Both these authors contributed equally to this study.
Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson’s disease
Article first published online: 8 OCT 2009
© 2009 The Authors. Journal Compilation © 2009 International Society for Neurochemistry
Journal of Neurochemistry
Volume 111, Issue 6, pages 1478–1489, December 2009
How to Cite
Carta, A. R., Kachroo, A., Schintu, N., Xu, K., Schwarzschild, M. A., Wardas, J. and Morelli, M. (2009), Inactivation of neuronal forebrain A2A receptors protects dopaminergic neurons in a mouse model of Parkinson’s disease. Journal of Neurochemistry, 111: 1478–1489. doi: 10.1111/j.1471-4159.2009.06425.x
- Issue published online: 20 NOV 2009
- Article first published online: 8 OCT 2009
- Received March 2, 2009; revised manuscript received September 7, 2009; accepted September 29, 2009.
- tyrosine hydroxylase
Adenosine A2A receptors antagonists produce neuroprotective effects in animal models of Parkinson’s disease (PD). As neuroinflammation is involved in PD pathogenesis, both neuronal and glial A2A receptors might participate to neuroprotection. We employed complementary pharmacologic and genetic approaches to A2A receptor inactivation, in a multiple MPTP mouse model of PD, to investigate the cellular basis of neuroprotection by A2A antagonism. MPTP·HCl (20 mg/kg daily for 4 days) was administered in mice treated with the A2A antagonist SCH58261, or in conditional knockout mice lacking A2A receptors on forebrain neurons (fbnA2AKO mice). MPTP-induced partial loss of dopamine neurons in substantia nigra pars compacta (SNc) and striatum (Str), associated with increased astroglial and microglial immunoreactivity in these areas. Astroglia was similarly activated 1, 3, and 7 days after MPTP administration, whereas maximal microglial reactivity was detected on day 1, returning to baseline 7 days after MPTP administration. SCH58261 attenuated dopamine cell loss and gliosis in SNc and Str. Selective depletion of A2A receptors in fbnA2AKO mice completely prevented MPTP-induced dopamine neuron degeneration and gliosis in SNc, and partially counteracted gliosis in Str. Results provide evidence of a primary role played by neuronal A2A receptors in neuroprotective effects of A2A antagonists in a multiple MPTP injections model of PD. With the symptomatic antiparkinsonian potential of several A2A receptor antagonists being pursued in clinical trials, this study adds to the rationale for broader clinical benefit and use of these drugs early in the treatment of PD.