A Role for the Adenosine ADORA2B Receptor in Midazolam Induced Cognitive Dysfunction
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Jennifer Gile1, Yoshimasa Oyama1, Sydney Shuff1
1Department of Anesthesiology, University of Colorado School of Medicine, Aurora, CO 80045, United States.
Background:
We recently reported a role for the circadian rhythm protein Period 2 (PER2) in midazolam induced cognitive dysfunction. Based on previous studies showing a critical role for the adenosine A2B receptor (ADORA2B) in PER2 regulation, we hypothesized that hippocampal ADORA2B is crucial for cognitive function.
Methods:
Midazolam treated C57BL/6J mice were analyzed for Adora2b hippocampal mRNA expression levels, and spontaneous T-maze alternation was determined in Adora2b-/- mice. Using the specific ADORA2B agonist BAY-60-6583 in midazolam treated C57BL/6J mice, we analyzed hippocampal Per2 mRNA expression levels and spontaneous T-maze alternation. Finally, Adora2b-/- mice were assessed for mRNA expression of markers for inflammation or cognitive function in the hippocampus.
Results:
Midazolam treatment significantly downregulated Adora2b or Per2 mRNA in the hippocampus of C57BL/6J mice, and hippocampal PER2 protein expression or T-maze alternation was significantly reduced in Adora2b-/- mice. ADORA2B agonist BAY-60-6583 restored midazolam mediated reduction in spontaneous alternation in C57BL/6J mice. Analysis of hippocampal Tnf-α or Il-6 mRNA levels in Adora2b-/- mice did not reveal an inflammatory phenotype. However, C-fos, a critical component of hippocampus-dependent learning and memory, was significantly downregulated in the hippocampus of Adora2b-/- mice.
Conclusion:
These results suggest a role of ADORA2B in midazolam induced cognitive dysfunction. Further, our data demonstrate that BAY-60-6583 treatment restores midazolam induced cognitive dysfunction, possibly via increases of Per2. Additional mechanistic studies hint towards C-FOS as another potential underlying mechanism of memory impairment in Adora2b-/- mice. These findings suggest the ADORA2B agonist as a potential therapy in patients with midazolam induced cognitive dysfunction.
Insights
Adenosine A2B receptor (ADORA2B) plays a key role in midazolam-induced cognitive dysfunction. Targeting ADORA2B with BAY-60-6583 may restore memory function, potentially offering a therapeutic strategy for related cognitive impairments.
Area of Science:
- Neuroscience
- Pharmacology
- Chronobiology
Background:
- Previous research implicated the circadian rhythm protein Period 2 (PER2) in midazolam-induced cognitive dysfunction.
- The adenosine A2B receptor (ADORA2B) is known to regulate PER2, suggesting its involvement in cognitive processes.
Purpose of the Study:
- To investigate the role of hippocampal ADORA2B in cognitive function.
- To determine if ADORA2B modulation can ameliorate midazolam-induced cognitive deficits.
Main Methods:
- Assessed hippocampal Adora2b and Per2 mRNA expression in midazolam-treated mice.
- Evaluated spontaneous T-maze alternation in Adora2b knockout mice and after ADORA2B agonist treatment.
- Examined hippocampal inflammatory markers and C-fos expression in Adora2b knockout mice.
Main Results:
- Midazolam treatment downregulated hippocampal Adora2b and Per2 mRNA.
- Adora2b knockout mice exhibited reduced PER2 expression and impaired T-maze alternation.
- The ADORA2B agonist BAY-60-6583 reversed midazolam-induced cognitive deficits.
- C-fos, a memory-related gene, was downregulated in Adora2b knockout mice, but no inflammatory phenotype was observed.
Conclusions:
- ADORA2B is implicated in midazolam-induced cognitive dysfunction.
- BAY-60-6583 treatment shows potential for restoring cognitive function, possibly through PER2 modulation.
- C-FOS downregulation may also contribute to memory impairment, suggesting ADORA2B agonists as a therapeutic avenue.
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