Ocular toxicity of AUY922 in pigmented and albino rats.

AUY922, a heat shock protein 90 inhibitor is associated with ocular adverse events (AEs). To provide a better understanding of ocular AEs in patients, 4 investigative studies were performed in a step-wise approach to assess retinal structure and function in pigmented (Brown Norway) and albino (Wistar) rats. In rats administered 30mg/kg of AUY922, the AUC0-24h and Cmax are comparable to that in patients at 70mg/m(2). AUY922 at ≥30mg/kg was poorly tolerated by rats with morbidity or mortality generally after the third weekly treatment. Electroretinography (ERG) changes were observed at doses ≥30mg/kg. The ERG changes were dose dependent, consistent with an effect on the photoreceptors, and fully reversible. The ERG effects could not be minimized by decreasing the Cmax while maintaining AUC. Histopathological changes were seen mainly when rats were administered AUY922 at 100mg/kg. The 2-hour infusion of AUY922 at 100mg/kg caused disorganization of the outer segment photoreceptor morphology in male Brown Norway rats; the severity of the disorganization increased with the number of administrations, but was reversible during a 4-week posttreatment period. There was no major difference in ocular response between Brown Norway and Wistar rats. No changes in serum iron levels, and no changes in rhodopsin, PDE6α, ß-transducin concentrations, or retinal pigment epithelium-specific protein RPE65 expression were observed after single and multiple infusions of AUY922 at 100mg/kg compared to vehicle-treated controls. AUY922 retinal toxicity in rats recapitulates and further characterizes that reported in patients and is shown to be reversible, while a precise molecular mechanism for the effect was not determined.

Sweep visual evoked potential testing as a predictor of recognition acuity in albinism.

OBJECTIVE: To determine if sweep visual evoked potential (VEP) acuity is predictive of recognition acuity in children with albinism. METHODS: A retrospective review was performed in children with albinism who underwent sweep VEP testing from 1992 to 2003. All patients had a complete ophthalmologic examination with either binocular or monocular sweep VEP testing and at least 5 years of follow-up. Positive predictability of sweep VEP acuity was defined as final recognition acuity within 1 Snellen line of initial sweep VEP acuity. RESULTS: Of the 13 patients included in the study, 11 had nystagmus, iris transillumination defects, and foveal hypoplasia at initial examination. The mean age at initial sweep VEP testing was 3.1 years (range, 0.1-10.0 years). Five of 13 patients had initial sweep VEP acuity that was predictive of final recognition acuity. Five additional patients had final recognition acuity, which surpassed initial sweep VEP acuity by 2 to 3 lines. Of these 10 patients, the mean duration for recognition acuity to reach VEP acuity was 5.4 years. There was no correlation between predictive VEP acuity and foveal pigmentation, refractive error, strabismus, nystagmus, or longer follow-up. CONCLUSIONS: Sweep VEP testing can be used as a predictive tool for recognition acuity in children with albinism. Predictability was found in a clinical spectrum of albinism.

Mitochondrial signal transduction in accelerated wound and retinal healing by near-infrared light therapy.

Photobiomodulation by light in the red to near infrared range (630-1000 nm) using low energy lasers or light-emitting diode (LED) arrays has been shown to accelerate wound healing, improve recovery from ischemic injury in the heart and attenuate degeneration in the injured optic nerve. Recent evidence indicates that the therapeutic effects of red to near infrared light result, in part, from intracellular signaling mechanisms triggered by the interaction of NIR light with the mitochondrial photoacceptor molecule cytochrome c oxidase. We have demonstrated that NIR-LED photo-irradiation increases the production of cytochrome oxidase in cultured primary neurons and reverses the reduction of cytochrome oxidase activity produced by metabolic inhibitors. We have also shown that NIR-LED treatment prevents the development of oral mucositis in pediatric bone marrow transplant patients. Photobiomodulation improves wound healing in genetically diabetic mice by upregulating genes important in the promotion of wound healing. More recent studies have provided evidence for the therapeutic benefit of NIR-LED treatment in the survival and functional recovery of the retina and optic nerve in vivo after acute injury by the mitochondrial toxin, formic acid generated in the course of methanol intoxication. Gene discovery studies conducted using microarray technology documented a significant upregulation of gene expression in pathways involved in mitochondrial energy production and antioxidant cellular protection. These findings provide a link between the actions of red to near infrared light on mitochondrial oxidative metabolism in vitro and cell injury in vivo. Based on these findings and the strong evidence that mitochondrial dysfunction is involved in the pathogenesis of numerous diseases processes, we propose that NIR-LED photobiomodulation represents an innovative and non-invasive therapeutic approach for the treatment of tissue injury and disease processes in which mitochondrial dysfunction is postulated to play a role including diabetic retinopathy, age-related macular degeneration, Leber's hereditary optic neuropathy and Parkinson's disease.

Use of the multifocal electroretinogram in the evaluation of a patient with central areolar choroidal dystrophy.

PURPOSE: To assess the multifocal electroretinogram and full-field electroretinogram findings in a patient with advanced central areolar choroidal dystrophy. DESIGN: Observational case report. METHODS: A 53-year-old man with central areolar choroidal dystrophy underwent multifocal electroretinogram and full-field electroretinogram testing. RESULTS: The multifocal electroretinogram demonstrated relative preservation of foveal function compared with the severely depressed retinal function of the perifoveal macula corresponding to the location of the retinal and retinal pigment epithelium atrophy. The full-field electroretinogram was normal for both photopic and scotopic responses. CONCLUSION: Despite a normal full-field electroretinogram, the multifocal electroretinogram demonstrated significant macular dysfunction with relative preservation of foveal function in a patient with central areolar choroidal dystrophy.

Harnessing the cell's own ability to repair and prevent neurodegenerative disease.

Near-IR light treatment modifies cellular function, promotes cell survival, and improves outcomes in laboratory and mouse models of Parkinson's disease.

Effects of reference electrode location on monopolar-derived multifocal electroretinograms in cynomolgus monkeys.

The purpose of this study is to determine the effect of reference electrode location on the multifocal electroretinographic waveform. Multifocal electroretinograms (mfERGs) were recorded from 20 ocularly normal cynomolgus monkeys. The corneal electrode was an ERG-jet referenced to an ipsilaterally (outer canthus) situated subdermal needle electrode and to the contralateral corneal electrode. Testing was monocular and recordings from both montages were obtained simultaneously. The stimulus array consisted of 103 equal-sized hexagonal elements, which subtended +/-44 degrees about the central visual axis. Mean luminance of the display was 100 cd/m2. First-order (K1) and second-order (first slice) kernels (K2.1) of the mfERG were grouped in (a) 4 rings, representing the central 56 degrees of visual field and (b) in 15-element quadrants. The mfERG waveform measures included amplitude, implicit time, and root mean square (RMS) of the oscillatory potentials (OP) and response waveform. K1 and K2.1 ring and quadrant amplitudes were larger with the contralateral than with the ipsilateral reference, but more notably signal-to-noise ratios (S:N) of the response waveform were always larger with the ipsilateral reference. Implicit times were longer for the contralateral than ipsilateral reference montage. K1 and K2.1 implicit times in males were longer than in females. Quadrant groupings revealed generally larger K1 and K2.1 amplitudes in nasal than in temporal retina.