Adenosine A2A receptors in bone marrow-derived cells but not in forebrain neurons are important contributors to 3-nitropropionic acid-induced striatal damage as revealed by cell-type-selective inactivation.
Endogenous adenosine acting at the adenosine A2A receptor (A2AR) can modify brain injury in a variety of neurological disorder models. However, both A2AR activation and inactivation have been shown to be neuroprotective in different situations, raising the intriguing possibility that A2ARs in distinct cellular elements may have different and even opposing effects. In this study, we developed three novel transgenic models to dissect out cell-type-specific actions of A2ARs on striatal damage by the mitochondrial toxin 3-nitropropionic acid (3-NP). Whereas global inactivation of A2ARs exacerbated 3-NP-induced neurological deficit behaviors and striatal damage, selective inactivation of A2ARs in forebrain neurons (using the Cre/loxP strategy) did not affect neurological deficit or striatal damage after the acute systemic treatment of 3-NP and intrastriatal injection of malonate. However, selective inactivation of A2ARs in bone marrow-derived cells (BMDCs) by transplanting bone marrow cells from global A2AR knock-out (KO) mice into wild-type C57BL/6 mice produced a similar phenotype of global A2AR KO mice, i.e., exacerbation of 3-NP-induced striatal damage. Thus, cell-type-selective inactivation of A2ARs reveals that A2ARs in BMDCs but not in forebrain neurons are an important contributor to striatal damage induced by mitochondrial dysfunction.
Huang
Qing-Yuan
QY
Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, USA.
Wei
Catherine
C
Yu
Liqun
L
Coelho
Joana E
JE
Shen
Hai-Ying
HY
Kalda
Anti
A
Linden
Joel
J
Chen
Jiang-Fan
JF
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D001854:Bone Marrow Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005260:Female; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D009574:Nitro Compounds / Q000633:toxicity*; D011422:Propionates / Q000633:toxicity*; D016548:Prosencephalon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D043705:Receptor, Adenosine A2A / Q000378:metabolism / Q000502:physiology*
D058917:Adenosine A2 Receptor Antagonists; D009574:Nitro Compounds; D011422:Propionates; D043705:Receptor, Adenosine A2A; C015392:3-nitropropionic acid