Reversal of Oxidative Stress-Induced Anxiety by Inhibition of Phosphodiesterase-2 in Mice

Abstract

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-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.Anxiety and fear are normal emotional responses to threatening stimuli. These responses are abnormal in human anxiety disorders, such as panic disorder, post-traumatic stress disorder, social phobias, and generalized anxiety disorder. The development of anxiety/stress-related disorders involves complex interactions among various body mechanisms involving the limbic system and the hypothalamic-pituitaryadrenal axis; their interactions play a significant role in the manifestation of disease pathology (Chrousos and Gold, 1992;Ray et al., 1993). Exposure to stressful stimuli produces widespread physiological and behavioral effects in animals. In recent studies, oxidative stress has been shown to be associated with anxiety in different behavioral models (Gingrich, 2005;Hovatta et al., 2005;Berry et al., 2007).The nervous system, due to enriched concentrations of polyunsaturated fatty acids, is particularly susceptible to the deleterious effects of oxidative stress; this can lead to loss of membrane integrity, protein damage, and neuronal dysfunction. Recent studies have shown that social phobia, depression, anxiety, and other neuropsychiatric disorders result in signs of oxidative stress such as increased reactive oxygen generation and decreased antioxidant capacity (Arranz et al., 2007;Bouayed et al., 2007). There is increasing evidence that oxidati...

Phosphodiesterase 11A in brain is enriched in ventral hippocampus and deletion causes psychiatric disease-related phenotypes

“…The PDE10A family has also received much attention in recent years, particularly in the context of schizophrenia because genetic deletion or inhibition of PDE10A results in antipsychotic-like effects in rodents (24)(25)(26). Deletion or inhibition of PDE1, -2, and -5 have also been shown to affect behavior and cognition (27)(28)(29), and up-regulation of PDE1 has been shown in a mouse model of schizophrenia (30). It will be of interest to future studies to determine if the deleterious behavioral profile observed in PDE11A KO mice may be due, in part, to an up-regulation of other PDE families.…”

“…If PDE11A is expressed only in a subpopulation of cells within a discrete subregion of the brain, one might not expect to detect expression when analyzing samples prepared from an entire brain (region). Evidence implicating other PDE families in brain function and psychiatric disease (12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30), along with a recent report linking PDE11A to major depressive disorder and antidepressant response (31), suggest that it is important to understand the role of PDE11A in the brain. Using in situ hybridization, quantitative real-time PCR, and Western blot, we clarify here where in the brain PDE11A is expressed and, by using PDE11A-deleted mice, we demonstrate a role for PDE11A in brain function.…”

Apocynin decreases hydrogen peroxide and nirtate concentrations in exhaled breath in healthy subjects

“…Reactive oxygen species have a strong impact on homeostasis and are thought to play an important role in inflammation in asthma and COPD [4]. ROS play a key role in initiation as well as amplification of inflammation in asthmatic airways.…”

“…When imbalance between reactive oxygen species concentration and the endogenous antioxidant system emerges, oxidative stress occurs. Oxidant-antioxidant imbalance leads to pathophysiological effects associated with asthma such as vascular permeability, mucus hypersecretion, smooth muscle contraction, and epithelial shedding [4,5]. The concentrations of nitric oxide and hydrogen peroxide in exhaled air are increased in asthmatics and it is considered to reflect the state of airway inflammation [6].…”

Age-Related Changes of Reliability of Antioxidant Enzyme Defense Are Associated With Adaptive Behavior of Primates

“…Действительно, в ответ на мяг-кое стрессовое воздействие (гипоксию, тепловой стресс, физическую нагрузку) отмечалось повы-шение уровня восстановленного глутатиона в ней-ронах, миоцитах, фибробластах и эритроцитах, сопровождаемого активацией GR [29][30][31][32][33]. Наличие запасов восстановленного глутатиона повышало устойчивость клеток к более сильному стрессор-ному воздействию [29][30][31][32].…”