Vasodilator Effects of Ibudilast on Retinal Blood Vessels in Anesthetized Rats

Noguchi, Masahiro; Mori, Akira; Sakamoto, Kenji; Nakahara, Tsutomu; Ishii, Kunio

doi:10.1248/bpb.32.1924

Cited by 9 publications

(4 citation statements)

References 30 publications

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“…12) Briefly, the pupils were dilated with one drop of 1% atropine sulfate (Nihon Tenganyaku Institute, Nagoya). To protect the eye, 0.3% sodium hyalurate (Santen Pharmaceutical, Osaka) was dropped onto the cornea.…”

Section: Measurement Of Retinal Blood Vessel Diametermentioning

confidence: 99%

Vasodilator Effects of Flunarizine on Retinal Blood Vessels in Anesthetized Rats

Noguchi

Mori

Sakamoto

et al. 2009

Biological & Pharmaceutical Bulletin

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The aim of this study was to investigate the effects of intravenous administration of flunarizine on the diameter of retinal blood vessels and blood pressure in anesthetized rats and to compare the effects of this antagonist with those of nicardipine and nifedipine. Retinal vascular images were captured with a fundus camera system for small animals and the diameter of retinal blood vessels contained in the images was measured using imageprocessing softwares on a personal computer. Blood pressure was continuously measured. Flunarizine [1-30 m mg/kg, intravenously (i.v.)] dose-dependently increased the diameter of retinal blood vessels without significantly changing systemic blood pressure. Nicardipine (1-30 m mg/kg, i.v.) increased the retinal blood vessel diameter but decreased blood pressure in a dose-dependent manner. Nifedipine (10-100 m mg/kg, i.v.) failed to dilate the retinal blood vessels, although it produced comparable depressor responses as those to nicardipine. These results suggest that flunarizine selectively acts on the retinal blood vessels rather than on the peripheral resistance vessels. Flunarizine could therefore be considered as a candidate for therapeutic drugs to treat diseases associated with disorders of retinal circulation without severe cardiovascular side-effects.

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Section: Measurement Of Retinal Blood Vessel Diametermentioning

confidence: 99%

Vasodilator Effects of Flunarizine on Retinal Blood Vessels in Anesthetized Rats

Noguchi

Mori

Sakamoto

et al. 2009

Biological & Pharmaceutical Bulletin

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“…The reason for this hippocampal regional effect of IBU remains to be determined. However, since the DG is known to be vulnerable to aging and to be affected in the early stages of AD it is possible that the DG is also the most responsive to treatment 29 30 . Overall, our data clearly demonstrate the potential of IBU to lessen deficits in spatial learning and memory, to mitigate plaque and tangle pathology, and to diminish neuronal loss and gliosis in the hippocampus of the Tg-AD rats.…”

Section: Discussionmentioning

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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“…After the addition of sufficient aliquots of the agonist to produce the chosen concentration, a plateau response was allowed to develop (5 to 20 min) before the addition of the next dose of the same agonist. To investigate the influences of the various factors that might contribute to relaxation in the present preparations, we examined the cassiarin A-induced relaxation in the presence or absence of various inhibitors: 1) the cyclooxygenase (COX) inhibitor indomethacin (10 mM) 19,20) ; 2) the nitric oxide synthase (NOS) inhibitor L-NNA (100 mM) 15,21,22) ; 3) the guanylyl cyclase inhibitor ODQ (10 mM) 27,28) ; or 7) the selective BK Ca inhibitor iberiotoxin (100 nM). 22,26,27) Rings were incubated with the appropriate inhibitor(s) for 30 min before the administration of phenylephrine.…”

Section: Drugs and Chemicals Phenylephrine Indomethacin Nmentioning

confidence: 99%

Vasodilator Effect of Cassiarin A, a Novel Antiplasmodial Alkaloid from Cassia siamea, in Rat Isolated Mesenteric Artery

Matsumoto

Kobayashi

Ishida

et al. 2010

Biological & Pharmaceutical Bulletin

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Cassia siamea (Leguminosae), a small-to medium-sized tree, is one of the most commonly cultivated trees in Southeast Asia. Different parts of this plant can be used for a variety of medical purposes, giving the plant considerable medicinal potential. In traditional folk medicine, its stem bark is used as a mild, pleasant, safe purgative; a decoction of the bark is given to treat diabetes; a paste is used as a dressing for ringworm and chilblains; the roots are used as an antipyretic; and the leaves are used for the treatment of constipation, hypertension, and insomnia.1,2) A number of compounds, including barakol, emodin, b-and g-sitosterol, lupeol, luteolin, D-pinitol, chromone alkaloids, flavonoid glycosides, and a number of anthraquinones and bianthraquinones, have been isolated from Cassia siamea. 1,3,4) Although members of the genus Cassia are widely distributed in tropical and subtropical regions, where they have long been used in traditional folk medicine, particularly for the treatment of periodic fever and malaria, 5) we only recently have isolated the novel heteroaromatic alkaloid cassiarin A (Fig. 1) from the leaves of Cassia siamea. 6) This was followed a year later by the first total synthesis of cassiarin A, a process completed in eight steps from a known compound, methyl 2,4-dihydroxybenzoate.7) This alkaloid possesses an unprecedented tricyclic skeleton and exhibits potent antiplasmodial activity. 6,8,9) Although we have recently reported that some alkaloids and peptides exhibit not only antiplasmodial activity, but also vasorelaxant activity in the rat aorta, 10-12) the effect of cassiarin A on vascular tone remains unclear. We have very recently found that cassiarin A induces relaxation in the rat thoracic aorta and this was largely due to endotheliumderived nitric oxide (NO).9) However, no study has investigated the effects of cassiarin A on vascular tone in other, smaller arteries. The primary purpose of this study was therefore to test the hypothesis that cassiarin A induces in vitro vascular relaxation in rat mesenteric arteries precontracted with phenylephrine. In addition, we wanted to determine whether the vascular relaxation is endothelium dependent or whether cassiarin A acts directly upon vascular smooth muscle. MATERIALS AND METHODS Drugs and Chemicals, glibenclamide, 4-aminopyridine (4-AP), and tetraethylammonium (TEA) were all purchased from Sigma Chemical Co. (St. Louis, MO, U.S.A.). Acetylcholine chloride was from Daiichi-Sankyo Pharmaceuticals (Tokyo, Japan), 1H-[1,2,4]oxadiazolo[4,3-a]-quinoxalin-1-one (ODQ) was from Wako (Osaka, Japan), and iberiotoxin was from the Peptide Institute Inc. (Osaka, Japan). Drugs were dissolved in saline, except for glibenclamide [dissolved in dimethyl sulfoxide (DMSO)] and indomethacin (dissolved first in a small amount of Na 2 CO 3 0.1 M solution, then made up to the final volume with distilled water).Cassiarin A was prepared as previously reported. 6) Briefly, leaves of Cassia siamea (collected at the Purwodadi Botanical Garden, Pasuruan, Indon...

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Vasodilator Effects of Ibudilast on Retinal Blood Vessels in Anesthetized Rats

Cited by 9 publications

References 30 publications

Vasodilator Effects of Flunarizine on Retinal Blood Vessels in Anesthetized Rats

Vasodilator Effects of Flunarizine on Retinal Blood Vessels in Anesthetized Rats

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

Vasodilator Effect of Cassiarin A, a Novel Antiplasmodial Alkaloid from Cassia siamea, in Rat Isolated Mesenteric Artery

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