Sildenafil-Induced Reversible Impairment of Rod and Cone Phototransduction in Monkeys

Kinoshita, Junzo; Iwata, Noriaki; Shimoda, Hitomi; Kimotsuki, Tomofumi; Yasuda, Mitsuya

doi:10.1167/iovs.14-15985

Cited by 23 publications

(10 citation statements)

References 29 publications

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“…The ERG performed in 5 weeks old db/db mice detected reduced amplitude values of b rod and b mix and, importantly, an initial decoupling in the OP. The latter is related to a failure in signal amplification of the synaptic transmission [40] that precedes the severe defects in the visual function detected in more advanced stages [20]. Notably, at 5 weeks of age, systemic endotoxemia and elevated pro-inflammatory cytokines (TNFα and IL6) were detected in db/db mice, probably reflecting alterations in intestinal barrier permeability and gut microbiota at this early period [26].…”

Section: Discussionmentioning

confidence: 97%

Modulation of microglia polarization dynamics during diabetic retinopathy in db / db mice

Arroba

Alcalde-Estévez

Garcia-Ramírez

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Retinal diseases linked to inflammation are often accompanied by macrophage/microglial cells activation. However, the dynamics between M1 (pro-inflammatory) and M2 (anti-inflammatory) polarization of microglia during diabetic retinopathy (DR) has not been investigated and it might be therapeutically useful. We assessed microglia polarization in retinas from db/db mice and human diabetic donors and also the microgliamediated anti-inflammatory effects of the bicyclic nojirimycin derivative (1R)-1-dodecylsulfinyl-5N,6O-oxomethylidenenojirimycin (R-DS-ONJ). Visual function in mice was evaluated by electroretinogram (ERG). Expression of pro-and anti-inflammatory markers in the retina was analyzed by immunofluorescence, Western-blot and quantitative real-time PCR. Lipopolysaccharide (LPS)-mediated polarization profile was studied in Bv.2 microglial cells in the absence or presence of anti-inflammatory cytokines (IL4/IL13) or R-DS-ONJ. At 5 weeks of age, reduced ERG amplitude values of rod and mixed waves were detected in db/db compared to db/+ mice that correlated with elevated circulating endotoxemia and pro-inflammatory cytokines. At this early stage of DR, the marker of activated microglia Iba-1 co-localized with the M2 marker arginase-1 in the retina. Conversely, in retinas from 8 weeks old db/db mice Iba-1-colocalized with active caspase-1, a key component of the inflammasome, reflecting an opposite pattern of microglia polarization. Markers of activated microglia were detected in retinas of diabetic donors. Treatment of Bv.2 cells with LPS and IL4/IL13 or R-DS-ONJ switched the M1 response towards M2. In retinal explants from db/db mice, R-DS-ONJ induced a M2 response. In conclusion, the modulation of microglia polarization dynamics towards a M2 status at early stages of DR offers novel therapeutic interventions.

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Section: Discussionmentioning

confidence: 97%

Modulation of microglia polarization dynamics during diabetic retinopathy in db / db mice

Arroba

Alcalde-Estévez

Garcia-Ramírez

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Immediately before the photopic ERG section of the standard full-field ERGs recording period, responses for the a-wave analysis were recorded in the same manner as that described in our previous reports. 12,13 Briefly, three steps of stimuli were used to elicit the rod-and cone-driven response in the fully dark-adapted state. Thereafter, the cone-driven response in the fully dark-adapted state was elicited by means of a transient rod-saturation procedure, in which the white test stimulus was delivered 500 ms after the conditioning white flash of 4.0 log scot td-s. To elicit the cone-driven response, three steps of test stimuli, which were identical to those used to elicit the rod-and conedriven response, were used.…”

Section: Erg Recording and Analysismentioning

confidence: 99%

N-Methyl-N-Nitrosourea–Induced Acute Alteration of Retinal Function and Morphology in Monkeys

Kinoshita

Iwata

Maejima

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. The purpose of this study was to investigate both functional and morphologic alteration of the retina acutely induced by N-methyl-N-nitrosourea (MNU) in monkeys.METHODS. The MNU was administered intravenously at a single dose of 40 mg/kg to six cynomolgus monkeys, and standard full-field electroretinograms (ERGs) were recorded 1, 3, and 7 days after dosing. In addition, the rod and cone a-waves in response to high-intensity flashes were analyzed by the a-wave fitting model (a-wave analysis). The photopic negative response (PhNR) was also recorded at the same time points. Furthermore, the retinas of two animals each were examined histopathologically 1, 3, or 7 days after dosing. RESULTS.The MNU attenuated all the standard full-field ERGs including the rod-driven and cone-driven responses; in the combined rod-cone response, the b-wave was more affected than the a-wave. In the a-wave analysis, the sensitivity parameters (S) of the rod and cone awaves had decreased on the day after dosing and remained unchanged thereafter. The maximum response parameter (R max ) of the rod a-wave gradually decreased. On the other hand, the R max in the cone a-wave transiently increased on the day after dosing and decreased thereafter; the PhNR amplitude showed a similar time course change. Histopathologically, the retinal lesion on the day after dosing mainly consisted of pyknosis and karyorrhexis in the photoreceptor nucleus. Depletion of some photoreceptor nuclei, and shortening and disorientation of the photoreceptor segments became prominent at 3 and 7 days after dosing. Localization of degenerated photoreceptors was consistent with that of rhodopsin-positive photoreceptors, resulting in a well-preserved central fovea. CONCLUSIONS.Our results indicated that MNU acutely induced rod-dominant photoreceptor degeneration in monkey retinas, but the photoreceptor function was impaired in both the rods and cones. Functional involvement of the postreceptoral components was also indicated.

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“…When taking the recommended dose ranging of 25 to 100mg/day for male ED and 20 mg three times a day for PAH [8], the incidence of ocular side effects, including a sense of blue-tinted vision and changes in brightness perception in the form of increased sensitivity to light, was 0.1-11% [4][5][6][7].There was a reduction in a-wave, b-wave amplitude and sensitivity of S-cone [9,10], and a prolongation of the photopic a-wave and scotopic b-wave [11].The visual symptoms and ERG changes were almost transient [3,12], which were at peak periods in 1~2 hours and disappeared in 3~24 hours after taking sildenafil [9,13].…”

Section: Discussionmentioning

confidence: 99%

High dose sildenafil citrate induced persistent binocular anomalopia: A case report

Huang

Zhu

et al. 2019

Preprint

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Background: When taking the recommended dose of sildenafil citrate for male erectile dysfunction (ED) and pulmonary hypertension (PAH), the incidence of ocular side effects, including a sense of blue-tinted vision and changes in brightness perception in the form of increased sensitivity to light, was 0.1–11%, and the visual symptoms were almost transient. Only a few cases reported the large dose of sildenafil citrate. The visual symptoms of these cases were all reversible. Up to now, no case was reported that the visual symptoms was irreversible, except this one. Case Presentation: A 39-year-old man was sent to emergency department for taking over dosage of 800mg sildenafil citrate (trade name Viagra) to commit suicide. Visual symptoms appeared 4 hours later, including photophobia, blue halo in center field and gray stripes over red background. Sildenafil citrate toxicity caused the damage to outer layer of retina, including of myoid zone, ellipsoidal zone and interdigitation zone on OCT. Pattern visual evoked potential (P-VEP) demonstrated that the amplitudes of bilateral 1 degree spatial frequency P100 was declined mildly, and full-field electroretinogram (ERG) showed slightly-reduced amplitudes of dark-adapted ERG b-wave in both eyes. The patient was diagnosed as bilateral drug toxic retinopathy and ametropia. He was treated with compound anisodine hydrobromide. At 3-week follow-up, myoid zone, ellipsoidal zone and interdigitation zone of macular was improved on OCT, the amplitude of bilateral 1 degree spatial frequency P100 and dark-adapted ERG b-wave was improved slightly, but still remained abnormal. However, the visual symptoms did not improve any more over more than 1 year. Conclusions: High dose of sildenafil may lead to irreversible death of the photoreceptor cells and permanent visual impairment. The ocular side effects of recommended dose and potential visual risks of drug overdose should be paid more attention. Keywords: Sildenafil citrate, high dose, anomalopia, persistent, outer layer of retina.

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Sildenafil-Induced Reversible Impairment of Rod and Cone Phototransduction in Monkeys

Cited by 23 publications

References 29 publications

Modulation of microglia polarization dynamics during diabetic retinopathy in db / db mice

Modulation of microglia polarization dynamics during diabetic retinopathy in db / db mice

N-Methyl-N-Nitrosourea–Induced Acute Alteration of Retinal Function and Morphology in Monkeys

High dose sildenafil citrate induced persistent binocular anomalopia: A case report

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