Neuroprotective Roles of the Adenosine A3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury

Bozdemir, Eda; Vigil, Fabio A; Chun, Sang H; Espinoza, Liliana; Bugay, Vladislav; Khoury, Sarah M; Holstein, Deborah; Stoja, Aiola; Lozano, Damian; Tunca, Ceyda; Sprague, Shane; Cavazos, Jose ́E.; Brenner, Robert; Liston, Theodore E.; Shapiro, Mark S.; Lechleiter, James D.

doi:10.1007/s13311-021-01113-7

Cited by 13 publications

(13 citation statements)

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“…Subsequent work showed these phosphorylated nucleotides were rapidly metabolized in vivo and that the active cerebroprotective compounds were likely the metabolites of MRS2365 and 2MeSADP, AST-004 and 2-methylthioadenosine, respectively (Liston et al, 2020). We confirmed AST-004 treatments were cerebroprotective after TBI in mice (Bozdemir et al, 2021) and tMCAO in non-human primates (Liston et al, 2022). Binding studies showed AST-004 was primarily an A3R agonist with some affinity for A1Rs (Liston et al, 2020).…”

Section: Discussionsupporting

confidence: 65%

“…We tested 3 AST-004 doses a full log difference from each other: low (0.022 mg/kg), mid (0.22 mg/kg), and high (2.2 mg/kg) concentrations. Previous work by our group had demonstrated significant cerebroprotective efficacy after traumatic brain injury at the mid-dose (0.22 mg/kg) ( Bozdemir et al, 2021 ). We found that all 3 doses significantly decreased lesion volume ( Figures 1B , C ).…”

Section: Resultsmentioning

confidence: 93%

“…We also found increased levels of A3R mRNA following stroke, revealing an intrinsic protective response that could be exploited for treatment. A3R agonists have been reported as cerebroprotective against stroke since the mid-1990s ( Rudolphi et al, 1992 ; von Lubitz et al, 1994 , 1995 , 1999 , 2001 ; Rudolphi and Schubert, 1995 ; Fedorova et al, 2003 ; Choi et al, 2005 , 2011 ; Chen et al, 2006 ; Bjorklund et al, 2008 ), and most recently for TBI ( Farr et al, 2020 ; Bozdemir et al, 2021 ). Together, these studies confirm that certain A3R agonists, such as AST-004, may be exciting new treatment options that need to be developed for clinical evaluation.…”

Section: Introductionmentioning

confidence: 99%

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Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke

et al. 2022

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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.

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Section: Discussionsupporting

confidence: 65%

Section: Resultsmentioning

confidence: 93%

Section: Introductionmentioning

confidence: 99%

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Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke

et al. 2022

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“…In a mouse model of traumatic brain injury, the adenosine A 3 receptor agonist AST-004 decreased the permeability of BBB and neuroinflammation, and enhanced spatial memory ( Bozdemir et al, 2021 ). Intervention with AST-004 boosted ATP production in astrocytes and enhanced neuroprotective efficacy after brain injury; however, the precise mechanism of enhancing BBB function requires additional investigation.…”

Section: Adenosine and Adenosine (P1) Receptorsmentioning

confidence: 99%

Purinergic signaling: A gatekeeper of blood-brain barrier permeation

Wang

Zhu²,

Wang³

et al. 2023

Front. Pharmacol.

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This review outlined evidence that purinergic signaling is involved in the modulation of blood-brain barrier (BBB) permeability. The functional and structural integrity of the BBB is critical for maintaining the homeostasis of the brain microenvironment. BBB integrity is maintained primarily by endothelial cells and basement membrane but also be regulated by pericytes, neurons, astrocytes, microglia and oligodendrocytes. In this review, we summarized the purinergic receptors and nucleotidases expressed on BBB cells and focused on the regulation of BBB permeability by purinergic signaling. The permeability of BBB is regulated by a series of purinergic receptors classified as P2Y1, P2Y4, P2Y12, P2X4, P2X7, A1, A2A, A2B, and A3, which serve as targets for endogenous ATP, ADP, or adenosine. P2Y1 and P2Y4 antagonists could attenuate BBB damage. In contrast, P2Y12-mediated chemotaxis of microglial cell processes is necessary for rapid closure of the BBB after BBB breakdown. Antagonists of P2X4 and P2X7 inhibit the activation of these receptors, reduce the release of interleukin-1 beta (IL-1β), and promote the function of BBB closure. In addition, the CD39/CD73 nucleotidase axis participates in extracellular adenosine metabolism and promotes BBB permeability through A1 and A2A on BBB cells. Furthermore, A2B and A3 receptor agonists protect BBB integrity. Thus, the regulation of the BBB by purinergic signaling is complex and affects the opening and closing of the BBB through different pathways. Appropriate selective agonists/antagonists of purinergic receptors and corresponding enzyme inhibitors could modulate the permeability of the BBB, effectively delivering therapeutic drugs/cells to the central nervous system (CNS) or limiting the entry of inflammatory immune cells into the brain and re-establishing CNS homeostasis.

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“…Furthermore, in the mouse transient middle cerebral artery occlusion (MCAO) ligation model, increased cerebral damage was noted in A 3 AR KO compared to WT mice [ 131 ]. Although the cerebroprotective effects of A 3 AR agonists were initially only demonstrated in mice, gerbils and rats [ 148 , 149 ], recently the efficacy of a mixed A 1 /A 3 agonist AST-004 (MRS4322) was observed in the MCAO model in macaques [ 150 ]. Thus, the role of the A 3 AR in cardiac and brain ischemia has been confirmed in several species.…”

Section: A 3 Ar Functions In Cells Tissues or Anim...mentioning

confidence: 99%

Species dependence of A3 adenosine receptor pharmacology and function

Gao

Auchampach

Jacobson

2022

Purinergic Signalling

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Efforts to fully understand pharmacological differences between G protein-coupled receptor (GPCR) species homologues are generally not pursued in detail during the drug development process. To date, many GPCRs that have been successfully targeted are relatively well-conserved across species in amino acid sequence and display minimal variability of biological effects. However, the A 3 adenosine receptor (AR), an exciting drug target for a multitude of diseases associated with tissue injury, ischemia, and inflammation, displays as little as 70% sequence identity among mammalian species (e.g., rodent vs. primate) commonly used in drug development. Consequently, the pharmacological properties of synthetic A 3 AR ligands vary widely, not only in binding affinity, selectivity, and signaling efficacy, but to the extent that some function as agonists in some species and antagonists in others. Numerous heterocyclic antagonists that have nM affinity at the human A 3 AR are inactive or weakly active at the rat and mouse A 3 ARs. Positive allosteric modulators, including the imidazo [4,5-c]quinolin-4-amine derivative LUF6000, are only active at human and some larger animal species that have been evaluated (rabbit and dog), but not rodents. A 3 AR agonists evoke systemic degranulation of rodent, but not human mast cells. The rat A 3 AR undergoes desensitization faster than the human A 3 AR, but the human homologue can be completely re-sensitized and recycled back to the cell surface. Thus, comprehensive pharmacological evaluation and awareness of potential A 3 AR species differences are critical in studies to further understand the basic biological functions of this unique AR subtype. Recombinant A 3 ARs from eight different species have been pharmacologically characterized thus far. In this review, we describe in detail current knowledge of species differences in genetic identity, G protein-coupling, receptor regulation, and both orthosteric and allosteric A 3 AR pharmacology.

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Neuroprotective Roles of the Adenosine A3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury

Cited by 13 publications

References 70 publications

Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke

Adenosine A1R/A3R agonist AST-004 reduces brain infarction in mouse and rat models of acute ischemic stroke

Purinergic signaling: A gatekeeper of blood-brain barrier permeation

Species dependence of A3 adenosine receptor pharmacology and function

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