Ibudilast, a mixed PDE3/4 inhibitor, causes a selective and nitric oxide/cGMP-independent relaxation of the intracranial vertebrobasilar artery

Yamazaki, Takanobu; Anraku, Tsuyoshi; Matsuzawa, Shigeki

doi:10.1016/j.ejphar.2010.10.033

Cited by 11 publications

(5 citation statements)

References 19 publications

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“…IBU, an anti-inflammatory drug firstly developed to treat asthma, is a cyclic nucleotide PDE inhibitor, which mainly acts by increasing the amount of cAMP and cGMP, while downregulating the pro-inflammatory factors, such as TNFα, macrophage migration inhibitory factor (MIF) and Toll-like receptor 4 (TLR-4) [ 68 , 69 ]. Pharmacologically, IBU may provide significantly prolonged time-to-first relapse and attenuate brain volume shrinkage in patients with relapsing-remitting and/or secondary progressive multiple sclerosis [ 70 ].…”

Section: Discussionmentioning

confidence: 99%

Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice

López-Blanch,

Salvador-Palmer,

Oriol-Caballo

et al. 2024

Neurotherapeutics

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Section: Discussionmentioning

confidence: 99%

Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice

López-Blanch,

Salvador-Palmer,

Oriol-Caballo

et al. 2024

Neurotherapeutics

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“…PDE3-induced vasorelaxation is potentiated when NO/cGMP is suppressed as PDE3 inhibition increases both cAMP and cGMP, in which cGMP inhibits cAMP degradation. PDE4 inhibition only increases cAMP and thus is unaffected by NO/cGMP suppression [23]. PDE3 seems to be more responsible for cAMP degradation at low intracellular cAMP concentrations, whereas PDE4 is more important for control of cAMP at higher concentrations [24].…”

Section: Pde3 and Pde4mentioning

confidence: 98%

“…Overexpression of nitric oxide synthase in both endothelial and airway epithelial cells resulted in diminished airway inflammation [22]. Under normal conditions of NO/cGMP signaling, PDE4, with a high Km for cAMP, is thought to degrade cAMP because PDE3 with a lower Km for cAMP is inhibited by endogenous cGMP and thus can increase cAMP [23]. PDE3-induced vasorelaxation is potentiated when NO/cGMP is suppressed as PDE3 inhibition increases both cAMP and cGMP, in which cGMP inhibits cAMP degradation.…”

Section: Pde3 and Pde4mentioning

confidence: 99%

Phosphodiesterase 3 and 4 Inhibition: Facing a Bright Future in Asthma Control

Beute¹,

Manganiello²,

KleinJan³

2018

Asthma Diagnosis and Management - Approach Based on Phenotype and Endotype

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A recent status on asthmaticus multiple case report by Beute demonstrated the beneficial effects of phosphodiesterase III (PDE3) and phosphodiesterase IV (PDE4) inhibition. This chapter reviews the possible underlying mechanisms, beside the known effect, for the beneficial effects of a mixed PDE3/4 inhibitor in allergic airway inflammation. Structural cells of the lung and immune system express PDE3 and 4. PDE3 and 4 inhibition have a number of consequences related to physical function and cytokine production. The most direct effect of PDE3 inhibition being relaxation of smooth muscle cells results in bronchodilation. However, PDE3 inhibition appears to go further than a mere inhibitory activity in bronchial smooth muscle. It also affects structural cells, and more importantly, it creates an improved barrier function in endothelial cells. PDE3 and 4 inhibition therefore strengthens the immune barrier; but in addition, it modifies the cells of the immune system itself, as these also express PDE3 and 4 activity, thus changing their function. All aspects of asthma-related pathophysiology seem to be affected by PDE3 and 4 inhibition. Clinical use of a mixed PDE3/4 inhibitor in respiratory diseases is currently limited to a few studies, including life-threatening asthma in which mixed PDE3/4 inhibition has a beneficial effect.

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“…As a phosphodiesterase inhibitor, IBU is able to maintain cyclic AMP levels and inhibit T-cell immune function 19 . Furthermore, IBU helps promote IL10 production, while simultaneously inhibiting the production of TNF α and NO 20 .…”

Section: Introductionmentioning

confidence: 99%

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal-dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer’s disease

Oliveros

Chaudry

et al. 2021

Preprint

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Alzheimer's disease (AD) is a multifactorial disease that exhibits cognitive deficits, neuronal loss, amyloid plaques, neurofibrillary tangles and neuroinflammation in the brain. We developed a multi-scale predictive modeling strategy that integrates machine learning with biophysics and systems pharmacology to model drug actions from molecular interactions to phenotypic responses. We predicted that ibudilast (IBU), a phosphodiesterase inhibitor and toll-like receptor 4 (TLR4) antagonist, inhibited multiple kinases (e.g., IRAK1 and GSG2) as off-targets, modulated multiple AD-associated pathways, and reversed AD molecular phenotypes. We address for the first time the efficacy of ibudilast (IBU) in a transgenic rat model of AD. IBU-treated transgenic rats showed improved cognition and reduced hallmarks of AD pathology. RNA sequencing analyses in the hippocampus showed that IBU affected the expression of pro-inflammatory genes in the TLR signaling pathway. Our results identify IBU as a potential therapeutic to be repurposed for reducing neuroinflammation in AD by targeting TLR signaling.

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Ibudilast, a mixed PDE3/4 inhibitor, causes a selective and nitric oxide/cGMP-independent relaxation of the intracranial vertebrobasilar artery

Cited by 11 publications

References 19 publications

Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice

Nicotinamide riboside, pterostilbene and ibudilast protect motor neurons and extend survival in ALS mice

Phosphodiesterase 3 and 4 Inhibition: Facing a Bright Future in Asthma Control

Multi-scale predictive modeling discovers Ibudilast as a polypharmacological agent to improve hippocampal-dependent spatial learning and memory and mitigate plaque and tangle pathology in a transgenic rat model of Alzheimer’s disease

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