science:
- Neuroscience
- Ischemia Research
- Aging Studies
Background:
- Stroke risk and severity increase with age.
- Alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPAR) and inflammation are implicated in ischemia-induced brain damage.
- Age-related changes in AMPAR subunits and their editing enzymes may influence vulnerability to ischemia.
Purpose of the Study:
- To investigate how aging and meloxicam treatment affect AMPAR subunits (GluR1, GluR2) and ADAR2 mRNA levels following global brain ischemia/reperfusion (I/R).
- To explore the role of inflammation in age-dependent vulnerability to I/R injury.
Main Methods:
- Global brain I/R model in young (3-month) and aged (18-month) Sprague-Dawley rats.
- Analysis of AMPAR subunits GluR1 and GluR2, and ADAR2 mRNA levels using real-time PCR, Western blotting, and immunohistochemistry.
- Assessment of meloxicam's effect on young animals post-I/R.
Main Results:
- Aging attenuated I/R-induced downregulation of GluR1 and GluR2, altering the GluR1/GluR2 mRNA ratio structurally.
- Older rats exhibited greater ADAR2 mRNA downregulation compared to younger rats.
- Meloxicam treatment prevented I/R-induced transcriptional arrest.
Conclusions:
- Age-associated alterations in AMPAR isoforms may contribute to differential brain region vulnerability to ischemia.
- While GluR2 editing appears involved in age-dependent ischemia vulnerability, it doesn't fully explain regional differences.
- Inflammation may confer protection against I/R-induced brain injury.
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