Search Results (119)

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

Extracellular vesicles (EVs) are bilayer lipid membrane particles that are released by every cell type. These secretions are further classified as exosomes, ectosomes, and microvesicles. They contain biomolecules (RNAs, proteins, metabolites, and lipids) with the ability to modulate various biological processes and have been shown to play a role in intercellular communication and cellular rejuvenation. Various studies suggest exosomes and/or microvesicles as a potential platform for drug delivery. EVs may deliver lipids and nucleotides directly to an injury site in an axon, promoting growth cone stabilization and membrane expansion as well as repair, thus positively modulating adult axon regeneration. In this review, we will provide a perspective on the metabolite composition of EVs in adult axonal regeneration relevant to the central nervous system (CNS), specifically that pertaining to the optic nerve. We will present an overview of the methods for isolation, enrichment, omics data analysis and quantification of extracellular vesicles with the goal of providing direction for future studies relevant to axon regeneration. We will also include current resources for multi-omics data integration relevant to extracellular vesicles from diverse cell types. Full article

Background: Intracranial pressure (ICP) monitoring is crucial in managing acute brain injury (ABI) to prevent secondary brain injury. While invasive techniques remain the gold standard, they can carry notable risks, such as infection and hemorrhage. Non-invasive techniques are increasingly used, but their inter-modality correlation and concordance have not been systematically evaluated. This study aimed to assess the correlation and concordance among four commonly used non-invasive neuromonitoring tools in patients with ABI undergoing invasive ICP monitoring. Methods: This was a secondary analysis of prospectively collected data from 100 adult patients admitted to the intensive care unit with traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), or intracerebral hemorrhage (ICH) who underwent invasive ICP monitoring. Simultaneous assessments using optic nerve sheath diameter (ONSD), transcranial Doppler-derived pulsatility index (PI), estimated ICP (eICP), and the neurological pupil index (NPi) were performed. Correlation between modalities was assessed using Spearman’s correlation coefficient (ρ), and concordance was evaluated with Cohen’s kappa coefficient (k). Results: We found weak correlations between ONSD and PI (ρ = 0.29), ONSD and NPi (ρ = −0.33), and PI and NPi (ρ = −0.33); moderate correlations between ONSD and eICP (ρ = 0.54) and PI and eICP (ρ = 0.48); and a strong inverse correlation between eICP and NPi (ρ = −0.71; all p < 0.05). Concordance was generally low, with the highest agreement between PI and eICP (k = 0.69). Most other tool pairings showed poor-to-fair concordance (k ≤ 0.30). Conclusions: Non-invasive neuromonitoring tools show variable correlation and limited agreement, suggesting they are not interchangeable. Each modality captures different aspects of cerebral physiology, supporting the use of a multimodal approach to improve accuracy in ICP estimation. Full article

Wipe-out is defined as a sudden, unexplained, and irreversible loss of residual central vision following glaucoma surgery, typically in eyes with advanced visual field damage and severely compromised optic nerves. The purpose of this review is to critically assess the current incidence, risk factors, pathophysiological mechanisms, and clinical relevance of “wipe-out”, a rare but devastating complication of glaucoma surgery characterized by sudden, unexplained central vision loss postoperatively. A comprehensive literature review was conducted, analyzing key peer-reviewed studies from electronic databases (PubMed, Medline, and Google Scholar) published up to 2025. The data from the literature published prior to the year 2000 suggest that wipe-out incidences range broadly from <1% to 13%. Contemporary prospective studies and large-scale reviews indicate a significantly lower current incidence, frequently below 1%. Identified risk factors include severe preoperative visual field loss (especially split fixation), older age, immediate postoperative hypotony, and compromised optic nerve head perfusion. The proposed mechanisms involve acute vascular insults, ischemia–reperfusion injury, and accelerated apoptosis of already vulnerable retinal ganglion cells. Modern MIGS and refined trabeculectomy techniques exhibit notably lower wipe-out risks compared to historical data. The literature emphasizes preventive management, including careful patient selection, incremental intraocular pressure reduction, and minimally invasive anesthetic approaches. Although wipe-out syndrome represents a serious complication, its incidence in modern glaucoma surgery is minimal. The considerable benefits of contemporary surgical approaches—particularly MIGS—in preserving vision clearly outweigh this very low risk. Ophthalmologists should remain vigilant but confident in the safety and efficacy of modern glaucoma surgical techniques, emphasizing proactive intervention to prevent blindness rather than avoiding necessary surgery in consideration of the minimal risk of wipe-out. Full article

Older age is a risk factor for glaucoma, in which progressive retinal ganglion cell (RGC) loss leads to visual field defects and irreversible visual impairment and even blindness. We recently identified the involvement of cellular senescence in RGC cell death post-optic nerve injury. Here we further aimed to delineate the profile of RGC survival in mice with aging, a physiological process with increasing cellular senescence. The numbers of senescent cells in the ganglion cell layer (GCL) significantly and progressively increased starting at 8 months of age. Yet, significant reduction of ganglion cell complex layer thickness began in the 10-month-old mice, and significant reduction in the number of RGCs began in the 12-month-old mice as compared to the 2-month-old mice. Meanwhile, pyroptosis and ferroptosis markers as well as cellular senescence-related cell cycle arrest proteins p15^Ink4b, p16^Ink4a, p21^Cip1, and p53 were significantly and progressively increased in GCL. In contrast, there were no significant changes in dendritic field, complexity, and branches with increasing ages. Comparing between the 2- and 16-month-old mouse retinas, the differentially expressed genes were involved in the pathways of neurodegeneration, innate immunity, and mitochondrial ATP synthesis. In summary, this study revealed the gradual increase in senescent cells as well as pyroptosis and ferroptosis with progressive RGC reduction in mice with aging. Cellular senescence and the related cell death pathways are potential targets for age-related RGC reduction. Full article

Background/objectives: Common carotid artery occlusion can cause oxidant and inflammatory damage to the optic nerve. In this study, the effect of sunitinib was investigated, the antioxidant and anti-inflammatory properties of which have been previously reported and shown to be protective in I/R injury and in preventing bilateral optic nerve ischemia–reperfusion (I/R) injuries after unilateral common carotid artery ligation in rats. Methods: In this study, 18 Albino Wistar male rats were divided into SG (sham-operated), CCU (clamping and unclamping), and SCCU (sunitinib + clamping and unclamping) groups. One hour before the surgical procedures, sunitinib (25 mg/kg, oral) was given to SCCU rats. Anesthesia was induced with ketamine (60 mg/kg, ip) and sevoflurane. The right common carotid arteries of all rats were accessed under anesthesia. While the skin opened in SG rats was closed with sutures, the right common carotid arteries of CCU and SCCU rats were clipped, and an ischemia period was created for 10 min. Then, reperfusion (6 h) was achieved by unclipping. After euthanasia with ketamine (120 mg/kg, intraperitoneally), the right and left optic nerves of the rats were removed and examined biochemically and histopathologically. Results: Malondialdehyde, tumor necrosis factor α, interleukin-1β, and interleukin-6 were increased, and total glutathione levels had decreased in both ipsilateral and contralateral optic nerves (p < 0.05). These changes were more prominent on the ipsilateral side. Similarly, histopathological damage was observed to be more on the ipsilateral side (p < 0.05). Biochemical and histopathological changes were significantly suppressed in rats receiving sunitinib treatment (p < 0.05). Conclusions: Sunitinib may protect optic nerve tissue against I/R injury by reducing oxidative stress and inflammation. Full article

The association between 17β-estradiol (E2) deprivation, seen in menopause, and a risk for developing glaucoma has been shown. Thus, exogenous supplementation of E2 may protect against retinal ganglion cell (RGC) degradation and vision loss. Here, we investigated the utility of topical 10β,17β-dihydroxyestra-1,4-dien-3-one (DHED), a prodrug of E2 that selectively produces the neuroprotective hormone in the retina, on visual function after optic nerve crush (ONC) and ovariectomy (OVX). We used female Brown Norway rats that underwent either Sham or OVX surgeries. After ONC, OVX animals received DHED or vehicle eye drops for 12 weeks. Visual function, via the optomotor reflex, and retinal thickness, via optical coherence tomography, were followed longitudinally. Afterward, we performed mass spectrometry-based label-free retina proteomics to survey retinal protein interaction networks in our selected animal model and to identify E2-responsive proteins after OVX on neurodegeneration. We found that ONC with OVX caused a significant decline in visual functions that were ameliorated by DHED treatments. Discovery-driven retina proteomics identified numerous proteins associated with neurodegenerative processes due to ONC that were remediated by DHED eye drops. Altogether, our three-pronged phenotypic preclinical evaluation of the topical DHED in the OVX + ONC model of glaucoma reveals the therapeutic potential of the prodrug to prevent visual deficits after glaucomatous retinal injury. Full article

Background/Objectives: Resection of tumors invading the cavernous sinus (CS) carries a risk of injury to the cranial nerves and internal carotid artery. Therefore, radical surgery involving lesions around the CS remains challenging, especially for lesions invading the CS, optic sheath, and oculomotor cave. Here, we describe a surgical strategy for meningiomas invading these structures and report on the clinical outcomes. Methods: Surgical resection was indicated in patients with neurological symptoms or rapid tumor growth for the restoration of cranial nerve function. We investigated 13 patients who had preoperative images of CS invasion, underwent surgical resection, and were followed-up with magnetic resonance imaging for at least 1 year between July 2017 and July 2024. Their preoperative symptoms, postoperative course, adjuvant therapy, postoperative complications, degree of resection, and recurrence were evaluated. Results: The mean patient age was 59.1 years (range, 23–73 years), and 10 were female. Major preoperative symptoms included oculomotor nerve paresis in 8 patients (61.5%), abducens nerve paresis in 6 (46.2%), visual disturbance in 7 (53.8%), and brain swelling in 3 (23.1%). These symptoms improved at least partially after surgery in 7 (87.5%), 5 (83.3%), 7 (100%), and 3 (100%) patients, respectively. Major postoperative complications included contralateral visual deterioration in 1 patient (7.7%) and brief transient slight hemiparesis caused by internal carotid vasospasm or dissection in 2 (15.4%). Four patients with residual atypical meningioma in the CS underwent intensity-modulated radiotherapy (IMRT). The lesions in 6 patients recurred or regrew, resulting in additional treatment with stereotactic radiosurgery in 2 patients, IMRT in 3, and resection in 1. Conclusions: Our surgical strategy for the surgical resection of meningiomas in and around the CS for the restoration of cranial nerve function is safe and effective, with only transient acceptable injuries. Even if the tumor in the CS is too stiff to be removed, it is important to open the optic nerve sheath and oculomotor cave widely to effectively remove the tumor. Full article

Traumatic optic neuropathy (TON) has been regarded a vision-threatening condition caused by either ocular or blunt/penetrating head trauma, which is characterized by direct or indirect TON. Injury happens during sports, vehicle accidents and mainly in military war and combat exposure. Earlier, we have demonstrated that remote ischemic post-conditioning (RIC) therapy is protective in TON, and here we report that AMPKα1 activation is crucial. AMPKα1 is the catalytic subunit of the heterotrimeric enzyme AMPK, the master regulator of cellular energetics and metabolism. The α1 isoform predominates in immune cells including macrophages (Mφs). Myeloid-specific AMPKα1 KO mice were generated by crossing AMPKα1^Flox/Flox and LysM^cre to carry out the study. We induced TON in mice by using a controlled impact system. Mice (mixed sex) were randomized in six experimental groups for Sham (mock); Sham (RIC); AMPKα1^F/F (TON); AMPKα1^F/F (TON+RIC); AMPKα1^F/F LysM^Cre (TON); AMPKα1^F/F LysM^Cre (TON+RIC). RIC therapy was given every day (5–7 days following TON). Data were generated by using Western blotting (pAMPKα1, ICAM1, Brn3 and GAP43), immunofluorescence (pAMPKα1, cd11b, TMEM119 and ICAM1), flow cytometry (CD11b, F4/80, CD68, CD206, IL-10 and LY6G), ELISA (TNF-α and IL-10) and transmission electron microscopy (TEM, for demyelination and axonal degeneration), and retinal oxygenation was measured by a Unisense sensor system. First, we observed retinal morphology with funduscopic images and found TON has vascular inflammation. H&E staining data suggested that TON increased retinal inflammation and RIC attenuates retinal ganglion cell death. Immunofluorescence and Western blot data showed increased microglial activation and decreased retinal ganglion cell (RGCs) marker Brn3 and axonal regeneration marker GAP43 expression in the TON [AMPKα1^F/F] vs. Sham group, but TON+RIC [AMPKα1^F/F] attenuated the expression level of these markers. Interestingly, higher microglia activation was observed in the myeloid AMPKα1^F/F KO group following TON, and RIC therapy did not attenuate microglial expression. Flow cytometry, ELISA and retinal tissue oxygen data revealed that RIC therapy significantly reduced the pro-inflammatory signaling markers, increased anti-inflammatory macrophage polarization and improved oxygen level in the TON+RIC [AMPKα1^F/F] group; however, RIC therapy did not reduce inflammatory signaling activation in the myeloid AMPKα1 KO mice. The transmission electron microscopy (TEM) data of the optic nerve showed increased demyelination and axonal degeneration in the TON [AMPKα1^F/F] group, and RIC improved the myelination process in TON [AMPKα1^F/F], but RIC had no significant effect in the AMPKα1 KO mice. The myeloid AMPKα1c deletion attenuated RIC induced anti-inflammatory macrophage polarization, and that suggests a molecular link between RIC and immune activation. Overall, these data suggest that RIC therapy provided protection against inflammation and neurodegeneration via myeloid AMPKα1 activation, but the deletion of myeloid AMPKα1 is not protective in TON. Further investigation of RIC and AMPKα1 signaling is warranted in TON. Full article

Background: Bleeding within the orbit in the form of a subperiosteal or retrobulbar hematoma is a relatively common complication of trauma and surgery. It affects up to 30% of patients fractures involving the orbital bones. Most cases do not require surgical intervention because they do not cause retinal ischemia or optic nerve neuropathy. The above symptoms occur in only 0.5–1% of patients developing Orbital Compartment Syndrome (OCS). Due to the short period (60–100 min) of time in which the optic nerve and retina can tolerate increased intraocular pressure, it seemed reasonable to evaluate and standardize the surgical management protocol for this rare complication. Objective: The aim of this retrospective study was to retrospectively analyze cases of inframammary haematomas with clinically relevant correlations. Methods: Eighteen patients treated at the Department of Maxillofacial Surgery due to OCS, in Lodz and Poznan, Poland, between 2009 and 2022, were included. APTT, INR, systemic diseases, cause, location and size of hematoma, presence and number of fractures, visual disturbances and pupillary response on the day after surgery and one month after, the type of intervention and time between admission to the hospital and surgery were evaluated. Results: Statistically significant correlations were obtained between the size of the hematoma and the patients’ age, the degree of visual disturbance and the weakening of pupillary constriction, severe initial symptoms and poor postoperative outcomes at both postoperative periods studied, immediate and distant poor outcome after decompression surgery and good postoperative outcome persisting one month after. Conclusions: The results obtained in the study and the surgical protocol proposed by the authors are in line with the current state of knowledge regarding orbital hematomas. Some of the correlations described in the literature (such as OCS and anticoagulant treatment) were not demonstrated, but this is probably due to the small study group. Maintaining the 100 min limit as a standard was possible only in early postoperative diagnoses (only 1 of the patients was operated on up to 100 min after the appearance of symptoms). In other cases, the specialized diagnosis took an average of 2785 ± 4020 min or 46 ± 67 h. Full article

Hereditary optic neuropathies (HONs) are a class of genetic disorders that may lead to vision loss due to either acute or progressive injury to the optic nerve. Although HONs may commonly manifest as isolated optic atrophy, these disorders can also have a variety of characteristic clinical features and time courses that may narrow the differential diagnosis. While the two most prevalent HONs are Leber Hereditary Optic Neuropathy (LHON) and Dominant Optic Atrophy (DOA), the phenotypic spectrum of these conditions, as well as genetic landscape of less common optic neuropathies, have been better characterized through advances in molecular diagnostic testing. Treatment targeting various pathogenic mechanisms has been investigated, although studies of clinical applicability remain nascent. Present management largely remains supportive. In this review, we discuss the clinical features, molecular diagnosis, current treatment, and future directions for HONs. Full article

The effects of brain-derived neurotrophic factor (BDNF) on retinal ganglion cell (RGC) survival and visual function were assessed in rat and mouse models of optic nerve (ON) crush. ONs were crushed on Day 1, followed by intravitreal injections of a vehicle or BDNF on Days 1 and 8. The spatial frequency threshold was measured using optokinetic tracking on Days 7 and 14. On Day 15, ganglion cell complex (GCC) thickness was quantified using optical coherence tomography. Furthermore, all eyes were enucleated for immunohistochemical analysis of the surviving RGC somas and axons. BDNF significantly reduced the RGC soma in mice and increased GCC thickness in intact eyes, with apparent axonal swelling in both species. It displayed significantly greater RGC soma survival in eyes with ON injury, with moderately thicker axonal bundles in both species and a thicker GCC in rats. Visual function was significantly reduced in all ON-crushed animals, regardless of BDNF treatment. Thus, we obtained a comprehensive analysis of the structural and functional impact of BDNF in intact and ON-crushed eyes in two rodent models. Our results provide a foundation for further BDNF evaluation and the design of preclinical studies on neuroprotectants using BDNF as a reference positive control. Full article

BAX plays an essential role in retinal ganglion cell (RGC) death induced by optic nerve injury. Recently, we developed M109S, an orally bioactive and cytoprotective small compound (CPSC) that inhibits BAX-mediated cell death. We examined whether M109S can protect RGC from optic nerve crush (ONC)-induced apoptosis. M109S was administered starting 5 h after ONC for 7 days. M109S was orally administered in two groups (5 mg/kg twice a day or 7.5 mg/kg once a day). The retina was stained with anti-BRN3A and cleaved Caspase-3 (active Caspase-3) that are the markers of RGC and apoptotic cells, respectively. ONC decreased the number of BRN3A-positive RGC and increased the number of active Caspase-3-expressing apoptotic cells. In ONC-treated retina, there were cells that were double stained with anti-BRN3A and ant-cleaved Caspase-3, indicating that apoptosis in BRN3A-positive RGCs occurred. M109S inhibited the decrease of BRN3A-positive cells whereas it inhibited the increase of active Caspase-3-positive cells in the retina of ONC-treated mice, suggesting that M109S inhibited apoptosis in RGCs. M109S did not induce detectable histological damage to the lungs or kidneys in mice, suggesting that M109S did not show toxicities in the lung or kidneys when the therapeutic dose was used. The present study suggests that M109S is effective in rescuing damaged RGCs. Since M109S is an orally bioactive small compound, M109S may become the basis for a portable patient-friendly medicine that can be used to prevent blindness by rescuing damaged optic nerve cells from death. Full article

Neural regeneration and neuroprotection represent strategies for future management of neurodegenerative disorders such as Alzheimer’s disease (AD) or glaucoma. However, the complex molecular mechanisms that are involved in neuroprotection are not clearly understood. A promising candidate that maintains neuroprotective signaling networks is neuroserpin (Serpini1), a serine protease inhibitor expressed in neurons which selectively inhibits extracellular tissue-type plasminogen activator (tPA)/plasmin and plays a neuroprotective role during ischemic brain injury. Abnormal function of this protein has been implicated in several conditions including stroke, glaucoma, AD, and familial encephalopathy with neuroserpin inclusion bodies (FENIB). Here, we explore the potential biochemical roles of Serpini1 by comparing proteome changes between neuroserpin-deficient (NS^−/−) and control mice, in the retina (RE), optic nerve (ON), frontal cortex (FC), visual cortex (VC), and cerebellum (CB). To achieve this, a multiple-plex quantitative proteomics approach using isobaric tandem mass tag (TMT) technology was employed followed by functional enrichment and protein–protein interaction analysis. We detected around 5000 proteins in each tissue and a pool of 6432 quantified proteins across all regions, resulting in a pool of 1235 differentially expressed proteins (DEPs). Principal component analysis and hierarchical clustering highlighted similarities and differences in the retina compared to various brain regions, as well as differentiating NS^−/− proteome signatures from control samples. The visual cortex revealed the highest number of DEPs, followed by cerebellar regions. Pathway analysis unveiled region-specific changes, including visual perception, focal adhesion, apoptosis, glutamate receptor activation, and supramolecular fiber organization in RE, ON, FC, VC, and CB, respectively. These novel findings provide comprehensive insights into the region-specific networking of Serpini1 in the central nervous system, further characterizing its potential role as a neuroprotective agent. Data are available via ProteomeXchange with identifier PXD046873. Full article

Purpose: Chemical eye injury is an acute emergency that can result in vision loss. Neurotrophic keratitis (NK) is the most common long-term manifestation of chemical injury. NK due to alkali burn affects ocular surface health and is one of its most common causes. Here, we established a rabbit model of corneal alkali burns to evaluate the severity of NK-associated changes. Material methods: Alkali burns were induced in NZ rabbits by treating the cornea with (i) a 5 mm circular filter paper soaked in 0.75 N NaOH for 10 s (Mild NK) and (ii) trephination using a guarded trephine (5 mm diameter and 150-micron depth), followed by alkali burn, with a 5 mm circular filter paper soaked in 0.75 N NaOH for 10 s (a severe form of NK). Immediately after, the cornea was rinsed with 10 mL of normal saline to remove traces of NaOH. Clinical features were evaluated on Day 0, Day 1, Day 7, Day 15, and Day 21 post-alkali burn using a slit lamp, Pentacam, and anterior segment optical coherence tomography (AS-OCT). NK-like changes in epithelium, sub-basal nerve plexus, and stroma were observed using in vivo confocal microscopy (IVCM), and corneal sensation were measured using an aesthesiometer post alkali injury. After 21 days, pro-inflammatory cytokines were evaluated for inflammation through ELISA. Results: Trephination followed by alkali burn resulted in the loss of epithelial layers (manifested using fluorescein stain), extensive edema, and increased corneal thickness (550 µm compared to 380 µm thickness of control) evaluated through AS-OCT and increased opacity score in alkali-treated rabbit (80 compared to 16 controls). IVCM images showed complete loss of nerve fibers, which failed to regenerate over 30 days, and loss of corneal sensation—conditions associated with NK. Cytokines evaluation of IL6, VEGF, and MMP9 indicated an increased angiogenic and pro-inflammatory milieu compared to the milder form of NK and the control. Discussion: Using clinical parameters, we demonstrated that the alkali-treated rabbit model depicts features of NK. Using IVCM in the NaOH burn animal model, we demonstrated a complete loss of nerve fibers with poor self-healing capability associated with sub-basal nerve degeneration and compromised corneal sensation. This pre-clinical rabbit model has implications for future pre-clinical research in neurotrophic keratitis. Full article