Reversal of oxidative stress-induced anxiety by inhibition of phosphodiesterase-2 in mice.
The pathogenesis of several neuropsychiatric disorders, including anxiety and depression, has been linked to oxidative stress, in part via alterations in cyclic nucleotide signaling. Phosphodiesterase-2 (PDE2), which regulates cGMP and cAMP signaling, may affect anxiety-related behavior through reduction of oxidative stress. The present study evaluated the effects of oxidative stress on behavior and assessed the anxiolytic effects of the PDE2 inhibitor Bay 60-7550 [(2-(3,4-dimethoxybenzyl)-7-{(1R)-1-[(1R)-1-hydroxyethyl]-4-phenylbutyl}-5-methyl imidazo-[5,1-f][1,2,4]triazin-4(3H)-one)]. Treatment of mice with L-buthionine-(S,R)-sulfoximine (300 mg/kg), an inducer of oxidative stress, caused anxiety-like behavioral effects in elevated plusmaze, open-field, and hole-board tests through the NADPH oxidase pathway; these effects were antagonized by Bay 60-7550 (3 mg/kg) and apocynin (3 mg/kg), an inhibitor of NADPH oxidase. The Bay 60-7550-mediated decrease in oxidative stress (i.e., superoxide anion and reactive oxygen species generation in cultured neurons and total antioxidant capacity and lipid peroxides in amygdala and hypothalamus) and expression of NADPH oxidase subunits (i.e., p47 phox and gp91 phox expression in amygdala, hypothalamus, and cultured neurons) was associated with increased cGMP and phosphorylation of vasodilator-stimulated phosphoprotein at Ser239, suggesting an important role of cGMP-protein kinase G signaling in reduction of anxiety. Overall, the present results indicate that oxidative stress induces anxiety-like behavior in mice and that PDE2 inhibition reverses it through an increase in cGMP signaling. Thus, PDE2 may be a novel pharmacological target for treatment of anxiety in neuropsychiatric and neurodegenerative disorders that involve oxidative stress.
Masood
Anbrin
A
Department of Behavioral Medicine and Psychiatry and Neurobiology and Anatomy, West Virginia University Health Sciences Center, P.O. Box 9128, Morgantown, WV 26506, USA. amasood@hsc.wvu.edu
Nadeem
Ahmed
A
Mustafa
S Jamal
SJ
O'Donnell
James M
JM
D000818:Animals; D000975:Antioxidants / Q000378:metabolism; D001007:Anxiety / Q000188:drug therapy* / Q000201:enzymology / Q000209:etiology / Q000503:physiopathology; D001522:Behavior, Animal / Q000187:drug effects*; D019328:Buthionine Sulfoximine; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors*; D004195:Disease Models, Animal; D008054:Lipid Peroxides / Q000378:metabolism; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D051379:Mice; D008813:Mice, Inbred ICR; D019255:NADPH Oxidases / Q000096:biosynthesis; D009474:Neurons / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010766:Phosphorylation; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000975:Antioxidants; D008054:Lipid Peroxides; D010726:Phosphodiesterase Inhibitors; D017382:Reactive Oxygen Species; D019328:Buthionine Sulfoximine; D019255:NADPH Oxidases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; D006152:Cyclic GMP