Rodent Models of Retinal Degeneration: From Purified Cells in Culture to Living Animals.

Rodent models of retinal degeneration are essential for the development of therapeutic strategies. In addition to living animal models, we here also discuss models based on rodent cell cultures, such as purified retinal ganglion cells and retinal explants. These ex vivo models extend the possibilities for investigating pathological mechanisms and assessing the neuroprotective effect of pharmacological agents by eliminating questions on drug pharmacokinetics and bioavailability.

Vision Restoration by Optogenetic Therapy and Developments Toward Sonogenetic Therapy.

After revolutionizing neuroscience, optogenetic therapy has entered successfully in clinical trials for restoring vision to blind people with degenerative eye diseases, such as retinitis pigmentosa. These clinical trials still have to evaluate the visual acuity achieved by patients and to determine if it reaches its theoretical limit extrapolated from ex vivo experiments. Different strategies are developed in parallel to reduce required light levels and improve information processing by targeting various cell types.

Assessing Photoreceptor Status in Retinal Dystrophies: From High-Resolution Imaging to Functional Vision.

Purpose: To describe the value of integrating phenotype/genotype data, disease staging, and evaluation of functional vision in patient-centered management of retinal dystrophies.

Methods: (1) Cross-sectional structure-function and retrospective longitudinal studies to assess the correlations between standard fundus autofluorescence (FAF), optical coherence tomography, visual acuity (VA), and perimetry (visual field [VF]) examinations to evaluate photoreceptor functional loss in a cohort of patients with rod-cone dystrophy (RCD); (2) flood-illumination adaptive optics (FIAO) imaging focusing on photoreceptor misalignment and orientation of outer segments; and (3) evaluation of the impact of visual impairment in daily life activities, based on functional (visual and mobility) vision assessment in a naturalistic environment in visually impaired subjects with RCD and subjects treated with Luxturna for RPE65-related Leber congenital amaurosis before and after therapy.

Results: The results of the cross-sectional transversal study showed that (1) VA and macular sensitivity were weakly correlated with the structural variables; and (2) functional impairment (VF) was correlated with reduction of anatomical markers of photoreceptor structure and increased width of autofluorescent ring.

The primate model for understanding and restoring vision.

Retinal degenerative diseases caused by photoreceptor cell death are major causes of irreversible vision loss. As only primates have a macula, the nonhuman primate (NHP) models have a crucial role not only in revealing biological mechanisms underlying high-acuity vision but also in the development of therapies. Successful translation of basic research findings into clinical trials and, moreover, approval of the first therapies for blinding inherited and age-related retinal dystrophies has been reported in recent years.

Let There Be Light: Gene and Cell Therapy for Blindness.

Retinal degenerative diseases are a leading cause of irreversible blindness. Retinal cell death is the main cause of vision loss in genetic disorders such as retinitis pigmentosa, Stargardt disease, and Leber congenital amaurosis, as well as in complex age-related diseases such as age-related macular degeneration. For these blinding conditions, gene and cell therapy approaches offer therapeutic intervention at various disease stages.

Optogenetics.

Purpose Of Review: In this review, we will discuss the recent developments in optogenetics and their potential applications in ophthalmology to restore vision in retinal degenerative diseases.

Recent Findings: In recent years, we have seen major advances in the field of optogenetics, providing us with novel opsins for potential applications in the retina. Microbial opsins with improved light sensitivity and red-shifted action spectra allow optogenetic stimulation at light levels well below the safety threshold in the human eye.

Clinical characteristics and current therapies for inherited retinal degenerations.

Inherited retinal degenerations (IRDs) encompass a large group of clinically and genetically heterogeneous diseases that affect approximately 1 in 3000 people (>2 million people worldwide) (Bessant DA, Ali RR, Bhattacharya SS. 2001. Molecular genetics and prospects for therapy of the inherited retinal dystrophies.

Toward postnatal reversal of ocular congenital malformations.

Aniridia is a panocular disorder that severely affects vision in early life. Most cases are caused by dominantly inherited mutations or deletions of the PAX6 gene, which encodes a transcription factor that is essential for the development of the eye and the central nervous system. In this issue of the JCI, Gregory-Evans and colleagues demonstrate that early postnatal topical administration of an ataluren-based formulation reverses congenital malformations in the postnatal mouse eye, providing evidence that manipulation of PAX6 after birth may lead to corrective tissue remodeling.

Dry age-related macular degeneration: A currently unmet clinical need.

Age-related macular degeneration (AMD) is a leading cause of severe visual impairment and disability in older people worldwide. Although considerable advances in the management of the neovascular form of AMD have been made in the last decade, no therapy is yet available for the advanced dry form of AMD (geographic atrophy). This review focuses on current trends in the development of new therapies targeting specific pathophysiological pathways of dry AMD.

Effect of Aronia melanocarpa fruit juice on indomethacin-induced gastric mucosal damage and oxidative stress in rats.

Aronia melanocarpa fruits are rich in phenolic substances-mainly flavonoids from the anthocyanin subclass. The anthocyanins are water-soluble plant pigments with antioxidant, anti-inflammatory, antimicrobial, hepatoprotective, gastroprotective and other activities. We studied the effect of A.

In vitro neuroprotection by novel antioxidants in guinea-pig urinary bladder subjected to anoxia-glucopenia/reperfusion damage.

In a previous study, the neuroprotection provided by some hindered phenols of synthetic nature and alpha-tocopherol in guinea-pig detrusor strips subjected to ischaemia/reperfusion-like conditions was shown to be related directly to the antioxidant activity. The aim of the present study was to estimate the capability of three novel chimeric molecules derived by assembling known antioxidant moieties, namely FeAOX-6, comprising a chromanyl head and the polyisoprenyl sequence characteristic for lycopene, FeCD-52, derived from the conjugation of ascorbic acid and a polyphenol moiety (FeRS-4) and FeDG-17, derived from the combination of ascorbic acid and a chromanyl head, to confer neuroprotection in an in vitro model of guinea-pig whole urinary bladder subjected to anoxia-glucopenia/reperfusion injury. The antioxidant potential of these compounds was determined by oxygen radical absorbance capacity (ORAC) and phochemiluminescence (PCL) assays to test their peroxyl and anion superoxide (O2(*-)) radical trapping activity, respectively.

Functional characterization and expression of PBR in rat gastric mucosa: stimulation of chloride secretion by PBR ligands.

Previous studies have demonstrated that gastric mucosa contained high levels of the polypeptide diazepam binding inhibitor, the endogenous ligand of the peripheral-type benzodiazepine receptor (PBR). However, the expression and function of this receptor protein in these tissues have not been investigated. Immunohistochemistry identified an intense PBR immunoreactivity in the mucous and parietal cells of rat gastric fundus and in the mucous cells of antrum.

Gastric mucosal lesions in influenza virus infected mice: role of gastric lipid peroxidation.

The present study provides direct experimental proof that the combination of influenza virus infection A/Aichi/2/68 (H3N3) with different models of oxidative stress, such as immobilization, cold and cold-restraint, is associated with graduated oxidative disturbances in the stomach of mice, despite the absence of virus replication and inflammation in this tissue. It was found that experimental influenza virus infection is accompanied with significant changes in gastric mucosal integrity, as well as an increase in the products of lipid peroxidation in the stomachs of mice. Preliminary exposure of mice to immobilization stress and subsequent inoculation of influenza virus did not significantly influence gastric ulceration or lipid peroxidation compared with infected mice.

Effects of paracetamol and propacetamol on gastric mucosal damage and gastric lipid peroxidation caused by acetylsalicylic acid (ASA) in rats.

We have studied the effect of paracetamol and its pro-drug propacetamol on gastric mucosal damage induced by acetylsalicylic acid (ASA) and its possible relation to changes in gastric lipid peroxidation status in rats. Paracetamol or propacetamol were administered intragastrically 1h before ASA (300 mg kg(-1)) in the following equivalent doses: 62.5, 125.

Trypsin is produced by and activates protease-activated receptor-2 in human cancer colon cells: evidence for new autocrine loop.

In this work, we showed that human colon cancer cell lines produce trypsin which can activate a receptor for trypsin, the protease-activated receptor-2 (PAR-2), in these cells. RT-PCR experiments showed that trypsinogen transcripts were present in four colon cancer cell lines: T84, Caco-2, HT-29 and C1.19A.

Mechanical response to electrical field stimulation of rat, guinea-pig, monkey and human detrusor muscle: a comparative study.

The aim of the present investigation was to compare mechanical responses to electrical field stimulation (EFS), as well as cholinergic and non-adrenergic, noncholinergic (NANC) neurotransmission in guinea-pig, rat, monkey and human detrusor muscle strips. Responses to EFS (0.05, 0.

On the mechanisms of the antispasmodic action of some hindered phenols in rat aorta rings.

The antispasmodic effects of 3-t-butyl-4-hydroxyanisole (BHA) and some structurally related compounds were investigated in endothelium-intact rat aorta rings. Nordihydroguaieretic acid (NDGA), BHA, 3,5-di-t-butyl-4-hydroxyanisole (DTBHA), 2,6-di-isopropyl phenol (propofol) and 2,2'-dihydroxy-3,3'-di-t-butyl-5, 5'-dimethoxydiphenyl (DIBHA) did not cause relaxation when added at the plateau of phenylephrine-evoked contraction, nor did they affect the concentration-relaxation curve for acetylcholine in precontracted rings. In rings depolarised with physiological salt solution (PSS) containing 40 mM K(+), NDGA, BHA, DTBHA, 2, 5-di-t-butyl-1,4-benzohydroquinone (BHQ), propofol and nifedipine, but not DIBHA, inhibited the contraction induced by cumulative addition of Ca(2+) (0.

Gastroprotective effect of propacetamol against cold/restraint stress ulcers in rats.

Background: Comparative evaluation of propacetamol and morphine on the cold restraint stress ulcers in rats.

Methods: The present study compared the effects of propacetamol hydrochloride (250 and 500 mg.kg-1 i.

Effect of roxatidine bismuth citrate (MX1) against acetylsalicylic acid- and indomethacin-induced gastric mucosal damage in rats.

We have studied the effect of the newly synthesized agent, roxatidine bismuth citrate (N-[3-(3-(1-piperidinyl-methyl)phenoxy)propyl]-hydroxyacetamide-2- hydroxypropane-1,2,3-tricarboxylate-bismuth(3+) complex), code name MX1, against acetylsalicylic acid (ASA)- and indomethacin-induced gastric mucosal damage in rats. Effects of MX1 (12.5, 50, 125, 184, 250 mg/kg) were compared to the effects of equimolar doses of roxatidine and bismuth subcitrate.

Effects of 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ) on rat aorta smooth muscle.

To characterise the pharmacological activity of 2,5-di-t-butyl-1,4-benzohydroquinone (BHQ) on vascular smooth muscle, the different effects of BHQ on rat aorta were investigated under several experimental conditions. In aortic rings at rest or depolarised with 80 mM K+ in the presence of 1 microM nifedipine, BHQ evoked a slow tonic contraction which was antagonised by 1 mM Ni2+. Depolarised rings contracted in response to addition of 1 mM Ca2+, with an EC50 value of 32.

Gastroprotective effect of MX1 (a novel salt of the active metabolite of roxatidine with a complex of bismuth and citric acid) against stress ulcers in rats.

We have studied the effect of the newly synthesized agent MX1, a salt of the active metabolite of the H2-blocker roxatidine with a complex of bismuth and citric acid (N-[3-(3-(1-piperidinylmethyl)phenoxy)propyl]-hydroxyacetamide+ ++ -2-hydroxypropane-1,2,3-tricarboxilate-bismuth(3+) complex), against restraint stress ulcers in rats (24 h immobilization). The effects of MX1 (12.5, 50, 125, 184 and 250 mg kg-1) were compared with the effects of equimolar doses of roxatidine (6.