Effect of 2-(6-cyano-1-hexyn-1-yl)adenosine on ocular blood flow in rabbits

Konno, Takashi; Uchibori, Takehiro; Nagai, Atsushi; Kogi, Kentaro; Nakahata, Norimichi

doi:10.1016/j.lfs.2006.11.053

Cited by 7 publications

(5 citation statements)

References 40 publications

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“…Our findings have shown that final concentrations of DMSO as low as 0.1% (v/v) are toxic in vivo (1, 2, 4, and 8% v/v stock; 5 μl injected volume) causing significant retinal apoptosis. This is different to what has been previously reported, and the widely accepted belief that DMSO is well tolerated at concentrations <10% (8, 16–19). In previous intravitreal in vivo studies (2–4, 7, 10–15, 19, 39, 40), the stock concentrations of DMSO administered are reported, although we have also quantified corresponding final vitreous concentration of 0.1, 0.2, 0.4, 0.7, 0.9, 1.4, and 2.3% (v/v) based on the DA rat vitreous volume of 55 μl.…”

Section: Discussioncontrasting

confidence: 99%

“…DMSO is used widely in the eye as a vehicle control (8, 9, 12, 14–19, 42), and there are several studies claiming no adverse effects (43–45). It has been used topically (1–50% v/v; refs.…”

Section: Discussionmentioning

confidence: 99%

“…17, 18), 2‐(6‐cyano‐1‐hexyn‐1‐yl) adenosine [2‐CN‐Ado, 50% (v/v) DMSO; ref. 19], and histone H4 deacetylation DMSO (1 μl; ref. 8).…”

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confidence: 99%

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Unexpected low‐dose toxicity of the universal solvent DMSO

et al. 2013

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Dimethyl sulfoxide (DMSO) is an important aprotic solvent that can solubilize a wide variety of otherwise poorly soluble polar and nonpolar molecules. This, coupled with its apparent low toxicity at concentrations <10%, has led to its ubiquitous use and widespread application. Here, we demonstrate that DMSO induces retinal apoptosis in vivo at low concentrations (5 μl intravitreally dosed DMSO in rat from a stock concentration of 1, 2, 4, and 8% v/v). Toxicity was confirmed in vitro in a retinal neuronal cell line, at DMSO concentrations >1% (v/v), using annexin V, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT), and AlamarBlue cell viability assays. DMSO concentrations >10% (v/v) have recently been reported to cause cellular toxicity through plasma membrane pore formation. Here, we show the mechanism by which low concentrations (2-4% DMSO) induce caspase-3 independent neuronal death that involves apoptosis-inducing factor (AIF) translocation from mitochondria to the nucleus and poly-(ADP-ribose)-polymerase (PARP) activation. These results highlight safety concerns of using low concentrations of DMSO as a solvent for in vivo administration and in biological assays. We recommend that methods other than DMSO are employed for solubilizing drugs but, where no alternative exists, researchers compute absolute DMSO final concentrations and include an untreated control group in addition to DMSO vehicle control to check for solvent toxicity.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Unexpected low‐dose toxicity of the universal solvent DMSO

et al. 2013

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“…To this day no generally accepted therapy for increasing ocular blood flow is available despite the fact that many frequent and sight threatening eye diseases, most notably glaucoma and AMD, are associated with reduced blood flow (Ciulla et al 2001;Flammer et al 2002). Previous efforts (Lee et al 1993;Uchida et al 2002;Konno et al 2007;Miwa et al 2009) with the type 5 PDE inhibitor sildenafil being the most intensively studied substance (Grunwald et al 2001;Paris et al 2001;Koksal et al 2005;Harris et al 2008;Kerr & Danesh-Meyer 2009). Similar to our results with moxaverine sildenafil increases blood flow in the retrobulbar and choroidal circulation, and most studies suggest an increase in choroidal blood flow, with a lesser effect on the retinal vasculature (Kerr & Danesh-Meyer 2009).…”

Section: Discussionmentioning

confidence: 99%

The effects of moxaverine on ocular blood flow in patients with age‐related macular degeneration or primary open angle glaucoma and in healthy control subjects

Pemp

Garhöfer

Lasta

et al. 2012

Acta Ophthalmologica

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ABSTRACT.Purpose: The phosphodiesterase inhibitor moxaverine has been shown to increase choroidal blood flow (BF) in young healthy subjects. The present study was performed to investigate the effect of intravenously administered moxaverine on ocular BF in patients with age-related macular degeneration (AMD), primary open angle glaucoma (POAG) and in age-matched control subjects. Methods: Twenty patients with AMD, 20 patients with POAG and 20 control subjects were included. Moxaverine 150 mg was applied intravenously over 30 min. BF was measured in the choroid and in the optic nerve head (ONH) using laser-Doppler flowmetry and in retinal vessels combining laser-Doppler velocimetry with retinal vessel analysis before and 30, 60 and 90 min after start of drug administration. BF velocities in the retrobulbar vessels were measured using colour Doppler imaging. Results: Moxaverine increased choroidal BF by 9 ± 22% (p = 0.012), ONH BF by 13 ± 33% (p = 0.021), mean flow velocity in the ophthalmic artery by 23 ± 34% (p < 0.001) and in the posterior ciliary arteries by 25 ± 35% (p < 0.001). Moxaverine had no significant effect on retinal vessel diameters and retinal BF. There were no significant differences in any of the measured parameters between the three groups. Conclusion: The present study indicates that systemic administration of moxaverine increases choroidal and ONH BF in elderly patients with eye diseases associated with hypoperfusion and in age-matched controls. Further studies in patients are needed to investigate whether long-term treatment with moxaverine is clinically beneficial for patients with ocular diseases.

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“…The conjunctiva shows an aggressive wound-healing response, and as a result the rabbit has been used extensively in glaucoma research [2,27,38,50,52,53,57,70,107]. It is also an established model in proliferative vitreoretinopathy research [13,24,25,27,48,52,53,62,86,112].…”

Section: Rabbitmentioning

confidence: 99%

A review of in vivo animal studies in retinal prosthesis research

Bertschinger¹,

Beknazar²,

Silva

et al. 2008

Graefes Arch Clin Exp Ophthalmol

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Background The development of a functional retinal prosthesis for acquired blindness is a great challenge. Rapid progress in the field over the last 15 years would not have been possible without extensive animal experimentation pertaining to device design and fabrication, biocompatibility, stimulation parameters and functional responses. This paper presents an overview of in vivo animal research related to retinal prosthetics, and aims to summarize the relevant studies. Methods A Pubmed search of the English language literature was performed. The key search terms were: retinal implant, retinal prosthesis, artificial vision, rat, rabbit, cat, dog, sheep, pig, minipig. In addition a manual search was performed based on references quoted in the articles retrieved through Pubmed. Results We identified 50 articles relevant to in vivo animal experimentation directly related to the development of a retinal implant. The highest number of publications related to the cat (n=18). Conclusion The contribution of animal models to the development of retinal prosthetic devices has been enormous, and has led to human feasibility studies. Grey areas remain regarding long-term tissue-implant interactions, biomaterials, prosthesis design and neural adaptation. Animals will continue to play a key role in this rapidly evolving field.

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Effect of 2-(6-cyano-1-hexyn-1-yl)adenosine on ocular blood flow in rabbits

Cited by 7 publications

References 40 publications

Unexpected low‐dose toxicity of the universal solvent DMSO

Unexpected low‐dose toxicity of the universal solvent DMSO

The effects of moxaverine on ocular blood flow in patients with age‐related macular degeneration or primary open angle glaucoma and in healthy control subjects

A review of in vivo animal studies in retinal prosthesis research

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