Inactivation of neuronal forebrain A receptors protects dopaminergic neurons in a mouse model of Parkinson's disease.
Adenosine A(2A) receptors antagonists produce neuroprotective effects in animal models of Parkinson's disease (PD). As neuroinflammation is involved in PD pathogenesis, both neuronal and glial A(2A) receptors might participate to neuroprotection. We employed complementary pharmacologic and genetic approaches to A(2A) receptor inactivation, in a multiple MPTP mouse model of PD, to investigate the cellular basis of neuroprotection by A(2A) antagonism. MPTP.HCl (20 mg/kg daily for 4 days) was administered in mice treated with the A(2A) antagonist SCH58261, or in conditional knockout mice lacking A(2A) receptors on forebrain neurons (fbnA(2A)KO 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 A(2A) receptors in fbnA(2A)KO 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 A(2A) receptors in neuroprotective effects of A(2A) antagonists in a multiple MPTP injections model of PD. With the symptomatic antiparkinsonian potential of several A(2A) 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.
Carta
Anna R
AR
Department of Toxicology, University of Cagliari, Italy. acarta@unica.it
Kachroo
Anil
A
Schintu
Nicoletta
N
Xu
Kui
K
Schwarzschild
Michael A
MA
Wardas
Jadwiga
J
Morelli
Micaela
M
D058917:Adenosine A2 Receptor Antagonists; D000818:Animals; D039481:CD11b Antigen / Q000378:metabolism; D003342:Corpus Striatum / Q000473:pathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D005904:Glial Fibrillary Acidic Protein; D020267:MPTP Poisoning / Q000139:chemically induced / Q000188:drug therapy / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009457:Neuroglia / Q000378:metabolism / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D016548:Prosencephalon / Q000473:pathology*; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use; D043683:Receptors, Adenosine A2 / Q000172:deficiency / Q000378:metabolism*; D013378:Substantia Nigra / Q000473:pathology; D014230:Triazoles / Q000494:pharmacology / Q000627:therapeutic use; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
C098657:5-amino-7-(2-phenylethyl)-2-(2-furyl)pyrazolo(4,3-e)-1,2,4-triazolo(1,5-c)pyrimidine; D058917:Adenosine A2 Receptor Antagonists; D039481:CD11b Antigen; D005904:Glial Fibrillary Acidic Protein; D009419:Nerve Tissue Proteins; D018696:Neuroprotective Agents; D011743:Pyrimidines; D043683:Receptors, Adenosine A2; D014230:Triazoles; C528900:glial fibrillary astrocytic protein, mouse; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine