Neuroprotective Roles of the Adenosine A 3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury

Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported that stimulation of astrocyte mitochondrial metabolism by P2Y receptor agonists significantly reduced cerebral edema and reactive gliosis in a T...

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Published inNeurotherapeutics Vol. 18; no. 4; p. 2707
Main Authors Bozdemir, Eda, Vigil, Fabio A, Chun, Sang H, Espinoza, Liliana, Bugay, Vladislav, Khoury, Sarah M, Holstein, Deborah M, Stoja, Aiola, Lozano, Damian, Tunca, Ceyda, Sprague, Shane M, Cavazos, Jose E, Brenner, Robert, Liston, Theodore E, Shapiro, Mark S, Lechleiter, James D
Format Journal Article
LanguageEnglish
Published United States 01.10.2021
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Abstract Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported that stimulation of astrocyte mitochondrial metabolism by P2Y receptor agonists significantly reduced cerebral edema and reactive gliosis in a TBI model. Subsequent data on the pharmacokinetics (PK) and rapid metabolism of these compounds suggested that neuroprotection was likely mediated by a metabolite, AST-004, which binding data indicated was an adenosine A receptor (A R) agonist. The neuroprotective efficacy of AST-004 was tested in a control closed cortical injury (CCCI) model of TBI in mice. Twenty-four (24) hours post-injury, mice subjected to CCCI and treated with AST-004 (0.22 mg/kg, injected 30 min post-trauma) exhibited significantly less secondary brain injury. These effects were quantified with less cell death (PSVue794 fluorescence) and loss of blood brain barrier breakdown (Evans blue extravasation assay), compared to vehicle-treated TBI mice. TBI-treated mice also exhibited significantly reduced neuroinflammatory markers, glial-fibrillary acidic protein (GFAP, astrogliosis) and ionized Ca -binding adaptor molecule 1 (Iba1, microgliosis), both at the mRNA (qRT-PCR) and protein (Western blot and immunofluorescence) levels, respectively. Four (4) weeks post-injury, both male and female TBI mice presented a significant reduction in freezing behavior during contextual fear conditioning (after foot shock). AST-004 treatment prevented this TBI-induced impairment in male mice, but did not significantly affect impairment in female mice. Impairment of spatial memory, assessed 24 and 48 h after the initial fear conditioning, was also reduced in AST-004-treated TBI-male mice. Female TBI mice did not exhibit memory impairment 24 and 48 h after contextual fear conditioning and similarly, AST-004-treated female TBI mice were comparable to sham mice. Finally, AST-004 treatments were found to increase in vivo ATP production in astrocytes (GFAP-targeted luciferase activity), consistent with the proposed mechanism of action. These data reveal AST-004 as a novel A R agonist that increases astrocyte energy production and enhances their neuroprotective efficacy after brain injury.
AbstractList Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported that stimulation of astrocyte mitochondrial metabolism by P2Y receptor agonists significantly reduced cerebral edema and reactive gliosis in a TBI model. Subsequent data on the pharmacokinetics (PK) and rapid metabolism of these compounds suggested that neuroprotection was likely mediated by a metabolite, AST-004, which binding data indicated was an adenosine A receptor (A R) agonist. The neuroprotective efficacy of AST-004 was tested in a control closed cortical injury (CCCI) model of TBI in mice. Twenty-four (24) hours post-injury, mice subjected to CCCI and treated with AST-004 (0.22 mg/kg, injected 30 min post-trauma) exhibited significantly less secondary brain injury. These effects were quantified with less cell death (PSVue794 fluorescence) and loss of blood brain barrier breakdown (Evans blue extravasation assay), compared to vehicle-treated TBI mice. TBI-treated mice also exhibited significantly reduced neuroinflammatory markers, glial-fibrillary acidic protein (GFAP, astrogliosis) and ionized Ca -binding adaptor molecule 1 (Iba1, microgliosis), both at the mRNA (qRT-PCR) and protein (Western blot and immunofluorescence) levels, respectively. Four (4) weeks post-injury, both male and female TBI mice presented a significant reduction in freezing behavior during contextual fear conditioning (after foot shock). AST-004 treatment prevented this TBI-induced impairment in male mice, but did not significantly affect impairment in female mice. Impairment of spatial memory, assessed 24 and 48 h after the initial fear conditioning, was also reduced in AST-004-treated TBI-male mice. Female TBI mice did not exhibit memory impairment 24 and 48 h after contextual fear conditioning and similarly, AST-004-treated female TBI mice were comparable to sham mice. Finally, AST-004 treatments were found to increase in vivo ATP production in astrocytes (GFAP-targeted luciferase activity), consistent with the proposed mechanism of action. These data reveal AST-004 as a novel A R agonist that increases astrocyte energy production and enhances their neuroprotective efficacy after brain injury.
Author Tunca, Ceyda
Khoury, Sarah M
Shapiro, Mark S
Lozano, Damian
Chun, Sang H
Bozdemir, Eda
Sprague, Shane M
Espinoza, Liliana
Bugay, Vladislav
Stoja, Aiola
Cavazos, Jose E
Vigil, Fabio A
Liston, Theodore E
Lechleiter, James D
Holstein, Deborah M
Brenner, Robert
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  email: lechleiter@uthscsa.edu
  organization: Department of Cell Systems and Anatomy, UT Health San Antonio, 8403 Floyd Curl Drive, San Antonio, TX, 78229-3904, USA. lechleiter@uthscsa.edu
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Issue 4
Keywords Mitochondrial metabolism
Astrocytes
Concussion treatment
ADORA3
ATP
Language English
License 2021. The American Society for Experimental NeuroTherapeutics, Inc.
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Snippet Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported...
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StartPage 2707
SubjectTerms Adenosine - metabolism
Adenosine - pharmacology
Animals
Astrocytes - metabolism
Brain Injuries, Traumatic - complications
Brain Injuries, Traumatic - drug therapy
Brain Injuries, Traumatic - metabolism
Disease Models, Animal
Female
Gliosis - metabolism
Male
Mice
Mice, Inbred C57BL
Neuroprotection
Neuroprotective Agents - metabolism
Neuroprotective Agents - pharmacology
Neuroprotective Agents - therapeutic use
Title Neuroprotective Roles of the Adenosine A 3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury
URI https://www.ncbi.nlm.nih.gov/pubmed/34608616
Volume 18
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