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The Journal of Neuroscience, November 1, 2006, 26(44):11371-11378; doi:10.1523/JNEUROSCI.1907-06.2006

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Cellular/Molecular
Adenosine A_2A 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

Qing-Yuan Huang,¹ Catherine Wei,¹ Liqun Yu,¹ Joana E. Coelho,¹ Hai-Ying Shen,¹ Anti Kalda,¹ Joel Linden,² and Jiang-Fan Chen¹

¹Department of Neurology, Boston University School of Medicine, Boston, Massachusetts 02118, and ²Department of Internal Medicine, University of Virginia, Charlottesville, Virginia 22908

Correspondence should be addressed to Dr. Jiang-Fan Chen, Department of Neurology, Boston University School of Medicine, 715 Albany Street, E301, Boston, MA 02118. Email: chenjf{at}bu.edu

Endogenous adenosine acting at the adenosine A_2A receptor (A_2AR) can modify brain injury in a variety of neurological disorder models. However, both A_2AR activation and inactivation have been shown to be neuroprotective in different situations, raising the intriguing possibility that A_2ARs 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 A_2ARs on striatal damage by the mitochondrial toxin 3-nitropropionic acid (3-NP). Whereas global inactivation of A_2ARs exacerbated 3-NP-induced neurological deficit behaviors and striatal damage, selective inactivation of A_2ARs 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 A_2ARs in bone marrow-derived cells (BMDCs) by transplanting bone marrow cells from global A_2AR knock-out (KO) mice into wild-type C57BL/6 mice produced a similar phenotype of global A_2AR KO mice, i.e., exacerbation of 3-NP-induced striatal damage. Thus, cell-type-selective inactivation of A_2ARs reveals that A_2ARs in BMDCs but not in forebrain neurons are an important contributor to striatal damage induced by mitochondrial dysfunction.

Key words: adenosine A_2A receptor; 3-nitropropionic acid; forebrain; bone marrow-derived cells; striatum; Huntington's disease

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Received May 4, 2006; revised Aug. 31, 2006; accepted Sept. 17, 2006.

Correspondence should be addressed to Dr. Jiang-Fan Chen, Department of Neurology, Boston University School of Medicine, 715 Albany Street, E301, Boston, MA 02118. Email: chenjf{at}bu.edu

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				A. Ohta, A. Ohta, M. Madasu, R. Kini, M. Subramanian, N. Goel, and M. Sitkovsky A2A Adenosine Receptor May Allow Expansion of T Cells Lacking Effector Functions in Extracellular Adenosine-Rich Microenvironments J. Immunol., November 1, 2009; 183(9): 5487 - 5493. [Abstract] [Full Text] [PDF]

				G. K. Yang, J.-F. Chen, T. J. Kieffer, and Y. N. Kwok Regulation of Somatostatin Release by Adenosine in the Mouse Stomach J. Pharmacol. Exp. Ther., May 1, 2009; 329(2): 729 - 737. [Abstract] [Full Text] [PDF]

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