Lasting effects of prenatal exposure to Cannabis in the retina of the offspring: an experimental study in mice.

BACKGROUND: Prenatal exposure to Cannabis is a worldwide growing problem. Although retina is part of the central nervous system, the impact of maternal Cannabis use on the retinal development and its postnatal consequences remains unknown. As the prenatal period is potentially sensitive in the normal development of the retina, we hypothesized that recreational use of Cannabis during pregnancy may alter retina structure in the offspring. To test this, we developed a murine model that mimics human exposure in terms of dose and use. METHODS: Pregnant BalbC mice were exposed daily for 5 min to Cannabis smoke (0.2 g of Cannabis) or filtered air, from gestational day 5 to 18 (N = 10/group). After weaning period, pups were separated and examined weekly. On days 60, 120, 200, and 360 after birth, 10 pups from each group were randomly selected for Spectral Domain Optical Coherence Tomography (SD-OCT) analysis of the retina. All retina layers were measured and inner, outer, and total retina thickness were calculated. Other 37 mice from both groups were sacrificed on days 20, 60, and 360 for retinal stereology (total volume of the retina and volume fraction of each retinal layer) and light microscopy. Means and standard deviations were calculated and MANOVA was performed. RESULTS: The retina of animals which mother was exposed to Cannabis during gestation was 17% thinner on day 120 (young adult) than controls (P = 0.003) due to 21% thinning of the outer retina (P = 0.001). The offspring of mice from the exposed group presented thickening of the IS/OS in comparison to controls on day 200 (P < 0.001). In the volumetric analyzes by retinal stereology, the exposed mice presented transitory increase of the IS/OS total volume and volume fraction on day 60 (young adult) compared to controls (P = 0.008 and P = 0.035, respectively). On light microscopy, exposed mice presented thickening of the IS/OS on day 360 (adult) compared to controls (P = 0.03). CONCLUSION: Gestational exposure to Cannabis smoke may cause structural changes in the retina of the offspring that return to normal on mice adulthood. These experimental evidences suggest that children and young adults whose mothers smoked Cannabis during pregnancy may require earlier and more frequent clinical care than the non-exposed population.

Three-Year Clinical Follow-Up of Children Intrauterine Exposed to Zika Virus.

Congenital Zika virus (ZIKV) infection may present with a broad spectrum of clinical manifestations. Some sequelae, particularly neurodevelopmental problems, may have a later onset. We conducted a prospective cohort study of 799 high-risk pregnant women who were followed up until delivery. Eighty-three women and/or newborns were considered ZIKV exposed and/or infected. Laboratory diagnosis was made by polymerase chain reaction in the pregnant mothers and their respective newborns, as well as Dengue virus, Chikungunya virus, and ZIKV serology. Serology for toxoplasmosis, rubella, cytomegalovirus, herpes simplex virus, and syphilis infections were also performed in microcephalic newborns. The newborns included in the study were followed up until their third birthday. Developmental delay was observed in nine patients (13.2%): mild cognitive delay in three patients, speech delay in three patients, autism spectrum disorder in two patients, and severe neurological abnormalities in one microcephalic patient; sensorineural hearing loss, three patients and dysphagia, six patients. Microcephaly due to ZIKV occurred in three patients (3.6%). Clinical manifestations can appear after the first year of life in children infected/exposed to ZIKV, emphasizing the need for long-term follow-up.

Correlations Between Dark-Adapted Rod Threshold Elevations and ERG Response Deficits in Duchenne Muscular Dystrophy.

Purpose: The purpose of this study was to characterize changes in the full-field flash electroretinogram (ERG) in association with psychophysical dark-adapted visual thresholds in patients with genetically characterized Duchenne muscular dystrophy (DMD) either lacking Dp427 (Up 30) or at least Dp260 in addition to Dp427 (Down 30). Methods: Twenty-one patients with DMD and 27 age-similar controls participated in this study. Dark-adapted (0.01, 3.0, and 10 cd.s/m² flashes) and light-adapted (3.0 cd.s/m² flash) ERGs were recorded following International Society for Clinical Electrophysiology of Vision (ISCEV) standard protocols. Visual detection thresholds to 625-nm (cone function) and 527-nm (rod function) light-emitting diode (LED) flashes (2 degree diameter) were measured during a dark adaptation period after a 1-minute exposure to a bleaching light (3000 cd/m²). Initially, 8 minutes of interleaved 625-nm and 527-nm thresholds were measured. After an additional 5 minutes of dark-adaptation, a second set of threshold measurements to 527-nm stimuli was performed during the subsequent 6 minutes. Results: Dark-adapted b-wave amplitude was significantly reduced to all strengths of flash and a-wave in response to the strong flash stimulus was delayed (15.6 vs. 14.7 ms, P < 0.05) in patients with Down 30 compared with controls. Dark-adapted cone thresholds did not differ among the groups (-2.0, -1.8, and -1.7 log cd/m² for Down 30, Up 30, and controls, respectively, P = 0.21). In contrast, dark-adapted rod thresholds were elevated (F(2,36) = 8.537, P = 0.001) in patients with Down 30 (mean = -3.2 ± 1.1 log cd/m²) relative to controls (mean = -4.2 ± 0.3 log cd/m²). Dark-adapted b-wave amplitudes were correlated with dark-adapted rod sensitivity in patients with DMD (Spearman Rho = 0.943, P = 0.005). The changes were much smaller or absent in patients with intact Dp260. Conclusions: Dp260 is particularly required for normal rod-system function in dark adaptation.

Longitudinal visual acuity development in ZIKV-exposed children.

PURPOSE: To follow the visual acuity development of children exposed to or infected with the Zika virus (ZIKV) during gestation and to relate potential visual acuity deficits to their clinical condition. METHODS: In this prospective study, visual acuity was measured via Teller Acuity Cards in three groups of children: (1) those with confirmed ZIKV exposure (ZE) through the mother only, (2) those with confirmed infection (ZI), and (3) unaffected controls. Visual acuity was measured 2-4 times in each child during the first 30 months of age. RESULTS: The study included 22 children in the ZE group, 11 in the ZI group, and 27 controls. Visual acuity developed normally in both patient groups, including infected patients (ZI) that did not manifest clinical symptoms. In a small subgroup of patients with characteristics consistent with congenital Zika syndrome (CZS), visual acuity was within normative values, with the exception of single child with chorioretinal atrophy. CONCLUSIONS: In this southeastern Brazil study cohort, visual acuity development seemed to progress normally in infected children without CZS symptoms.

Effects of cannabis and its components on the retina: a systematic review.

Purpose: Cannabis is the most prevalent drug in the world and its consumption is growing. Cannabinoid receptors are present in the human central nervous system. Recent studies show evidence of the effects of cannabinoids on the retina, and synthesising the results of these studies may be relevant for ophthalmologists. Thus, this review adopts standardised, systematic review methodology to investigate the effects of exposure to cannabis and components on the retina.Methods: We searched five online databases for the combined terms for outcome ("retina") and exposure ("cannabis"). Eligibility of studies were conducted by two independent reviewers, and risk of bias was assessed.Results: We retrieved 495 studies, screened 229 studies, assessed 52 studies for eligibility, and included 16 studies for qualitative analysis. The cannabinoids most frequently investigated were delta-9-tetrahydrocannabinol (THC), abnormal cannabidiol, synthetic cannabinoid, and cannabidiol (CDB). The outcomes most studied were neuroretinal dysfunction, followed by vascular effects. The studies also included investigation of neuroprotective and anti-inflammatory effects and teratogenic effects.Conclusions: This review suggests that cannabinoids may have an important role in retinal processing and function.

Alterations in visual acuity and visual development in infants 1-24 months old either exposed to or infected by Zika virus during gestation, with and without microcephaly.

PURPOSE: To evaluate visual acuity and visual acuity development in children from the state of São Paulo, Brazil, who were exposed to the Zika virus (ZIKV) gestationally. METHODS: Children who had been exposed to ZIKV during gestation and age-matched control subjects received visual acuity and funduscopic examination. ZIKV exposure was confirmed by maternal quantitative polymerase chain reaction testing or serology assay. The ZIKV group was divided into two subgroups: exposed (ZE), with only the mother having confirmed ZIKV infection, and infected (ZI), with confirmed infection. Visual acuity development was compared with prior norms and quantified by measuring visual acuity correlation with age. RESULTS: A total of 110 children were included: 47 who had been exposed to ZIKV (ZE, 23; ZI, 24) and 63 controls. Abnormal visual acuity was found in 5 of 24 ZI children. Of the 4 children with microcephaly, only 2 had visual acuity loss (only 1 also had abnormal funduscopic findings). There was significant correlation between age and visual acuity in both the control group (R2 = 0.8; P < 0.0000) and the ZE subgroup (R2 = 0.6; P < 0.0000). However, visual acuity did not correlate with age in the ZI subgroup (R2 = 0.04; P = 0.38). Furthermore, the increment in octaves/month was much lower in the ZI subgroup. CONCLUSIONS: Our data indicate that visual acuity losses only occur in infants who suffered gestational-infection, not simply exposure. Lack of correlation between age and visual acuity in the ZI subgroup suggests a slowing of visual development even in the absence of microcephaly. This result may have broad implications for the deleterious effects of ZIKV on the central nervous system.

Comparison between albino and pigmented rabbit ERGs.

BACKGROUND: Pigmented and albino rabbits are commonly used in visual research; however, the lack of pigment in the eyes may affect retinal responses. Here, we compare and describe the differences of retinal function between pigmented (English Butterfly) and albino (New Zealand) rabbits. METHODS: Electroretinograms were recorded in pigmented and albino rabbits in the dark-adapted eye, in the light-adapted eye and for four temporal frequencies in the light-adapted eye. The implicit time and amplitude of the a- and b-waves were analyzed, as well as the amplitude and phase of the first harmonic component of the photopic flicker response. RESULTS: Albino rabbits presented significantly larger amplitudes for both a- and b-waves at all intensities and frequencies. The intensity-response function of the scotopic b-wave also showed that the albino retina is more sensitive than the pigmented retina and the larger flicker amplitudes found in the albino group also revealed post-receptoral changes specifically related to cone pathways. CONCLUSIONS: The larger amplitude of albino receptoral and post-receptoral activities might be attributed to greater availability of light due to scatter and reflection at the retinal layer, and as the differences in response amplitudes between the groups increase with flicker frequency, we suggest that ON bipolar cells recover faster in the albino group, suggesting that this might be a mechanism to explain the higher temporal resolution for albinos compared to the pigmented group.

Intravitreal injection of polysorbate 80: a functional and morphological study.

OBJECTIVE: to determine the functional and morphological effects at rabbits retina of PS80 concentration used in the preparation of intravitreal drugs. METHODS: eleven New Zealand rabbits received a intravitreal injection of 0.1ml of PS80. As control, the contralateral eye of each rabbit received the same volume of saline. Electroretinography was performed according to a modified protocol, as well as biomicroscopy and retina mapping before injection and seven and ten days after. Animals were euthanized in the 30th day and the retinas were analyzed by light microscopy. RESULTS: eyes injected with PS80 did not present clinical signs of intraocular inflammation. Electroretinography did not show any alteration of extent and implicit time of a and b waves at scotopic and photopic conditions. There were no morphological alterations of retinas at light microscopy. CONCLUSION: intravitreal injection of PS80 in the used concentration for intravitreal drug preparations do not cause any functional or morphological alterations of rabbit retinas. These results suggest that PS80 is not toxic to rabbit retinas and may be safely used in the preparation of new lipophilic drugs for intravitreal injection.

Intravitreal injection of polysorbate 80: a functional and morphological study / Injeção intravítrea de polissorbato 80: estudo funcional e morfológico

ABSTRACT Objective : to determine the functional and morphological effects at rabbits retina of PS80 concentration used in the preparation of intravitreal drugs. Methods: eleven New Zealand rabbits received a intravitreal injection of 0.1ml of PS80. As control, the contralateral eye of each rabbit received the same volume of saline. Electroretinography was performed according to a modified protocol, as well as biomicroscopy and retina mapping before injection and seven and ten days after. Animals were euthanized in the 30th day and the retinas were analyzed by light microscopy. Results: eyes injected with PS80 did not present clinical signs of intraocular inflammation. Electroretinography did not show any alteration of extent and implicit time of a and b waves at scotopic and photopic conditions. There were no morphological alterations of retinas at light microscopy. Conclusion: intravitreal injection of PS80 in the used concentration for intravitreal drug preparations do not cause any functional or morphological alterations of rabbit retinas. These results suggest that PS80 is not toxic to rabbit retinas and may be safely used in the preparation of new lipophilic drugs for intravitreal injection.

RESUMO Objetivo: determinar os efeitos funcionais e morfológicos na retina de coelhos da concentração de PS80 utilizada na preparação de drogas intravítreas. Métodos: onze coelhos New Zealand receberam injeção intravítrea de 0,1ml de PS80. Como controle, o olho contralateral de cada coelho recebeu o mesmo volume de soro fisiológico. Foram realizados eletrorretinogramas de acordo com o protocolo modificado, biomicroscopia e mapeamento de retina antes da injeção, sete e dez dias depois. Os animais foram sacrificados no 30o dia e as retinas analisadas por microscopia de luz. Resultados: os olhos injetados com PS80 não apresentaram sinais clínicos de inflamação intraocular. O eletrorretinograma não apresentou alteração de amplitude e tempo implícito das ondas a e b nas condições escotópica e fotópica. Não houve alteração morfológica da retina na microscopia de luz. Conclusão: a injeção intravítrea de PS80 na concentração utilizada na preparação de drogas intravítreas não causa alterações funcionais e morfológicas na retina de coelhos. Esses resultados sugerem que o PS80 não é tóxico para a retina de coelhos e pode ser usado com segurança na preparação de novas drogas lipofílicas para injeção intravítrea.

Dystrophin Is Required for Proper Functioning of Luminance and Red-Green Cone Opponent Mechanisms in the Human Retina.

PURPOSE: Visual information is processed in parallel pathways in the visual system. Parallel processing begins at the synapse between the photoreceptors and their postreceptoral neurons in the human retina. The integrity of this first neural connection is vital for normal visual processing downstream. Of the numerous elements necessary for proper functioning of this synaptic contact, dystrophin proteins in the eye play an important role. Deficiency of muscle dystrophin causes Duchenne muscular dystrophy (DMD), an X-linked disease that affects muscle function and leads to decreased life expectancy. In DMD patients, postreceptoral retinal mechanisms underlying scotopic and photopic vision and ON- and OFF-pathway responses are also altered. METHODS: In this study, we recorded the electroretinogram (ERG) while preferentially activating the (red-green) opponent or the luminance pathway, and compared data from healthy participants (n = 16) with those of DMD patients (n = 10). The stimuli were heterochromatic sinusoidal modulations at a mean luminance of 200 cd/m2. The recordings allowed us also to analyze ON and OFF cone-driven retinal responses. RESULTS: We found significant differences in 12-Hz response amplitudes and phases between controls and DMD patients, with conditions with large luminance content resulting in larger response amplitudes in DMD patients compared to controls, whereas responses of DMD patients were smaller when pure chromatic modulation was given. CONCLUSIONS: The results suggest that dystrophin is required for the proper function of luminance and red-green cone opponent mechanisms in the human retina.

Pharmacokinetics, electrophysiological, and morphological effects of the intravitreal injection of mycophenolic acid in rabbits.

PURPOSE: To determine the half-life of mycophenolic acid (MPA) in the vitreous of New Zealand albino rabbits after intravitreal injection and the retinal toxicity of different doses of MPA. METHODS: Ten micrograms of MPA (Roche Bioscience, Palo Alto, CA) was injected in the vitreous of 16 rabbits, animals were sacrificed at different time-points, and vitreous samples underwent high-performance liquid chromatography. For functional and morphological studies, 5 doses of MPA (0.05, 0.5, 2, 10, and 100 µg) were injected in the vitreous of 20 rabbits. As control, contralateral eyes were injected with aqueous vehicle. Electroretinograms (ERGs) were recorded before injection and at days 7, 15, and 30. Animals were sacrificed on day 30 and retinas were analyzed under light microscopy. RESULTS: MPA half-life in the vitreous was 5.0±0.3 days. ERG revealed photoreceptor functional impairment in eyes injected with 0.5 µg and higher on day 30, while eyes injected with 100 µg presented the same changes already from day 15. No morphological change was found. CONCLUSIONS: MPA vitreous half-life is 5.0 days. Intravitreal injection of 0.5 µg MPA and higher causes dose- and time-related photoreceptor sensitivity decrease in rabbits. The MPA dose of 0.05 µg may be safe for intravitreal use in rabbits.

Transscleral delivery of Nd: YLF laser at 1,047 nm causes vascular occlusion in experimental pigmented choroidal melanoma.

PURPOSE: The aims of this study were to determine the scleral attenuation of focused neodymium: yttrium-lanthanum-fluoride laser at 1,047 nm applied transsclerally and whether transscleral delivery can close the vascular supply at the base of experimental choroidal melanoma in rabbits. METHODS: Fifty-two New Zealand albino rabbits were included. Scleral laser attenuation was measured across fresh sclera. B16F10 melanomas were established in the subchoroidal space of 49 rabbits. Twenty-one animals were killed immediately after transscleral treatment, 14 were followed for 2 weeks to 4 weeks, and 14 were followed without treatment. Ophthalmoscopy, fundus photographs, and fluorescein angiography were performed before treatment, immediately after, and weekly during the follow-up. Eyes were examined by light microscopy. RESULTS: Sclera attenuated laser energy by 31% ± 7%. Immediately after treatment, angiography showed diffuse hypofluorescence in 71% (15 of 21 rabbits). Light microscopy showed vascular occlusion extending at least two thirds of the tumor thickness from the base. Seven of the 14 tumors followed for 15 days ± 8 days were eradicated. There was no correlation between tumor height and eradication. CONCLUSION: Rabbit sclera attenuated 31% ± 7% of laser energy. A single transscleral treatment causes tumor vascular closure at the base and may serve as an adjuvant therapy to ensure destruction of deep and intrascleral tumor cells.

In vitro evidence for mycophenolic acid dose-related cytotoxicity in human retinal cells.

PURPOSE: Mycophenolic acid (MPA) is an immunosuppressive agent that controls noninfectious uveitis. Intravitreal MPA delivery may be a potential adjuvant therapy in patients who have to discontinue steroid or immunosuppressive systemic therapy because of side effects. The aims of this study are to evaluate the in vitro effects of MPA over human retinal pigment epithelium (ARPE-19) and human Muller cells (MIO M-1). METHODS: ARPE-19 cells and MIO M-1 cells were exposed to 25, 50, and 100 µg/mL of MPA (Roche Bioscience, Palo Alto, CA) for 24 hours. Toxicity was evaluated by trypan blue dye-exclusion cell viability assay, caspase-3/7 apoptosis-related assay, and JC-1 mitochondrial membrane potential assay. RESULTS: The MPA (25 µg/mL and 50 µg/mL) did not cause reduction in cell viability or significant change in caspase-3/7 activity in both cell lines tested. Mycophenolic acid (100 µg/mL) caused a significant decrease in cell viability (P < 0.01) and higher caspase-3/7 activity (P < 0.05) in both cell lines compared with untreated cells. The JC-1 mitochondrial membrane potential did not show statistically significant differences for both cell lines and all concentration tested when compared with untreated controls (P > 0.05). CONCLUSION: Intraocular delivery may be a potential alternative for the treatment of noninfectious uveitis, either by intravitreal injection or sustained-release drug-delivery systems, in doses of 50 µg/mL or lower.

ON and OFF electroretinography and contrast sensitivity in Duchenne muscular dystrophy.

PURPOSE: The study investigated possible asymmetric dysfunction of the ON and OFF visual mechanisms in DMD (Duchenne muscular dystrophy) patients associated with specific genetic alterations. METHODS: nineteen DMD patients and 7 heterozygous dmd carriers were tested, as well as 19 age-matched controls.Full-field ergs were recorded using mesopic (1 cd/m(2)) and photopic (250 cd/m(2)) sawtooth luminance modulations as stimuli: rapid increase and ramping decrease (to isolate ON responses) or rapid decrease and ramping increase (for OFF responses). In addition, a psychophysical study comprised contrast sensitivity tests using two checkerboard stimuli at either higher (ON) or lower (OFF) luminance relative to the background: 0.3 cycles per degree (cpd) presented for 33 ms (low spatial frequency, short duration) and 2 cpd presented for 1500 ms (high spatial frequency, long duration). RESULTS: A significant ERG amplitude reduction, relative to controls, was detected in the DMD patients in the mesopic positive peaks for both ON and OFF stimuli, as well as for the photopic ON stimulus (P < 0.05). Contrast sensitivity was significantly lower in the DMD patients (P < 0.05) relative to controls for the ON stimuli. Neither the ERG nor the contrast sensitivities were altered in the carriers. CONCLUSIONS: This study suggests that there are ON and OFF ERG alterations when both rods and cones contribute to the ERG responses in DMD patients. When only cones are activated there is an asymmetrical ERG alteration, also revealed by the contrast sensitivity measurements.

Vitreous pharmacokinetics and electroretinographic findings after intravitreal injection of acyclovir in rabbits.

OBJECTIVES: Acute retinal necrosis is a rapidly progressive and devastating viral retinitis caused by the herpesvirus family. Systemic acyclovir is the treatment of choice; however, the progression of retinal lesions ceases approximately 2 days after treatment initiation. An intravitreal injection of acyclovir may be used an adjuvant therapy during the first 2 days of treatment when systemically administered acyclovir has not reached therapeutic levels in the retina. The aims of this study were to determine the pharmacokinetic profile of acyclovir in the rabbit vitreous after intravitreal injection and the functional effects of acyclovir in the rabbit retina. METHODS: Acyclovir (Acyclovir; Bedford Laboratories, Bedford, OH, USA) 1 mg in 0.1 mL was injected into the right eye vitreous of 32 New Zealand white rabbits, and 0.1 mL sterile saline solution was injected into the left eye as a control. The animals were sacrificed after 2, 9, 14, or 28 days. The eyes were enucleated, and the vitreous was removed. The half-life of acyclovir was determined using high-performance liquid chromatography. Electroretinograms were recorded on days 2, 9, 14, and 28 in the eight animals that were sacrificed 28 days after injection according to a modified protocol of the International Society for Clinical Electrophysiology of Vision. RESULTS: Acyclovir rapidly decayed in the vitreous within the first two days after treatment and remained at low levels from day 9 onward. The eyes that were injected with acyclovir did not present any electroretinographic changes compared with the control eyes. CONCLUSIONS: The vitreous half-life of acyclovir is short, and the electrophysiological findings suggest that the intravitreal delivery of 1 mg acyclovir is safe and well tolerated by the rabbit retina.

Vitreous pharmacokinetics and electroretinographic findings after intravitreal injection of acyclovir in rabbits

OBJECTIVES: Acute retinal necrosis is a rapidly progressive and devastating viral retinitis caused by the herpesvirus family. Systemic acyclovir is the treatment of choice; however, the progression of retinal lesions ceases approximately 2 days after treatment initiation. An intravitreal injection of acyclovir may be used an adjuvant therapy during the first 2 days of treatment when systemically administered acyclovir has not reached therapeutic levels in the retina. The aims of this study were to determine the pharmacokinetic profile of acyclovir in the rabbit vitreous after intravitreal injection and the functional effects of acyclovir in the rabbit retina. METHODS: Acyclovir (Acyclovir; Bedford Laboratories, Bedford, OH, USA) 1 mg in 0.1 mL was injected into the right eye vitreous of 32 New Zealand white rabbits, and 0.1 mL sterile saline solution was injected into the left eye as a control. The animals were sacrificed after 2, 9, 14, or 28 days. The eyes were enucleated, and the vitreous was removed. The half-life of acyclovir was determined using high-performance liquid chromatography. Electroretinograms were recorded on days 2, 9, 14, and 28 in the eight animals that were sacrificed 28 days after injection according to a modified protocol of the International Society for Clinical Electrophysiology of Vision. RESULTS: Acyclovir rapidly decayed in the vitreous within the first two days after treatment and remained at low levels from day 9 onward. The eyes that were injected with acyclovir did not present any electroretinographic changes compared with the control eyes. CONCLUSIONS: The vitreous half-life of acyclovir is short, and the electrophysiological findings suggest that the intravitreal delivery of 1 mg acyclovir is safe and well tolerated by the rabbit retina.

Experimental models of autoimmune inflammatory ocular diseases.

Ocular inflammation is one of the leading causes of blindness and loss of vision. Human uveitis is a complex and heterogeneous group of diseases characterized by inflammation of intraocular tissues. The eye may be the only organ involved, or uveitis may be part of a systemic disease. A significant number of cases are of unknown etiology and are labeled idiopathic. Animal models have been developed to the study of the physiopathogenesis of autoimmune uveitis due to the difficulty in obtaining human eye inflamed tissues for experiments. Most of those models are induced by injection of specific photoreceptors proteins (e.g., S-antigen, interphotoreceptor retinoid-binding protein, rhodopsin, recoverin, phosducin). Non-retinal antigens, including melanin-associated proteins and myelin basic protein, are also good inducers of uveitis in animals. Understanding the basic mechanisms and pathogenesis of autoimmune ocular diseases are essential for the development of new treatment approaches and therapeutic agents. The present review describes the main experimental models of autoimmune ocular inflammatory diseases.

New approaches and potential treatments for dry age-related macular degeneration.

Emerging treatments for dry age-related macular degeneration (AMD) and geographic atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification) and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid ß antibodies, aim to prevent apoptosis of retinal cells. Oxidative stress and depletion of essential micronutrients are targeted by the Age-Related Eye Disease Study (AREDS) formulation. Visual cycle modulators reduce the activity of the photoreceptors and retinal accumulation of toxic fluorophores and lipofuscin. Eyes with dry age-related macular degeneration present chronic inflammation and potential treatments include corticosteroid and complement inhibition. We review the current concepts and rationale of dry age-related macular degeneration treatment that will most likely include a combination of drugs targeting different pathways involved in the development and progression of age-related macular degeneration.

Experimental models of autoimmune inflammatory ocular diseases / Modelos experimentais para o estudo de doenças inflamatórias oculares autoimunes

Ocular inflammation is one of the leading causes of blindness and loss of vision. Human uveitis is a complex and heterogeneous group of diseases characterized by inflammation of intraocular tissues. The eye may be the only organ involved, or uveitis may be part of a systemic disease. A significant number of cases are of unknown etiology and are labeled idiopathic. Animal models have been developed to the study of the physiopathogenesis of autoimmune uveitis due to the difficulty in obtaining human eye inflamed tissues for experiments. Most of those models are induced by injection of specific photoreceptors proteins (e.g., S-antigen, interphotoreceptor retinoid-binding protein, rhodopsin, recoverin, phosducin). Non-retinal antigens, including melanin-associated proteins and myelin basic protein, are also good inducers of uveitis in animals. Understanding the basic mechanisms and pathogenesis of autoimmune ocular diseases are essential for the development of new treatment approaches and therapeutic agents. The present review describes the main experimental models of autoimmune ocular inflammatory diseases.

A inflamação ocular é uma das principais causas de perda visual e cegueira. As uveítes constituem um grupo complexo e heterogêneo de doenças caracterizadas por inflamação dos tecidos intraoculares. O olho pode ser o único órgão envolvido ou a uveíte pode ser parte de uma doença sistêmica. A etiologia é desconhecida em um número significativo de casos, que são considerados idiopáticos. Modelos animais têm sido desenvolvidos para estudar a fisiopatogênese da uveíte autoimune devido às dificuldades na obtenção de tecidos de olhos humanos inflamados para experimentos. Na maioria desses modelos, que simulam as uveítes autoimunes em humanos, a uveíte é induzida com proteínas específicas de fotorreceptores (antígeno-S, proteína ligadora de retinoide do interfotoreceptor, rodopsina, recoverina e fosducina). Antígenos não retinianos, como proteínas associadas à melanina e proteína básica de mielina, são também bons indutores de uveíte em animais. Entender os mecanismos básicos e a patogênese dessas doenças oculares é essencial para o desenvolvimento de novas formas de tratamento das uveítes autoimunes e de novos agentes terapêuticos. Nesta revisão serão abordados os principais modelos experimentais utilizados para o estudo de doenças inflamatórias oculares autoimunes.

New approaches and potential treatments for dry age-related macular degeneration / Novas abordagens e tratamentos potenciais da forma seca da degeneração macular relacionada à idade

Emerging treatments for dry age-related macular degeneration (AMD) and geographi c atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification) and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid β antibodies, aim to prevent apoptosis of retinal cells. Oxidative stress and depletion of essential micronutrients are targeted by the Age-Related Eye Disease Study (AREDS) formulation. Visual cycle modulators reduce the activity of the photoreceptors and retinal accumulation of toxic fluorophores and lipofuscin. Eyes with dry age-related macular degeneration present chronic inflammation and potential treatments include corticosteroid and complement inhibition. We review the current concepts and rationale of dry age-related macular degeneration treatment that will most likely include a combination of drugs targeting different pathways involved in the development and progression of age-related macular degeneration.

Os novos tratamentos para a forma seca da degeneração macular relacionada à idade (DMRI) e da atrofia geográfica têm sido baseados em duas estratégias que abordam componentes envolvidos nos mecanismos fisiopatológicos da doença: prevenção da perda de fotorreceptores e células do epitélio pigmentado da retina (indução de neuroproteção, diminuição do dano oxidativo e modificação do ciclo visual) e supressão da inflamação. As drogas neuroprotetoras visam evitar a apoptose das células retinianas, como o fator neurotrófico ciliar, o tartarato de brimonidina, a tandosporina e anticorpos antiamiloide β. A redução do dano oxidativo e a complementação de micronutrientes essenciais são os objetivos da fórmula AREDS. Os modificadores do ciclo visual reduzem a atividade dos fotorreceptores e o acúmulo de fluoróforos tóxicos e lipofuscina na retina. Olhos com a forma seca da degeneração macular relacionada à idade apresentam inflamação crônica e os novos tratamentos incluem corticosteroides e inibidores do sistema complemento. Neste artigo, revisamos o estágio atual do tratamento da forma seca da degeneração macular relacionada à idade que provavelmente será feito através da combinação de drogas que agem em diferentes componentes envolvidos no aparecimento e na progressão da degeneração macular relacionada à idade.