Type 4 phosphodiesterase enzyme inhibitor, rolipram rescues behavioral deficits in olfactory bulbectomy models of depression: Involvement of hypothalamic–pituitary–adrenal axis, cAMP signaling aspects and antioxidant defense system

Jindal, Ankur; Mahesh, Radhakrishnan; Bhatt, Shvetank

doi:10.1016/j.pbb.2015.02.017

Cited by 27 publications

(14 citation statements)

References 73 publications

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“…Among 17 NMNAT2 positive modulators confirmed by Western analysis, 5 compounds are known to increase cAMP signaling. These include 8-Br-cAMP, Ro20–17243940, caffeine41, the caffeine analog dipropyl-7-methylxanthine42, and rolipram4344. Both caffeine and rolipram act as phosphodiesterase inhibitors to reduce cAMP degradation and thus increase cAMP concentrations.…”

Section: Discussionmentioning

confidence: 99%

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Ali

Bradley

2017

Sci Rep

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Nicotinamide mononucleotide adenylyl transferase 2 (NMNAT2) is a key neuronal maintenance factor and provides potent neuroprotection in numerous preclinical models of neurological disorders. NMNAT2 is significantly reduced in Alzheimer’s, Huntington’s, Parkinson’s diseases. Here we developed a Meso Scale Discovery (MSD)-based screening platform to quantify endogenous NMNAT2 in cortical neurons. The high sensitivity and large dynamic range of this NMNAT2-MSD platform allowed us to screen the Sigma LOPAC library consisting of 1280 compounds. This library had a 2.89% hit rate, with 24 NMNAT2 positive and 13 negative modulators identified. Western analysis was conducted to validate and determine the dose-dependency of identified modulators. Caffeine, one identified NMNAT2 positive-modulator, when systemically administered restored NMNAT2 expression in rTg4510 tauopathy mice to normal levels. We confirmed in a cell culture model that four selected positive-modulators exerted NMNAT2-specific neuroprotection against vincristine-induced cell death while four selected NMNAT2 negative modulators reduced neuronal viability in an NMNAT2-dependent manner. Many of the identified NMNAT2 positive modulators are predicted to increase cAMP concentration, suggesting that neuronal NMNAT2 levels are tightly regulated by cAMP signaling. Taken together, our findings indicate that the NMNAT2-MSD platform provides a sensitive phenotypic screen to detect NMNAT2 in neurons.

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Section: Discussionmentioning

confidence: 99%

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Ali

Bradley

2017

Sci Rep

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“…Oxidative stress and lipid peroxidation play a crucial role in the development of alcohol-induced hepatic steatosis and progression of ALD [227,228]. Several studies have shown that cAMP pathway modulates the expression of antioxidants and antioxidant enzymes [229][230][231]. Our results show that alcohol induces oxidative stress and lipid peroxidation was markedly attenuated by PDE4…”

Section: Pde4 Inhibition Prevents Alcohol Mediated Decrease In Campsupporting

confidence: 56%

Role of phosphodiesterase-4 in alcohol-induced organ injury.

Avila

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“…PDE4 inhibition has been a target of therapeutic drug research since the 1970s, with the prototypic PDE4 inhibitor, rolipram being tested in clinical trials in the 1980s [92]. Notably, PDE4 inhibitor rolipram that readily produces antidepressant-like actions [93,94], which are associated with increased level of cAMP and its downstream targets of cAMP-dependent protein kinase A (PKA), CREB, and BDNF [95]; [68]. Therefore, the potential PDE4 inhibitors may be an eicient alternative strategy to play antidepressant action especially in depressive disorder induced by inflammation.…”

Section: Traditional Pde4 Inhibitorsmentioning

confidence: 99%

“…Notably, it has been recently reported that a pyrazolopyridine compound, etazolate, is a new-generation selective PDE4 inhibitor and is proven to be of particular signiicance in neuropsychiatric conditions [102,103]; [94]. Previous studies reported that etazolate belongs to PDE4 inhibitor family and that treatment with etazolate restored cAMP levels [66, 94,103].…”

Section: The Novel Potential Pde4 Inhibitorsmentioning

confidence: 99%

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Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

Wang¹,

Wang²,

Li³

et al. 2017

Mechanisms of Neuroinflammation

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Multiple lines of evidence support the pathogenic role of neuroinflammation in psychiatric illness. Cyclic adenosine monophosphate (cAMP) is a critical regulator of microglia homeostasis; as the predominant negative modulator of cyclic AMP signaling within microglia, and phosphodiesterase 4 (PDE4) represents a promising target for modulating immune function. The approach for pharmacological manipulation of cAMP levels using specifc PDE4 inhibitors provokes an ant-iinflammatory response. Specifcally, PDE4 inhibitors have recently emerged as a potential therapeutic strategy for neuroinflammatory, neurodegenerative, and psychiatric diseases. Mechanistically, PDE4 inhibitors produce an anti-inflammatory and neuroprotection efect by increasing the accumulation of cAMP and activating protein kinase A (PKA), the signaling pathway of which is thought to play an important role in the development of psychiatric disorders. This chapter reviews present knowledge of the relationship between neuroinflammation and classical psychiatric disorders (major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia) and demonstrates the signaling pathways that underlie the use of PDE4 inhibitors in neuroinflammation. In addition, among the four subtypes (A-D) of PDE4, it remains unclear which one exerts suppressive efects on neuroinflammation. Understanding how PDE4 and neuroinflammation interact can reveal pathogenic clues and help target new preventive and symptomatic therapies for psychiatric illness.

show abstract

Type 4 phosphodiesterase enzyme inhibitor, rolipram rescues behavioral deficits in olfactory bulbectomy models of depression: Involvement of hypothalamic–pituitary–adrenal axis, cAMP signaling aspects and antioxidant defense system

Cited by 27 publications

References 73 publications

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Screening with an NMNAT2-MSD platform identifies small molecules that modulate NMNAT2 levels in cortical neurons

Role of phosphodiesterase-4 in alcohol-induced organ injury.

Reducing Neuroinflammation in Psychiatric Disorders: Novel Target of Phosphodiesterase 4 (PDE4) and Developing of the PDE4 Inhibitors

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