Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke
Acute ischemic stroke (AIS) is the second leading cause of death globally. No Food and Drug Administration (FDA) approved therapies exist that target cerebroprotection following stroke. Our group recently reported significant cerebroprotection with the adenosine A1/A3 receptor agonist, AST-004, in a...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-11-01
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| Series: | Frontiers in Stroke |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fstro.2022.1010928/full |
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| author | Elizabeth S. Fisher Yanan Chen Mikaela M. Sifuentes Jeremy J. Stubblefield Damian Lozano Deborah M. Holstein JingMei Ren Matthew Davenport Nicholas DeRosa Tsung-pei Chen Gerard Nickel Theodore E. Liston James D. Lechleiter |
| author_facet | Elizabeth S. Fisher Yanan Chen Mikaela M. Sifuentes Jeremy J. Stubblefield Damian Lozano Deborah M. Holstein JingMei Ren Matthew Davenport Nicholas DeRosa Tsung-pei Chen Gerard Nickel Theodore E. Liston James D. Lechleiter |
| author_sort | Elizabeth S. Fisher |
| collection | DOAJ |
| description | Acute ischemic stroke (AIS) is the second leading cause of death globally. No Food and Drug Administration (FDA) approved therapies exist that target cerebroprotection following stroke. Our group recently reported significant cerebroprotection with the adenosine A1/A3 receptor agonist, AST-004, in a transient stroke model in non-human primates (NHP) and in a preclinical mouse model of traumatic brain injury (TBI). However, the specific receptor pathway activated was only inferred based on in vitro binding studies. The current study investigated the underlying mechanism of AST-004 cerebroprotection in two independent models of AIS: permanent photothrombotic stroke in mice and transient middle cerebral artery occlusion (MCAO) in rats. AST-004 treatments across a range of doses were cerebroprotective and efficacy could be blocked by A3R antagonism, indicating a mechanism of action that does not require A1R agonism. The high affinity A3R agonist MRS5698 was also cerebroprotective following stroke, but not the A3R agonist Cl-IB-MECA under our experimental conditions. AST-004 efficacy was blocked by the astrocyte specific mitochondrial toxin fluoroacetate, confirming an underlying mechanism of cerebroprotection that was dependent on astrocyte mitochondrial metabolism. An increase in A3R mRNA levels following stroke suggested an intrinsic cerebroprotective response that was mediated by A3R signaling. Together, these studies confirm that certain A3R agonists, such as AST-004, may be exciting new therapeutic avenues to develop for AIS. |
| first_indexed | 2024-03-08T11:10:05Z |
| format | Article |
| id | doaj.art-0f043b6362d049a0a27a5df5e874d5c6 |
| institution | Directory Open Access Journal |
| issn | 2813-3056 |
| language | English |
| last_indexed | 2024-03-08T11:10:05Z |
| publishDate | 2022-11-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Stroke |
| spelling | doaj.art-0f043b6362d049a0a27a5df5e874d5c62024-01-26T11:16:00ZengFrontiers Media S.A.Frontiers in Stroke2813-30562022-11-01110.3389/fstro.2022.10109281010928Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic strokeElizabeth S. Fisher0Yanan Chen1Mikaela M. Sifuentes2Jeremy J. Stubblefield3Damian Lozano4Deborah M. Holstein5JingMei Ren6Matthew Davenport7Nicholas DeRosa8Tsung-pei Chen9Gerard Nickel10Theodore E. Liston11James D. Lechleiter12Department of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesNeuroVasc Preclinical Services, Inc., Lexington, MA, United StatesNeuroVasc Preclinical Services, Inc., Lexington, MA, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesAstrocyte Pharmaceuticals Inc., Cambridge, MA, United StatesDepartment of Cell Systems and Anatomy, University of Texas Health at San Antonio, San Antonio, TX, United StatesAcute ischemic stroke (AIS) is the second leading cause of death globally. No Food and Drug Administration (FDA) approved therapies exist that target cerebroprotection following stroke. Our group recently reported significant cerebroprotection with the adenosine A1/A3 receptor agonist, AST-004, in a transient stroke model in non-human primates (NHP) and in a preclinical mouse model of traumatic brain injury (TBI). However, the specific receptor pathway activated was only inferred based on in vitro binding studies. The current study investigated the underlying mechanism of AST-004 cerebroprotection in two independent models of AIS: permanent photothrombotic stroke in mice and transient middle cerebral artery occlusion (MCAO) in rats. AST-004 treatments across a range of doses were cerebroprotective and efficacy could be blocked by A3R antagonism, indicating a mechanism of action that does not require A1R agonism. The high affinity A3R agonist MRS5698 was also cerebroprotective following stroke, but not the A3R agonist Cl-IB-MECA under our experimental conditions. AST-004 efficacy was blocked by the astrocyte specific mitochondrial toxin fluoroacetate, confirming an underlying mechanism of cerebroprotection that was dependent on astrocyte mitochondrial metabolism. An increase in A3R mRNA levels following stroke suggested an intrinsic cerebroprotective response that was mediated by A3R signaling. Together, these studies confirm that certain A3R agonists, such as AST-004, may be exciting new therapeutic avenues to develop for AIS.https://www.frontiersin.org/articles/10.3389/fstro.2022.1010928/fullAdora3stroke treatmentmitochondrial metabolismATPastrocytes |
| spellingShingle | Elizabeth S. Fisher Yanan Chen Mikaela M. Sifuentes Jeremy J. Stubblefield Damian Lozano Deborah M. Holstein JingMei Ren Matthew Davenport Nicholas DeRosa Tsung-pei Chen Gerard Nickel Theodore E. Liston James D. Lechleiter Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke Frontiers in Stroke Adora3 stroke treatment mitochondrial metabolism ATP astrocytes |
| title | Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke |
| title_full | Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke |
| title_fullStr | Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke |
| title_full_unstemmed | Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke |
| title_short | Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke |
| title_sort | adenosine a1r a3r agonist ast 004 reduces brain infarction in mouse and rat models of acute ischemic stroke |
| topic | Adora3 stroke treatment mitochondrial metabolism ATP astrocytes |
| url | https://www.frontiersin.org/articles/10.3389/fstro.2022.1010928/full |
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