Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation

Matsushita, Haruo; Matsuzaki, Mitsuhiro; Han, Xiao Jian; Nishiki, Tadaaki; Ohmori, Iori; Michiue, Hiroyuki; Matsui, Hideki; Tomizawa, Kazuhito

doi:10.1016/j.neuroscience.2011.11.001

Cited by 37 publications

(19 citation statements)

References 44 publications

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“…However, a speculative explanation for the effects of BS is that some chemical constituents of BS like isoflavonolignans such as butesuperin A, B, and (−) medicarpin may play an important role in the behavioral and neurochemical effects of BS in OBX animals. Ma et al (4) found that butesuperin A and B exerted inhibitory activities against phosphodiesterase type 3A and type 5 in in vitro, and recent studies demonstrated that selective phosphodiesterase-5 inhibitors such as Sildenafil, which are used for ED therapy, ameliorated emotional deficits like depression (41,42). Moreover, (−) medicarpin is reportedly an activator of the neurogenin2 promoter (43).…”

Section: Discussionmentioning

confidence: 99%

Butea superba–Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions

et al. 2014

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Abstract. This study investigated the effects of alcoholic extract of Butea superba (BS) on cognitive deficits and depression-related behavior using olfactory bulbectomized (OBX) mice and the underlying molecular mechanisms of its actions. OBX mice were treated daily with BS (100 and 300 mg/kg, p.o.) or reference drugs, tacrine (2.5 mg/kg, i.p.) and imipramine (10 mg/kg, i.p.) from day 3 after OBX. OBX impaired non-spatial and spatial cognitive performances, which were elucidated by the novel object recognition test and modified Y maze test, respectively. These deficits were attenuated by tacrine and BS but not imipramine. OBX animals exhibited depressionlike behavior in the tail suspension test in a manner reversible by imipramine and BS but not tacrine. OBX down-regulated phosphorylation of synaptic plasticity-related signaling proteins: NMDA receptor, AMPA receptor, calmodulin-dependent kinase II, and cyclic AMP-responsive element-binding protein. OBX also reduced choline acetyltransferase in the hippocampus. BS and tacrine reversed these neurochemical alterations. Moreover, BS inhibited ex vivo activity of acetylcholinesterase in the brain. These results indicate that BS ameliorates not only cognition dysfunction via normalizing synaptic plasticity-related signaling and facilitating central cholinergic systems but also depression-like behavior via a mechanism differing from that implicated in BS amelioration of cognitive function in OBX animals.

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Section: Discussionmentioning

confidence: 99%

Butea superba–Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions

et al. 2014

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“…Sildenafil induces activation of a MAP kinase cascade and increased the phosphorylation of CREB in the hippocampi of male mice [14]. A MAP kinase inhibitor attenuated the reduction in immobility time induced by sildenafil in male mice.…”

Section: Molecular Mechanism Of the Antidepressant-like Effect Of Ot mentioning

confidence: 93%

“…channels in the neurohypophysis [23] and enhances OT expression in the PVN without a sexual [37]. In a previous study, to test its potential as an antidepressant drug without sexual side effects, sildenafil was intraperitoneally administered to male mice and antidepressant-like effects were measured in the FST [14]. Wild-type males exhibited reduced depression-related behavior after administration of sildenafil, but OTR KO males did not.…”

Section: Antidepressant-like Effect Of Sildenafilmentioning

confidence: 99%

“…Oxytocin mediates an antidepressant-like effect in male mice, which disappears in OTR knockout (KO) mice [13,14]. In humans, moreover, there is a significant association between plasma OT levels and major depressive disorders (MDD) [15][16][17].…”

Section: Introductionmentioning

confidence: 99%

“…Both acute and chronic treatment with OT decreased immobility time in the forced swim test (FST) [25,26]. This antidepressant-like effect was blocked by an OTR antagonist and was absent in OTR KO mice [13,14,27]. An antidepressant-like effect of OT was also demonstrated in the tail suspension test [28].…”

Section: Introductionmentioning

confidence: 99%

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Oxytocin: a therapeutic target for mental disorders

et al. 2012

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We review here that oxytocin (OT) is released into blood and within distinct brain regions in response to stressful and social stimuli, and has been shown to have an antidepressant-like effect in animal studies. Clinical reports suggest OT to be a promising drug for psychiatric diseases such as depression, anxiety disorders, schizophrenia, and autism. OT may also have therapeutic potential in the treatment of major depressive disorders, even though OT administered into blood does not readily cross the blood-brain barrier. Physiological functions such as sexual activity and mating induce the release of OT in the central nervous system. A drug for the treatment of sexual dysfunction, sildenafil, enhances the electrically evoked release of OT from the posterior pituitary. This drug has antidepressant-like effects through activation of an OT signaling pathway. These results suggest that sildenafil may have promise as a potential antidepressant.

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Multimodal action of phosphodiesterase 5 inhibitors against neurodegenerative disorders: An update review

Singh,

Varshney

et al. 2024

J Biochem & Molecular Tox

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Phosphodiesterase type 5 (PDE5) is an enzyme primarily found in the smooth muscle of the corpus cavernosum and also highly expressed in the substantia nigra, cerebellum, caudate, hippocampal regions and cerebellar purkinje cells, responsible for selectively breaking down cyclic guanosine monophosphate (cGMP) into 5′‐GMP and regulate intracellular cGMP levels. As a second messenger, cyclic GMP enhances signals at postsynaptic receptors and triggers downstream effector molecules, leading to changes in gene expression and neuronal responses. Additionally, cGMP signaling transduction cascade, present in the brain, is also essential for learning and memory processes. Mechanistically, PDE5 inhibitors share structural similarities with cGMP, competitively binding to PDE5 and inhibiting cGMP hydrolysis. This action enhances the effects of nitric oxide, resulting in anti‐inflammatory and neuroprotective effects. Neurodegenerative disorders entail the progressive loss of neuron structure, culminating in neuronal cell death, with currently available drugs providing only limited symptomatic relief, rendering neurodegeneration considered incurable. PDE5 inhibitors have recently emerged as a potential therapeutic approach for neurodegeneration, neuroinflammation, and diseases involving cognitive impairment. This review elucidates the principal roles of 3′,5′‐cyclic adenosine monophosphate (cAMP) and cGMP signaling pathways in neuronal functions, believed to play pivotal roles in the pathogenesis of various neurodegenerative disorders. It provides an updated assessment of PDE5 inhibitors as disease‐modifying agents for conditions such as Alzheimer's disease, Parkinson's disease, multiple sclerosis, cerebral ischemia, Huntington's disease, and neuroinflammation. The paper aims to review the current understanding of PDE5 inhibitors, which concurrently regulate both cAMP and cGMP signaling pathways, positing that they may exert complementary and synergistic effects in modifying neurodegeneration, thus presenting a novel direction in therapeutic discovery. Moreover, the review provides critical about biological functions, therapeutic potentials, limitations, challenges, and emerging applications of selective PDE5 inhibitors. This comprehensive overview aims to guide future academic and industrial endeavors in this field.

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Antidepressant-like effect of sildenafil through oxytocin-dependent cyclic AMP response element-binding protein phosphorylation

Cited by 37 publications

References 44 publications

Butea superba–Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions

Butea superba–Induced Amelioration of Cognitive and Emotional Deficits in Olfactory Bulbectomized Mice and Putative Mechanisms Underlying Its Actions

Oxytocin: a therapeutic target for mental disorders

Multimodal action of phosphodiesterase 5 inhibitors against neurodegenerative disorders: An update review

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