Protective effects of phosphodiesterase 2 inhibitor on depression- and anxiety-like behaviors: Involvement of antioxidant and anti-apoptotic mechanisms

Abstract

Stress occurs in everyday life, but the relationship between stress and the onset or development of depression/anxiety remains unknown. Increasing evidence suggests that the impairment of antioxidant defense and the neuronal cell death are important in the process of emotional disorders. Chronic stress impairs the homeostasis of antioxidants/oxidation, which results in the aberrant stimulation of the cell cycle proteins where cGMP-PKG signaling is thought to have an inhibitory role. Phosphodiesterase 2 (PDE2) is linked to cGMP-PKG signaling and highly expressed in the limbic brain regions including hippocampus and amygdala, which may play important roles in the treatment of depression and anxiety. To address the possible effects of PDE2 inhibitors on depression-/anxiety-like behaviors and the underlying mechanisms, Bay 60-7550 (0.75, 1.5 and 3 mg/kg, i.p.) was administered 30 min before chronic stress. The results suggested that Bay 60-7550 not only restored the behavioral changes but also regulated Cu/Zn superoxide dismutase (SOD) levels differentially in hippocampus and amygdala, which were increased in the hippocampus while decreased in the amygdala. It was also significant that Bay 60-7550 regulated the abnormalities of pro- and anti-apoptotic components, such as Bax, Caspase 3 and Bcl-2, and the indicator of PKG signaling characterized by pVASPser239, in these two brain regions. The results suggested that Bay 60-7550 is able to alleviate oxidative stress and mediate part of the apoptotic machinery in neuronal cells possibly through SOD-cGMP/PKG-anti-apoptosis signaling and that inhibition of PDE2 may represent a novel therapeutic target for psychiatric disorders, such as depression and anxiety.

The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial

“…Furthermore, they could affect levels of brain-derived neurotrophic factor (BDNF) as their decreased levels are associated with MDD, playing a significant role in neuronal development [18]. Consequently, they can exert neuroprotective effects against cognitive disorders [19].…”

Anxiolytic Effect of Ocimum basilicum Extract in Rats Tested by Elevated Plus-Maze Task

“…Some studies have demonstrated the role of oxidative stress in the anxiety of rodents (48)(49)(50). Also, many reports suggest that the perturbation of antioxidant defense is important in the process of emotional disorders such as depression and anxiety (47). According to these reports, the induction of oxidative stress in mice CNS occurs concomitantly with anxiety (50).…”

“…Several studies have been conducted to explore multiple neural substrates and mechanisms that contribute to the etiology of anxiety, among them the imbalance between oxidation and antioxidant defense system has gained much attention (47). Some studies have demonstrated the role of oxidative stress in the anxiety of rodents (48)(49)(50).…”

Anxiolytic Effect of Borago officinalis (Boraginaceae) Extract in Male Rats

“…Wettasinghe and Shahidi investigated the antioxidant and reactive oxygen species (ROS) scavenging properties of borage meal extract (45,46). Extensive research has been conducted to reveal multiple neural substrates and mechanisms that contribute to the etiology of depression and anxiety, among which the imbalance between oxidation and antioxidant defense system has gained attention (30). Some studies demonstrated the role of oxidative stress in anxiety of rodents (47,48).…”

“…Furthermore, increasing evidence suggests that impairment of antioxidant defense is important in the process of emotional disorders, such as depression and anxiety (30). On the other hand, it has been reported that borage extract constitutes a cheap source of antioxidant activity (11,(31)(32)(33).…”