Jennifer Gile 1 , Yoshimasa Oyama 1 , Sydney Shuff 1 , Tobias Eckle 1 Show Affiliations »
Abstract
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. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
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 . Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.
Entities: CellLine
Chemical
Disease
Gene
Species
Keywords:
Adora2b; BAY-60-6583; Bdnf; C-fos; Per2; T maze; cognitive function; delirium
Year: 2020
PMID： 32294028 PMCID： PMC7572481 DOI： 10.2174/1381612826666200415171622
Source DB: PubMed Journal: Curr Pharm Des ISSN： 1381-6128 Impact factor: 3.116