Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons

Nakamizo, Tomoki; Kawamata, Jun; Yoshida, Kohei; Kawai, Yuko; Kanki, Rie; Sawada, Hideyuki; Kihara, Takeshi; Yamashita, Hirofumi; Shibasaki, Hiroshi; Akaike, Akinori; Shimohama, Shun

doi:10.1002/jnr.10483

Cited by 62 publications

(39 citation statements)

References 42 publications

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“…Moreover, the effects of Bay 60-7550 were antagonized by the PKG inhibitor KT-5823 but not by the PKA inhibitor H89, further suggesting that Bay 60-7550 exerts its effects via altered cGMP-PKG signaling. Some earlier studies also have shown inhibitory effects on oxidative stress via the cGMP- jpet.aspetjournals.org PKG pathway (Lee et al, 2003;Nakamizo et al, 2003). Because many neuropsychiatric/neurodegenerative disorders are associated with dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, as well as with oxidative stress, it is possible that oxidative stress disturbs the HPA-axis function, altering the level of corticosterone with subsequent effects on hypothalamus and amygdala.…”

Section: Discussionmentioning

confidence: 99%

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

Masood

Nadeem²,

Mustafa³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

208

168

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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...

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Section: Discussionmentioning

confidence: 99%

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

Masood

Nadeem²,

Mustafa³

et al. 2008

The Journal of Pharmacology and Experimental Therapeutics

208

168

View full text Add to dashboard Cite

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“…Cytoprotective effects have been observed in heart cells (Qin et al, 2004;Kukreja et al, 2005;Das et al, 2008), neurons and glia (Barger et al, 1995;Nakamizo et al, 2003;Zhang et al, 2003;Thippeswamy et al, 2005;Korkmaz et al, 2009a,b;Paquet-Durand et al, 2009) and epithelial cells (Chan and Fiscus, 2003). Precise mechanisms for these protective effects are undoubtedly complex.…”

Section: F Cytoprotective Processesmentioning

confidence: 99%

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

Francis

Busch

Corbin

2010

Pharmacological Reviews

880

713

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“…Secondary measures were changes from baseline in the six-item Erectile Function domain of the International Index of Erectile Function and, for the plethysmography subgroup, the duration of penile tumescence and rigidity. The Erectile Function domain has a score range of 1-30, with ED graded as severe (1-10), moderate (11)(12)(13)(14)(15)(16), mild to moderate (17-21), mild (22)(23)(24)(25) and none (26)(27)(28)(29)(30). 12 …”

Section: Efficacy Measuresmentioning

confidence: 99%

“…26,27 Similarly, in patients with type 2 diabetes, low-dose sildenafil improved vascular endothelial function. 28 Also, phosphodiesterase 5 inhibitors have been shown to be neuroprotective to cultured spinal motor and nonmotor neurons, 29 and sildenafil increased neurogenesis and reduced neurological deficits in rats treated within 24 h of stroke. 30 Thus, therapeutic postoperative intervention with sildenafil may improve corpus cavernosum endothelial function and promote recovery of nerve function.…”

Section: Duration Of Base Rigidity (Min)mentioning

confidence: 99%

Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy

et al. 2008

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Four weeks after bilateral nerve-sparing radical retropubic prostatectomy, men with normal erectile function before surgery were randomized to double-blind sildenafil (50 or 100 mg) or placebo nightly for 36 weeks, followed by an 8-week drug-free period before assessment of erectile function. Enrollment was prematurely ceased and only 76 men completed because, assuming a placebo response rate similar to the published literature (for example, 34% in meta-analysis), the 25% response at blinded interim review suggested a lack of treatment effect. On the contrary, spontaneous erectile function (a combined score of X8 for questions 3 and 4 of the International Index of Erectile Function and a positive response to 'Were erections good enough for satisfactory sexual activity?') occurred in only 4% of the placebo group (n ¼ 1 of 25) versus 27% (n ¼ 14 of 51, P ¼ 0.0156, Fisher's exact test) of the sildenafil group. Nightly sildenafil administration for 36 weeks after surgery markedly increased the return of normal spontaneous erections.

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Phosphodiesterase inhibitors are neuroprotective to cultured spinal motor neurons

Cited by 62 publications

References 42 publications

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

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

cGMP-Dependent Protein Kinases and cGMP Phosphodiesterases in Nitric Oxide and cGMP Action

Randomized, double-blind, placebo-controlled study of postoperative nightly sildenafil citrate for the prevention of erectile dysfunction after bilateral nerve-sparing radical prostatectomy

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