Visual signals in the retina: from photons to synapses

Lagnado, Leon

doi:10.1017/s0958067000019667

Cited by 5 publications

(5 citation statements)

References 40 publications

(46 reference statements)

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“…These symptoms likely arise from off-target inhibition of PDE6 in the retina. PDE6 expression in retina is restricted to rod and cone outer segments, where it contributes to phototransduction 248 . PDE5 inhibitors currently prescribed having varying selectivity for PDE5 over PDE6: 10-fold for sildenafil 249 , 15-fold for vardenafil 250 , and 700-fold for tadalafil 251 .…”

Section: The No-gc-1-cgmp Pathway As a Target For Glaucoma Therapeuticsmentioning

confidence: 99%

The nitric oxide-guanylate cyclase pathway and glaucoma

2018

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Glaucoma is a prevalent optic neuropathy characterized by the progressive dysfunction and loss of retinal ganglion cells (RGCs) and their optic nerve axons, which leads to irreversible visual field loss. Multiple risk factors for the disease have been identified, but elevated intraocular pressure (IOP) remains the primary risk factor amenable to treatment. Reducing IOP however does not always prevent glaucomatous neurodegeneration, and many patients progress with the disease despite having IOP in the normal range. There is increasing evidence that nitric oxide (NO) is a direct regulator of IOP and that dysfunction of the NO-Guanylate Cyclase (GC) pathway is associated with glaucoma incidence. NO has shown promise as a novel therapeutic with targeted effects that: 1) lower IOP; 2) increase ocular blood flow; and 3) confer neuroprotection. The various effects of NO in the eye appear to be mediated through the activation of the GC- guanosine 3:5'-cyclic monophosphate (cGMP) pathway and its effect on downstream targets, such as protein kinases and Ca channels. Although NO-donor compounds are promising as therapeutics for IOP regulation, they may not be ideal to harness the neuroprotective potential of NO signaling. Here we review evidence that supports direct targeting of GC as a novel pleiotrophic treatment for the disease, without the need for direct NO application. The identification and targeting of other factors that contribute to glaucoma would be beneficial to patients, particularly those that do not respond well to IOP-dependent interventions.

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Section: The No-gc-1-cgmp Pathway As a Target For Glaucoma Therapeuticsmentioning

confidence: 99%

The nitric oxide-guanylate cyclase pathway and glaucoma

2018

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“…Retinitis pigmentosa (RP), an inherited retinal disease characterized by the loss of rod and cone photoreceptors, is the leading cause of progressive vision loss and inherited blindness ( 1 , 2 ). Photoreceptors are sensory neurons within the retina that convert light signals into electrical signals for visual signal processing ( 3 ). Patients with RP display signs of nyctalopia (night blindness) due to loss of rods, followed by loss of daytime vision due to secondary cone photoreceptor degeneration.…”

Section: Introductionmentioning

confidence: 99%

In vivo genome editing rescues photoreceptor degeneration via a Cas9/RecA-mediated homology-directed repair pathway

et al. 2019

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Although Cas9-mediated genome editing has been widely used to engineer alleles in animal models of human inherited diseases, very few homology-directed repair (HDR)–based genetic editing systems have been established in postnatal mouse models for effective and lasting phenotypic rescue. Here, we developed an HDR-based Cas9/RecA system to precisely correct Pde6b mutation with increased HDR efficiency in postnatal rodless (rd1) mice, a retinitis pigmentosa (RP) mutant model characterized by photoreceptor degeneration and loss of vision. The Cas9/RecA system incorporated Cas9 endonuclease enzyme to generate double-strand breaks (DSBs) and bacterial recombinase A (RecA) to increase homologous recombination. Our data revealed that Cas9/RecA treatment significantly promoted the survival of both rod and cone photoreceptors, restored the expression of PDE6B in rod photoreceptors, and enhanced the visual functions of rd1 mice. Thus, this study provides a precise therapeutic strategy for RP and other genetic diseases.

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“…PDE-5 has been demonstrated to be present in bipolar cells, ganglion cells and the endothelial and smooth muscle cells of the vascular wall in retinal and choroidal vessels [1]. PDE-6 is a key isoenzyme located in the outer segments of rods and cones for the conversion of light stimulation to electrical signals [2]. The relative selectivity of sildenafil for PDE-5 was10 times of PDE-6 [3].…”

Section: Introductionmentioning

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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Visual signals in the retina: from photons to synapses

Cited by 5 publications

References 40 publications

The nitric oxide-guanylate cyclase pathway and glaucoma

The nitric oxide-guanylate cyclase pathway and glaucoma

In vivo genome editing rescues photoreceptor degeneration via a Cas9/RecA-mediated homology-directed repair pathway

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

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