Search Results (425)

Myeloid-derived growth factor (MYDGF), named in reference to its secretion from myeloid cells in bone marrow, is a novel protein with anti-apoptotic and tissue-repairing properties. MYDGF is found in various human tissues affected by different diseases. To date, however, MYDGF expression has yet to be reported in the nervous system. Herein, we demonstrate for the first time that MYDGF mRNA levels increased in the zebrafish retina 1 h after optic nerve injury (ONI). MYDGF-producing cells were located in the photoreceptors and infiltrating leukocytic cells. We prepared the retina for MYDGF gene knockdown by performing intraocular injections using either MYDGF-specific morpholino or the CRISPR/Cas9 system. Under these MYDGF-knockdown retinal conditions, anti-apoptotic Bcl-2 mRNA was suppressed; in comparison, apoptotic caspase-3 and inflammatory TNFα mRNA were significantly upregulated in the zebrafish retina after ONI compared to the control. Furthermore, heat shock factor 1 (HSF1) was evidently suppressed under these conditions, leading to a significant number of apoptotic neurons. These findings indicate that MYDGF is a key molecule in the stimulation of neuronal regeneration in the central nervous system. Full article

This study presents transistor-level simulation results for a novel memristor emulator circuit. The design incorporates an inverter and a current-mode-controlled operational transconductance amplifier to stabilize the output voltage. Transient performance is evaluated across a 20 MHz to 100 MHz frequency range. Simulations using 0.18 μm TSMC technology confirm the circuit’s functionality, demonstrating a power consumption of 0.1 mW at a 1.2 V supply. The memristor model’s reliability is verified through corner simulations, along with Monte Carlo and temperature variation tests. Furthermore, the emulator is applied in a Memristive Integrate-and-Fire neuron circuit, a CMOS-based system that replicates biological neuron behavior for spike generation, enabling ultra-low-power computing and advanced processing in retinal prosthesis applications. Full article

Diabetic retinopathy (DR), a leading cause of blindness in working-age adults, arises from chronic hyperglycemia-induced oxidative stress, inflammation, and vascular dysfunction. Current therapies such as laser photocoagulation, intravitreal anti-vascular endothelial growth factor (VEGF) agents, and steroids target advanced stages but fail to prevent early neuronal and microvascular damage. Emerging evidence highlights oxidative stress as a key driver of DR pathogenesis, disrupting the blood-retinal barrier (BRB), promoting neurodegeneration and angiogenesis. Advances in imaging, particularly optical coherence tomography angiography (OCTA), enable earlier detection of neurodegeneration and microvascular changes, underscoring DR as a neurovascular disorder. Polyphenols, such as resveratrol, curcumin, and pterostilbene, exhibit multitarget antioxidant, anti-inflammatory, and anti-angiogenic effects, showing promise in preclinical and limited clinical studies. However, their low bioavailability limits therapeutic efficacy. Nanotechnology-based delivery systems enhance drug stability, tissue targeting, and sustained release, offering potential for early intervention. Future strategies should integrate antioxidant therapies and precision diagnostics to prevent early irreversible retinal damage in diabetic patients. Full article

Background: The retina, a light-sensitive tissue of the central nervous system that is located at the posterior part of the eye, is particularly vulnerable to alterations in oxygen levels. In various retinal diseases, such as central retinal vein occlusion, glaucoma, and diabetic retinopathy, hypoxia (a condition of low oxygen levels) is commonly observed. Müller glia, the principal glial cells in the retina, play a crucial role in supporting the metabolic needs of retinal neurons. They are also responsible for sensing oxygen levels and, in response to hypoxia, express Hypoxia-Inducible Factor 1 (HIF-1), a transcription factor that activates signaling pathways related to hypoxia. Methods: In this study, primary rat Müller glial cells were cultured and exposed to a 1% oxygen for 72 h. Following this, immunohistochemical assays were conducted to assess the effects of hypoxia on various parameters, including HIF-1α expression, cell survival, Müller glia-specific markers (CRALBP and GS), gliosis (GFAP expression), apoptosis (caspase-3 expression), cell proliferation (Ki-67 expression), and metabolic stress (indicated by the number of mitochondria per cell). Results: Under hypoxic conditions, a decrease in Müller glial survival and proliferation was observed. Conversely, there was an increase in HIF-1α expression, GFAP expression, caspase-3-positive cells, and the number of mitochondria per cell. However, no significant changes were noted in the expression of the Müller glial markers GS and CRALBP. Conclusions: In conclusion, hypoxia resulted in reduced proliferation and survival of Müller glial cells, primarily due to increased apoptosis and heightened metabolic stress. Full article

Objectives: Insulin plays a crucial role in neuronal survival and oxidative stress modulation, making it a potential therapeutic target. This study investigates the effects of insulin in combination with a mesenchymal cell-derived secretome in patients with degenerative neuroretinal diseases. Methods: Sixty-four patients with severe neuroretinal diseases who had previously undergone the Limoli Retinal Restoration Technique (LRRT) were included in this longitudinal study and divided into groups: group 1 received a single injection of 5 units of insulin lispro into the suprachoroidal space of the worse-seeing eye; group 2 received insulin injection in the better-seeing eye. Retinal function was assessed using microperimetry (MY) before and after treatment (approximately 1 year for eye drops). Group 3 consisted of patients who demonstrated improvement in MY after insulin injection. These patients continued treatment with daily insulin eye drops. Results: In group 1, insulin-treated eyes showed a significant increase in retinal sensitivity from 10.09 dB to 10.75 dB (p = 0.0067), while untreated eyes declined from 12.35 dB to 11.92 dB (p = 0.0448). In group 2, insulin-treated eyes improved from 10.8 dB to 11.63 dB (p = 0.05), whereas untreated eyes exhibited a decline from 8.68 dB to 8.50 dB (p = 0.6771). In group 3, patients using insulin eye drops showed a stabilization or mild increase in retinal sensitivity, from 11.39 dB to 11.73 dB (p = 0.231). Conclusions: The addition of insulin in patients previously treated with the LRRT was associated with improved sensitivity and a stabilizing effect on neuroretinal function. Full article

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019 (COVID-19), is known to affect multiple organ systems, including the respiratory tract and nervous and ocular systems. This retrospective study aimed to characterize the spatiotemporal distribution of viral antigen and associated pathological changes in the nose, lungs, brain, and eyes of K18-hACE2 mice intranasally infected with SARS-CoV-2. Using histology and immunohistochemistry, tissues were examined at 3, 6, and 7/8 days post-infection (dpi). In addition, lung and brain tissues were analyzed by means of RT-qPCR to determine viral RNA titers. Viral antigen was most pronounced in the nose, brain, and lung at 3, 6, and 7/8 dpi, respectively, whereas viral antigen was detected at 6 and 7/8 dpi in the retina. Quantitative PCR confirmed increasing viral RNA levels in both lung and brain, peaking at 7/8 dpi. Nasal and lung inflammation mirrored viral antigen distribution and localization. In the brain, the predominantly basal viral spread correlated with lymphohistiocytic meningoencephalitis, neuronal vacuolation, and altered neurofilament immunoreactivity. Retinal ganglion cells showed viral antigen expression without associated lesions. Microglial activation was evident in both the optic chiasm and the brain. These findings highlight the K18-hACE2 model’s utility for studying extrapulmonary SARS-CoV-2 pathogenesis. Understanding the temporal and spatial dynamics of viral spread enhances insights into SARS-CoV-2 neurotropism and its clinical manifestations. Full article

The retinal pigment epithelium (RPE) is a cellular source of retinal regeneration in lower vertebrates and a cellular source of retinal diseases in mammals, including humans. Both processes are based on a genetic program for the conversion of RPE cells into cells of other phenotypes: neural in the first case and mesenchymal in the second. RPE reprogramming in the neural direction is realized in tailed amphibians and bird embryos in vivo, but in higher vertebrates and humans, this process is realized in vitro. Epigenetic regulation determines the phenotypic plasticity of RPE cells, i.e., their choice of the cell differentiation pathway in animals of different classes. It has been suggested that the implementation of the genetic program for RPE reprogramming into different types of retinal neurons in adult amphibians and birds at the early stages of embryogenesis is conditioned by the specificity of the epigenetic landscape. The retinal RPE-dependent pathologies in mammals are characterized by different epigenetic signatures, and have a shared characteristic: specifically, a deficient epigenetic landscape (dysregulations in DNA methylation and histone modifications). Knowledge of the patterns and features of the epigenetic regulation of RPE cell behavior will allow us to obtain RPE cells that are in demand in medicine, from direct reprogramming with the possibility of epigenetically maintaining the cellular identities to the creation of neuro-regenerative technologies for the replacement therapy of RPE-dependent retinal pathologies in humans. Full article

Background: Traumatic optic neuropathy (TON) represents a major cause of vision loss worldwide, and treatment options are limited. Here, we study whether methylene blue (MB), a free radical scavenger, is able to prevent morphological and electrophysiological hallmarks of neuropathy in an animal model of TON. Methods: The left eyes of Wistar rats were subjected to intraorbital nerve crush (IONC) while the right ones were sham operated. The group of rats treated with MB (n = 16) received five intraperitoneal injections with 2.0 mg/kg MB in the 24 h following IONC while the control group (n = 16) received just vehicle (PBS) as a control. Twenty-one days after surgery, scotopic full field (scERG), scotopic oscillatory potentials (OP), photopic full field (phERG) and pattern (PERG) electroretinography were performed for retinal function assessment. Furthermore, the number of cell nuclei in the ganglion cell layer (GCL) was recorded in post mortem histological sections. Results: IONC induced very significant reductions in electrophysiological parameters including scotopic a- and b-wave, OPs, photopic b-wave, PhNR amplitude and N2 amplitude. In addition, it also generated a significant prolongation of the N2 implicit time, indicating a profound impact on retinal function. This was further corroborated by a very significant reduction in the number of neuronal nuclei in the GCL, suggesting an intense loss and functional impairment of retinal ganglion cells. MB treatment was able to prevent, partially or completely, all those parameters, indicating the efficiency of such approach. Conclusions: Since MB is already approved for clinical use and presents a high safety profile, it could be repurposed as a neuroprotective drug for ophthalmological applications once proper phase 2 clinical trials are accomplished. Full article

Background: The retina plays a vital role in vision, and its impairment can cause significant visual deficits. Current retinal disease treatments range from conventional anti-inflammatory drugs to advanced anti-VEGF therapies and monoclonal antibodies. TnP, a novel synthetic peptide in preclinical development, has demonstrated therapeutic potential in chronic inflammatory conditions such as multiple sclerosis and asthma due to its immunomodulatory properties. Using zebrafish—which share significant genetic homology with humans—we investigated TnP’s effects on retinopathy models mimicking diabetic retinopathy (DR) through either cobalt chloride (CoCl₂)-induced hypoxia or light-induced retinal damage (LIRD). Methods: We employed two retinal injury models (CoCl₂-induced hypoxia and LIRD) and subjected them to TnP treatment, assessing the outcomes through visual–motor response testing and histological examination. Results: CoCl₂ exposure impaired swimming activity, while light damage reduced the movement distance. Both models induced distinct retinal morphological changes. Although TnP failed to reverse most injury effects, it specifically restored the inner plexiform layer (IPL)’s thickness. Conclusions: Our findings suggest that TnP may enhance neuronal plasticity by promoting cell proliferation and synaptic connectivity. While showing promise as a therapeutic candidate for retinal and neurodegenerative disorders, TnP might achieve optimal efficacy when combined with complementary treatments. Full article

Until now, the ultimate solution for blind people has not been achieved, because challenges still exist. Retinal implants have emerged as a promising solution for restoring vision in individuals suffering from retinal degenerative diseases such as retinitis pigmentosa and age-related macular degeneration. Central to the efficacy of these implants is the design and functionality of the electrode arrays responsible for stimulating retinal neurons. This review evaluates the evolution of retinal implants, with particular emphasis on electrode specifications, physiological considerations for electrical stimulation, and recent advancements in electrode design. A comprehensive analysis of state-of-the-art published studies provides a detailed cross-comparison of electrode characteristics, offering insights into current state-of-the-art technologies and future directions. Full article

In this study, the perception of phosphenes was used as a surrogate identifier for stimulation sites for use in retinal-degenerative diseases. We aimed to investigate the influence of adaptation, electrode montage, and direction of view on electrically induced phosphenes. We developed a practical methodology to assess non-invasive ocular electrical stimulation, addressing specific areas in the retina. Phosphene thresholds were identified under light and dark adaptation for non-invasive transorbital electrical stimulation. The location and extent characterized the morphology of electrically induced retinal phosphenes for five directions of view and for seven electrode montages in 62 participants. Our results indicated the lowest phosphene thresholds under light adaptation. Cumulative charts of phosphenes visualized the location of phosphene hot spots and their focality for the investigated directions of view and electrode montages. Under consistent light adaptation, we found changes in electrode montage generated stronger changes in the phosphenes’ morphology and distribution. Adjusting the electrodes in the orbital vicinity was more effective than changing the direction of view to shift the phosphene hot spot location to a pathological region to induce neuronal activity there. In this study, we established the first practical methodology to adapt non-invasive transorbital electrical stimulation to address specific areas in the retina. Full article

Age-related retinopathy is one of the leading causes of visual impairment and irreversible blindness, characterized by progressive neuronal and myelin loss. The damages caused by oxidation contributes to the hallmarks of aging and represents fundamental components in pathological pathways that are thought to drive multiple age-related retinopathies. Quercetin (Que), a natural polyphenol abundant in vegetables, herbs, and fruits, has been extensively studied for its long-term antioxidative effects mediated through diverse mechanisms. Additionally, Que and its derivatives exhibit a broad spectrum of pharmacological characteristics in the cellular responses of age-related retinopathy induced by oxidative stress, including anti-inflammatory, anti-neovascularization, regulatory, and neuroprotective effects in autophagy and apoptosis processes. This review mainly focuses on the antioxidative mechanisms and curative effects of Que treatment for various age-related retinopathies, such as retinitis pigmentosa, diabetic retinopathy, age-related macular degeneration, and glaucoma. Furthermore, we discuss emerging technologies and methods involving Que and its derivatives in the therapeutic strategies for age-related retinopathies, highlighting their promise for clinical translation. Full article

Müller glia exhibit a remarkable regenerative capacity in zebrafish through spontaneous reprogramming post-injury but remain limited in mammals. This review highlights the key mechanisms underlying Müller glia reprogramming, including gene regulatory networks, cytokine signaling, signal transduction pathways, epigenetic modifications, and transcriptional regulation. Cross-species analyses have uncovered conserved gene networks that suppress neurogenesis in mammals, while injury-induced transcriptional profiles reveal divergent regenerative strategies. Combinatorial approaches may enhance the reprogramming of mammalian Müller glia into functional neurons. Nevertheless, significant challenges remain, such as variability in the efficacy of direct reprogramming methods and the limited regeneration of cone photoreceptors, even in regenerative species. We conclude that targeting epigenetic barriers and species-specific regulatory pathways offers promising avenues for clinical translation in retinal disorders such as glaucoma and retinitis pigmentosa. Moving forward, research efforts should prioritize the functional integration of regenerated neurons and the development of standardized methodologies to accelerate therapeutic advancements. Full article

Neuronal ceroid lipofuscinoses (NCLs) are a group of autosomal recessive neurogenetic disorders caused by mutations in 14 different genes. CLN6 disease manifests as variant late-infantile NCL (vLINCL) or as an adult variant. In childhood, symptoms include speech delay, vision loss, cognitive and motor decline, seizures, and early death. An in-depth characterization of a naturally occurring Cln6 mutant mouse (Cln6^nclf) is presented, with implications for translational research. The expanded phenotype provides data showing early death, vision loss, and motor deficits in male and female Cln6^nclf mice. Diminished visual acuity in Cln6^nclf mice was noted at 28 weeks of age, but the pathological loss of retinal layers began as early as 2 weeks or postnatal day 14 (P14). Apoptosis was confirmed by TUNEL staining in the Cln6^nclf mouse brain at P8 and in the retina at P12. A peak in glial fibrillary acidic protein (GFAP) expression was established as a normal developmental phenomenon in the wild-type and Cln6^nclf mouse brain cerebellum and the CA2–CA3 regions of the hippocampus at P8. In Cln6^nclf mice, GFAP levels were elevated at P12 in the cerebellum and hippocampus. In the retina, a developmental peak in gliosis was absent, with increased astrogliosis noted at P6 and P8 in female and male Cln6^nclf mice, respectively. This highlights the lack of a sex-dependent response in wild-type mice. These novel data position the Cln6^nclf mouse model as a useful tool for screening potential therapeutics for human CLN6 disease. Full article

The visual system has served as an expeditious entry point for discerning the mechanism of action of many brain systems, spearheading multiple fields of neuroscience in the process. It has additionally launched the careers of countless scientists, as we have crafted new means to understand neuronal structures and their functions, leading to advances in many areas of the sciences. Indeed, one can readily mark the onset of the scientific examination of the visual system with the 1851 invention of the ophthalmoscope by Hermann von Helmholtz, and the trichromatic theory of color vision in 1802. The Young–Helmholtz understanding the red–green–blue nature of color vision became the foundation to understanding sensory system function that visual artists and also contemporary flat panel displays rely on. It is fascinating to realize that the paintings of Georges Seurat and an iPhone display share a commonality of this application of the trichromatic theory. While it was not until 1956 that the existence of cells responsive to three different ranges of wavelengths was proven with the work of Gunnar Svaetichin, this proof in many ways marked the advancement of tools to visualize at a microscopic level, a full century after the Young–Helmholtz theory was developed. Just a decade later, in 1966, the person widely considered as the founder of modern neuroscience, Stephen Kuffler, founded the Harvard neurobiology department. It was from Kuffler’s work with his post-doctoral students that many new fields of study were created and from whom many of the neuroscience programs across the US were founded. In terms of the visual system, Kuffler and his team were key in detailing areas of retinal neuroanatomy, neurochemistry, neurophysiology, and developmental neurobiology. This paper traces areas in visual system research that provide our understanding of the disparate areas of brain sciences. As such, there are six categories that are evaluated, each of which spawned work in multiple areas that have become mainstays in neuroscience. These range from fields that were dominant a half century ago to ones that have their origins in this decade. The commonality is that all of these owe their origin to Helmholtz and Kuffler, polymaths of the nineteenth and twentieth centuries. We will examine the impact of vision research across the following fields of neuroscience: sensory system function, neuroanatomy, neurochemistry, neurophysiology, developmental neurobiology, and neurological health and disease. Full article