Polydopamine nanoparticles attenuate retina ganglion cell degeneration and restore visual function after optic nerve injury.

BACKGROUND: Oxidative stress contributes to retina ganglion cells (RGCs) loss in variety of ocular diseases, including ocular trauma, ocular vein occlusion, and glaucoma. Scavenging the excessed reactive oxygen species (ROS) in retinal neurovascular unit could be beneficial to RGCs survival. In this study, a polydopamine (PDA)-based nanoplatform is developed to protect RGCs. RESULTS: The PDA nanoparticles efficiently eliminate multi-types of ROS, protect endothelia and neuronal cells from oxidative damage, and inhibit microglia activation in retinas. In an optic nerve crush (ONC) model, single intravitreal injection of PDA nanoparticles could significantly attenuate RGCs loss via eliminating ROS in retinas, reducing the inflammatory response and maintaining barrier function of retinal vascular endothelia. Comparative transcriptome analysis of the retina implied that PDA nanoparticles improve RGCs survival probably by altering the expression of genes involved in inflammation and ROS production. Importantly, as a versatile drug carrier, PDA nanoparticles could deliver brimonidine (a neuroprotection drug) to synergistically attenuate RGCs loss and promote axon regeneration, thus restore visual function. CONCLUSIONS: The PDA nanoparticle-based therapeutic nanoplatform displayed excellent performance in ROS elimination, providing a promising probability for treating retinal degeneration diseases.

Approaching Retinal Ganglion Cell Modeling and FPGA Implementation for Robotics.

Taking inspiration from biology to solve engineering problems using the organizing principles of biological neural computation is the aim of the field of neuromorphic engineering. This field has demonstrated success in sensor based applications (vision and audition) as well as in cognition and actuators. This paper is focused on mimicking the approaching detection functionality of the retina that is computed by one type of Retinal Ganglion Cell (RGC) and its application to robotics. These RGCs transmit action potentials when an expanding object is detected. In this work we compare the software and hardware logic FPGA implementations of this approaching function and the hardware latency when applied to robots, as an attention/reaction mechanism. The visual input for these cells comes from an asynchronous event-driven Dynamic Vision Sensor, which leads to an end-to-end event based processing system. The software model has been developed in Java, and computed with an average processing time per event of 370 ns on a NUC embedded computer. The output firing rate for an approaching object depends on the cell parameters that represent the needed number of input events to reach the firing threshold. For the hardware implementation, on a Spartan 6 FPGA, the processing time is reduced to 160 ns/event with the clock running at 50 MHz. The entropy has been calculated to demonstrate that the system is not totally deterministic in response to approaching objects because of several bioinspired characteristics. It has been measured that a Summit XL mobile robot can react to an approaching object in 90 ms, which can be used as an attentional mechanism. This is faster than similar event-based approaches in robotics and equivalent to human reaction latencies to visual stimulus.

Low-dose carbon monoxide inhalation protects neuronal cells from apoptosis after optic nerve crush.

Glaucomatous optic neuropathy, including axonal degeneration and apoptotic death of retinal ganglion cells (RGCs), eventually leads to irreversible visual impairment. Carbon monoxide (CO) acts as a therapeutic agent against neural injury via its anti-apoptotic effect. Here we hypothesized that low-dose CO inhalation can protect RGCs in a rat model of optic nerve crush (ONC). ONC was performed on adult male Sprague Dawley rats to imitate glaucomatous optic damage. Low-dose CO (250 ppm) or air was inhaled for 1 h immediately after ONC, and all the tests were carried out 2 weeks later. Flash visual evoked potentials (FVEP) and pupil light relax (PLR) were recorded for the assessment of visual function. RGC density was evaluated by hematoxylin and eosin staining and Fluorogold labeling. Retinal apoptotic process was assessed by TUNEL staining and caspase-3 activity measurement. Low-dose CO treatment significantly ameliorated the abnormalities of FVEP and PLR induced by ONC. As expected, the RGC density was increased remarkably by CO inhalation after the glaucomatous optic nerve insult. Moreover, CO treatment after ONC significantly decreased the number of TUNEL-positive cells in ganglion cell layer and attenuated the retinal caspase-3 activity. Low-dose CO inhalation protects RGCs from optic nerve injury via inhibiting caspase-3 dependent apoptosis.

Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina.

Purpose: The aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA. Methods: Adult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose-response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs. Results: Administration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity. Conclusion: Subcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity.

Translocator protein 18 kDa regulates retinal neuron apoptosis and pyroptosis in glaucoma.

Glaucoma is the leading cause of blindness worldwide. However, our insufficient understanding of the pathogenesis of glaucoma has limited the development of effective treatments. Because recent research has highlighted the importance of non-coding RNAs (ncRNAs) in various diseases, we investigated their roles in glaucoma. Specifically, we detected expression changes of ncRNAs in cell and animal models of acute glaucoma. Further analysis revealed that the Ier2/miR-1839/TSPO axis was critical to cell loss and retinal damage. The knockdown of Ier2, the overexpression of miR-1839, and the silencing of TSPO effectively prevented retinal damage and cell loss. Furthermore, we found that the Ier2/miR-1839/TSPO axis regulated the pyroptosis and apoptosis of retinal neurons through the NLRP3/caspase1/GSDMD, cleaved-caspase3 pathways. In addition to high expression in the retina, TSPO expression was found to be significantly higher in the dorsal lateral geniculate nucleus (DLG) of the brain in the pathologically high intraocular pressure (ph-IOP) rat model, as well as in the peripheral blood mononuclear cells (PBMCs) of glaucoma patients with high IOP. These results indicate that TSPO, which is regulated by Ier2/miR-1839, plays an important role in the pathogenesis of glaucoma, and this study provides a theoretical basis and a new target for the diagnosis and treatment of glaucoma.

Axon regeneration after optic nerve injury in rats can be improved via PirB knockdown in the retina.

BACKGROUND: In the central nervous system (CNS), three types of myelin-associated inhibitors (MAIs) exert major inhibitory effects on nerve regeneration: Nogo-A, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp). MAIs have two co-receptors, Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Existing studies confirm that inhibiting NgR only exerted a modest disinhibitory effect in CNS. However, the inhibitory effects of PirB on nerve regeneration after binding to MAIs are controversial too. We aimed to further investigate the effect of PirB knockdown on the neuroprotection and axonal regeneration of retinal ganglion cells (RGCs) after optic nerve injury in rats. METHODS: The differential expression of PirB in the retina was observed via immunofluorescence and western blotting after 1, 3, and 7 days of optic nerve injury (ONI). The retina was locally transfected with adeno-associated virus (AAV) PirB shRNA, then, the distribution of virus in tissues and cells was observed 21 days after AAV transfection to confirm the efficiency of PirB knockdown. Level of P-Stat3 and expressions of ciliary neurotrophic factor (CNTF) were detected via western blotting. RGCs were directly labeled with cholera toxin subunit B (CTB). The new axons of the optic nerve were specifically labeled with growth associated protein-43 (GAP43) via immunofluorescence. Flash visual evoked potential (FVEP) was used to detect the P1 and N1 latency, as well as N1-P1, P1-N2 amplitude to confirm visual function. RESULTS: PirB expression in the retina was significantly increased after ONI. PirB knockdown was successful and significantly promoted P-Stat3 level and CNTF expression in the retina. PirB knockdown promoted the regeneration of optic nerve axons and improved the visual function indexes such as N1-P1 and P1-N2 amplitude. CONCLUSIONS: PirB is one of the key molecules that inhibit the regeneration of the optic nerve, and inhibition of PirB has an excellent effect on promoting nerve regeneration, which allows the use of PirB as a target molecule to promote functional recovery after ONI.

Exosome-Mediated Delivery of the Neuroprotective Peptide PACAP38 Promotes Retinal Ganglion Cell Survival and Axon Regeneration in Rats With Traumatic Optic Neuropathy.

Traumatic optic neuropathy (TON) refers to optic nerve damage caused by trauma, leading to partial or complete loss of vision. The primary treatment options, such as hormonal therapy and surgery, have limited efficacy. Pituitary adenylate cyclase-activating polypeptide 38 (PACAP38), a functional endogenous neuroprotective peptide, has emerged as a promising therapeutic agent. In this study, we used rat retinal ganglion cell (RGC) exosomes as nanosized vesicles for the delivery of PACAP38 loaded via the exosomal anchor peptide CP05 (EXO PACAP38 ). EXO PACAP38 showed greater uptake efficiency in vitro and in vivo than PACAP38. The results showed that EXO PACAP38 significantly enhanced the RGC survival rate and retinal nerve fiber layer thickness in a rat TON model. Moreover, EXO PACAP38 significantly promoted axon regeneration and optic nerve function after injury. These findings indicate that EXO PACAP38 can be used as a treatment option and may have therapeutic implications for patients with TON.

OCT parameters of the optic nerve head and the retina as surrogate markers of brain volume in a normal population, a pilot study.

The relationship between optical coherence tomography (OCT) measurements of the retinal structures has been described for various neurological diseases including Multiple Sclerosis (MS), Alzheimer's disease (AD) and Parkinson's disease (PD). Brain volume changes, both globally and by area, are associated with some of these same diseases, yet the correlation of OCT and disease is not fully elucidated. Our study looked at normal subjects, at the correlation of OCT measurements and brain volumes, both globally and for specific regions including the pericalcarine grey matter, entorhinal grey matter, and cerebellar volume using a retrospective, cross-sectional cohort study design. Thickness of the retinal nerve fiber layer (RNFL) as measured by OCT, correlated with volume of the pericalcarine grey matter, when adjusted for age and gender. Similarly, thickness of the ganglion cell layer-inner plexiform layer complex may be associated with both entorhinal grey matter volumes and total cerebellar volumes, although our pilot study did not reach statistical significance. This suggests that both eye and brain volumes follow a similar trajectory and understanding the inter-relationship of these structures will aid in the analysis of changes seen in disease. Further studies are needed to longitudinally demonstrate these relationships.

Paired Immunoglobulin-like Receptor B Inhibition in Müller Cells Promotes Neurite Regeneration After Retinal Ganglion Cell Injury in vitro.

In the central nervous system (CNS), three types of myelin-associated inhibitors (MAIs) have major inhibitory effects on nerve regeneration. They include Nogo-A, myelin-associated glycoprotein, and oligodendrocyte-myelin glycoprotein. MAIs possess two co-receptors, Nogo receptor (NgR) and paired immunoglobulin-like receptor B (PirB). Previous studies have confirmed that the inhibition of NgR only results in a modest increase in regeneration in the CNS; however, the inhibitory effects of PirB with regard to nerve regeneration after binding to MAIs remain controversial. In this study, we demonstrated that PirB is expressed in primary cultures of retinal ganglion cells (RGCs), and the inhibitory effects of the three MAIs on the growth of RGC neurites are not significantly decreased after direct PirB knockdown using adenovirus PirB shRNA. Interestingly, we found that retinal Müller cells expressed PirB and that its knockdown enhanced the regeneration of co-cultured RGC neurites. PirB knockdown also activated the JAK/Stat3 signaling pathway in Müller cells and upregulated ciliary neurotrophic factor levels. These findings indicate that PirB plays a novel role in retinal Müller cells and that its action in these cells may indirectly affect the growth of RGC neurites. The results also reveal that PirB in Müller cells affects RGC neurite regeneration. Our findings provide a novel basis for the use of PirB as a target molecule to promote nerve regeneration.

Optimal Information Transmission by Overlapping Retinal Cell Mosaics.

The retina provides an excellent system for understanding the trade-offs that influence distributed information processing across multiple neuron types. We focus here on the problem faced by the visual system of allocating a limited number neurons to encode different visual features at different spatial locations. The retina needs to solve three competing goals: 1) encode different visual features, 2) maximize spatial resolution for each feature, and 3) maximize accuracy with which each feature is encoded at each location. There is no current understanding of how these goals are optimized together. While information theory provides a platform for theoretically solving these problems, evaluating information provided by the responses of large neuronal arrays is in general challenging. Here we present a solution to this problem in the case where multi-dimensional stimuli can be decomposed into approximately independent components that are subsequently coupled by neural responses. Using this approach we quantify information transmission by multiple overlapping retinal ganglion cell mosaics. In the retina, translation invariance of input signals makes it possible to use Fourier basis as a set of independent components. The results reveal a transition where one high-density mosaic becomes less informative than two or more overlapping lower-density mosaics. The results explain differences in the fractions of multiple cell types, predict the existence of new retinal ganglion cell subtypes, relative distribution of neurons among cell types and differences in their nonlinear and dynamical response properties.