• Animals
• Optic Nerve Injuries/therapy
• Optic Nerve Injuries/physiopathology
• Mice
• Disease Models, Animal
• Retinal Ganglion Cells/pathology
• Electroretinography
• Hypothermia, Induced/methods
• Mice, Inbred C57BL
• Cell Count
• Male
• Cell Survival
• Body Temperature/physiology

• P30 EY014801 NEI NIH HHS
• R01 EY027311 NEI NIH HHS
• R56 AG053369 NIA NIH HHS

• adenosine monophosphate protein kinase α1 (AMPKα1)
• inflammation
• myeloid cell
• remote-limb ischemic conditioning (RIC)
• retinal ganglion cell (RGC)
• traumatic optic neuropathy (TON)

• Animals
• Mice
• AMP-Activated Protein Kinases/metabolism
• Signal Transduction
• Optic Nerve Injuries/metabolism
• Optic Nerve Injuries/pathology
• Optic Nerve Injuries/genetics
• Mice, Knockout
• Ischemic Postconditioning/methods
• Male
• Mice, Inbred C57BL
• Macrophages/metabolism
• Disease Models, Animal
• Female
• Myeloid Cells/metabolism
• Retinal Ganglion Cells/metabolism
• Retinal Ganglion Cells/pathology
• Transcription Factor Brn-3A/metabolism
• Transcription Factor Brn-3A/genetics

• R01 NS115834 NINDS NIH HHS
• VR210056 United States Department of Defense

• optic nerve decompression
• systemic steroid therapy
• trauma pediatric
• traumatic optic neuropathy (ton)
• treatment

• Optic canal fracture
• Optic nerve decompression
• Pterional approach
• Supraorbital approach
• Traumatic optic neuropathy

• Humans
• Decompression, Surgical/methods
• Male
• Optic Nerve Injuries/surgery
• Female
• Adult
• Middle Aged
• Retrospective Studies
• Visual Acuity
• Young Adult
• Treatment Outcome
• Neurosurgical Procedures/methods
• Optic Nerve/surgery
• Adolescent
• Orbit/surgery

• Optic Nerve
• Orbit
• Trauma

• Humans
• Decompression, Surgical/methods
• Male
• Female
• Optic Nerve Injuries/surgery
• Optic Nerve Injuries/physiopathology
• Prospective Studies
• Visual Acuity/physiology
• Adult
• Evoked Potentials, Visual/physiology
• Young Adult
• Middle Aged
• Treatment Outcome
• Follow-Up Studies
• Adolescent
• Surgery, Computer-Assisted/methods
• Orbit/surgery
• Optic Nerve/surgery

• Light perception
• TON
• Visual recovery

• Humans
• Optic Nerve Injuries/drug therapy
• Recovery of Function
• Retrospective Studies
• Treatment Outcome
• Visual Acuity

• catalase
• nanoreactors
• optic nerve crush
• reactive oxygen species scavengers
• tannin

• 32171386 National Natural Science Foundation of China
• 32201157 National Natural Science Foundation of China
• 81970772 National Natural Science Foundation of China
• 81870638 National Natural Science Foundation of China
• 81670816 National Natural Science Foundation of China
• NKYKK202207 Nankai University Eye Institute
• 21JCZDJC01250 Natural Science Foundation of Tianjin of China
• 22JCZXJC00030 Natural Science Foundation of Tianjin of China
• 22JCZDJC00260 Natural Science Foundation of Tianjin of China
• TJYXZDXK-016A Tianjin Key Medical Discipline (Specialty) Construction Project

• Huperzine A (HupA)
• axonal regeneration
• mTOR
• retinal ganglion cell (RGC)
• survival
• traumatic optic neuropathy (TON)

Traumatic optic neuropathy (TON) is a significant cause of vision loss and irreversible blindness worldwide. It is defined as retinal ganglion cell death and axon degeneration caused by injury. Optic nerve crush (ONC), a well-validated model of TON, activates retinal microglia and initiates neuroinflammation. High-mobility group box 1 (HMGB1), a non-histone chromosomal binding protein in the nucleus of eukaryotic cells, is an important inducer of microglial activation and pro-inflammatory cytokine release. The purpose of this study was to examine the protective effects and mechanism of the HMGB1 inhibitor BoxA to neuroinflammation-induced retinal ganglion cells (RGCs) damage in traumatic optic neuropathy. For that purpose, an optic nerve crush model was established in C57BL/6J mice at 10–12 weeks. Model mice received an intravitreal injection of PBS and the HMGB1 inhibitor BoxA. Our data demonstrated that HMGB1 expression increased after optic nerve crush. Retinal ganglion cell function and morphology were damaged, and retinal ganglion cell numbers were reduced after optic nerve crush. Intravitreal injection of BoxA after ONC can alleviate damage. Furthermore, BoxA reduced microglial activation and expression levels of nuclear factor κB (NF-kB), nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3), and apoptosis-associated speck-like protein containing a CARD (ASC) in experimental ONC mice. In summary, HMGB1 mediates NLRP3 inflammasome via NF-kB to participate in retinal inflammatory injury after ONC. Thus, intravitreal injection of BoxA has potential therapeutic benefits for the effective treatment of RGC death to prevent TON.

• BoxA
• HMGB1
• NF-kB
• ONC
• RGCs
• TON
• inflammasome
• neuroinflammation

• Animals
• Disease Models, Animal
• HMGB1 Protein/metabolism
• Mice
• Mice, Inbred C57BL
• NF-kappa B/metabolism
• NLR Family, Pyrin Domain-Containing 3 Protein/metabolism
• Nerve Crush
• Neuroinflammatory Diseases
• Optic Nerve Injuries/drug therapy
• Optic Nerve Injuries/metabolism
• Retinal Ganglion Cells/metabolism

• blindness
• closed head injury
• head trauma
• pediatric
• trauma
• traumatic optic neuropathy
• vision loss

• Adolescent
• Blindness/etiology
• Child
• Head Injuries, Closed/complications
• Head Injuries, Closed/diagnosis
• Humans
• Optic Nerve Injuries/diagnosis
• Optic Nerve Injuries/etiology
• Optic Nerve Injuries/therapy
• Orbit
• Vision, Monocular
• Young Adult

The vision loss in the Traumatic Optic Neuropathy is the impact of deformational forces. This occurs due to direct or indirect injuries during trauma to skull. The use of high dose corticosteroids is the primary line of treatment in such injuries still remains a matter of debate. Traumatic Optic Neuropathy is yet an unexplored topic of study in Ayurveda. The Traumatic Optic Neuropathy can be correlated with Abhighatajanya Vataprakopaj Drishtinash. The treatment principles of Vataprakopaj Vyadhi are Snehan (massage), Swedan (sudation), Basti (enema) and Nasya (oleation through nasal route). A 50 year old male patient came to outpatient department suffered from motorcycle accident and had a forehead trauma followed by loss of vision in both eyes after 5 days and diagnosed as Traumatic Optic Neuropathy. An electrophysiological assessment showed absence of waveform in Visual Evoked Potential (VEP). According to Ayurveda patient was diagnosed primarily as Abhighatajanya Vataprakopaj Drishtinash and started to follow the protocol of Vataprakopaj Vyadhi. Patient received Ayurvedic formulations in morning, after meal and at night for 12 months and a course of Yapan Basti (medicated decoction enema) followed by Netratarpan (eye satiation), Nasya and Abhyanga (body and foot massage). Patient showed an improvement in the visual quality from no perception of light to perception of light and rays in right eye in 9 month. Patient had improvement in P100 latencies of right eye in VEP report and subjective improvement in quality of vision to perceive the images and objects. Application of Ayurvedic principles and Panchakarma therapy resulted in improvement of the case. An early management of Traumatic Optic Neuropathy with Ayurvedic treatment can have a significant impact on the clinical/visual outcome in terms of recovery in damaged optic nerve fibers.

• Abhighatajanya Drishtinash
• Basti
• Nasya
• Netratarpan
• Traumatic Optic Neuropathy
• Visual Evoked Potential (VEP)

The diagnosis and treatment of gunshot injuries requires an understanding of the trajectory of the bullet in each individual case. The majority of gunshot wounds present with easily understandable trajectories resulting in a concise, stream-lined work-up. Occasionally, the initial work-up may reveal a trajectory that is atypical. This can be due to internal bullet deflection, bullet embolism, or bullets that traverse multiple body cavities. Here we present the case of a gentleman who was shot in the left posterior chest, with the bullet ultimately lying-in profile with the patient's pituitary gland. The patient suffered injuries to his left lung, left internal jugular vein, and right optic nerve. On hospital day 1, he required neurosurgical operative intervention for increased somnolence and computed tomography findings which revealed tension pneumocephalus. On hospital day 15, he was discharged home after making a full recovery with the exception of continued blindness in the right eye. Gunshot wounds involving multiple body cavities can increase the complexity of a patient's injury pattern and require increased vigilance and complete history, physical examination, and imaging to ensure optimal outcomes.

• Gunshot
• Penetrating trauma
• Pneumocephalus
• Trajectory

• PACAP38
• axon regeneration
• exosomes
• retina ganglion cell survival
• traumatic optic neuropathy

Messager RNA (mRNA) can be modified in a variety of ways, among which the modification of N6-methyladenosine (m6A) is one of the most common ones. Recent studies have found that the m6A modification in mRNA could functionally regulate the splicing, localization, translation, and stability of mRNA, which might be closely related to multiple diseases. However, the roles of m6A modification in traumatic optic neuropathy (TON) are unknown. Herein, we detected the expression of m6A-related genes via quantitative real-time PCR (qRT-PCR) and performed methylated RNA immunoprecipitation sequencing (MeRIP-seq) as well as RNA-sequencing to analyze the alteration profiles of m6A modification after TON. The results showed that the expression of m6A-related genes (METTL3, WTAP, FTO, and ALKBH5) were all upregulated after TON. In all, 2,810 m6A peaks were differentially upregulated and 689 m6A peaks were downregulated. In addition, the hypermethylated and hypomethylated profiles of mRNA transcripts were also identified. To sum up, our study revealed the differentially expressed m6A modification in the early stage of TON, which may provide novel insights into the mechanism and treatment of TON.

• N6-methyladenosine
• epigenetics
• optic nerve
• retina
• traumatic optic neuropathy

Activation of the nerve growth factor (NGF) signaling pathway is a potential method of treatment for retinal ganglion cell (RGC) loss due to traumatic optic neuropathy (TON). The present study aimed to explore the biological effects of injecting Astragalus membranaceus (A. mem) on RGCs in an experimental TON model. Adult male Wistar rats were randomly divided into three groups: sham-operated (SL), model (ML), and A. mem injection (AL). The left eyes of the rats were considered the experimental eyes, and the right eyes served as the controls. AL rats received daily intraperitoneal injections of A. mem (3 mL/kg), whereas ML and SL rats were administered the same volume of normal saline. The TON rat model was induced by optic nerve (ON) transverse quantitative traction. After two-week administration, the number of RGCs was determined using retrograde labeling with Fluoro-Gold. The protein levels of NGF, tyrosine kinase receptor A (TrkA), c-Jun N-terminal protein kinase (JNK), JNK phosphorylation (p-JNK), and nuclear factor kappa-B (NF-κB) were assessed using western blotting. The levels of p75 neurotrophin receptor (p75^NTR) and NF-κB DNA binding were examined using real-time PCR and an electrophoretic mobility shift assay. In addition, the concentrations of JNK and p-JNK were assessed using an enzyme-linked immunosorbent assay. Results. The number of RGCs in ML was found to be significantly decreased (P < 0.01) relative to both AL and SL, together with the downregulation of NGF (P < 0.01), TrkA (P < 0.05), and NF-κB (P < 0.01); upregulation of p75^NTR mRNA (P < 0.01); and increased protein levels of JNK (P < 0.05) and p-JNK (P < 0.05). Treatment using A. mem injection significantly preserved the density of RGCs in rats with experimental TON and markedly upregulated the proteins of NGF (P < 0.01), TrkA (P < 0.05), and NF-κB (P < 0.01) and downregulated the mRNA level of p75^NTR(P < 0.01), as well as the proteins of JNK (P < 0.05) and p-JNK (P < 0.01). Thus, A. mem injection could reduce RGC death in TON induced by ON transverse quantitative traction by stimulating the NGF signaling pathway.

• Traumatic optic neuropathy (TON)
• corticosteroids
• delayed wider decompression
• follow-up

• Inflammation
• Optic nerve injury
• Oxidative stress
• Remote-limb ischemic conditioning (RIC)
• Tight junction

• Fibroblasts
• Fibrotic scar
• Optic nerve crush
• Traumatic optic neuropathy
• Collagen1α1 cells

• Elamipretide
• Traumatic optic neuropathy
• Tumor necrosis factor

• Acute Disease
• Animals
• Cell Survival
• Humans
• Mitochondria/drug effects
• Mitochondria/metabolism
• Oligopeptides/pharmacology
• Optic Nerve Injuries/drug therapy
• Optic Nerve Injuries/metabolism
• Optic Nerve Injuries/pathology
• Retinal Ganglion Cells/drug effects
• Retinal Ganglion Cells/metabolism
• Retinal Ganglion Cells/pathology
• Tumor Necrosis Factor-alpha/antagonists & inhibitors
• Tumor Necrosis Factor-alpha/metabolism

• P30 EY014801 NEI NIH HHS
• R01 EY027311 NEI NIH HHS

• Carvedilol
• microglia
• optic nerve injury
• optic neuropathy
• p38 MPAK
• retinal ganglion cell.

• Endoscopy
• Optic canal decompression
• Prognosis
• Transethmosphenoid
• Transnasal
• Traumatic optic neuropathy

• endoscopic trans-ethmosphenoid optic canal decompression
• indirect traumatic optic neuropathy
• newly onset
• steroid
• visual acuity

Closed-globe injury can cause visual loss in military and civilian populations, with retinal cell death, including retinal ganglion cell (RGC) degeneration, leading to irreversible blindness. RGC and optic nerve (ON) degeneration after eye or head injury is termed traumatic optic neuropathy (TON). There are currently no treatments for RGC loss, therefore novel therapeutics to prevent RGC death or promote axonal regeneration are a priority. We investigated necroptotic signaling mechanisms in a rat blunt ocular injury model. After bilateral blunt trauma, protein expression and retinal localization of necroptosis pathway members (receptor interacting protein kinase 1, RIPK1; receptor interacting protein kinase 3, RIPK3; and mixed lineage kinase domain like pseudokinase, MLKL) were assessed by Western blot and immunohistochemistry (IHC), and potent necroptosis inhibitor Necrostatin-1s (Nec-1s) was delivered by intravitreal injection to one eye and vehicle to the contralateral eye. RGC and photoreceptor survival were assessed by cell counting and outer nuclear layer (ONL) thickness measurements on histology. The neuroprotective effects of Nec-1s were assessed in primary retinal culture by βIII-tubulin⁺ RGC cell counts. MLKL protein expression were upregulated at 48 h after injury and MLKL immunolocalised to retinal binding protein with multiple splice (RBPMS)⁺ RGC, inner nuclear cells and ONL cells, specifically at the retinal injury site. RIPK3 expression did not increase but RIPK3 co-immunolocalised with RBPMS⁺ RGC in intact and injured retinae. In vitro, a Nec-1s concentration of 0.01 pg/µL was RGC neuroprotective. In the blunt ocular injury rat model, Nec-1s prevented RGC death at the center of the impact site but did not protect against ONL thinning or provide functional restitution. RGC degeneration in our blunt ocular injury model is site-specific, with necroptosis driving death at the center of the focal impact site.

• cell death
• commotio retinae
• necroptosis
• photoreceptors
• retinal ganglion cells
• trauma
• traumatic optic neuropathy

• Endoscopy
• Optic canal decompression
• Review
• Transethmosphenoid
• Transnasal
• Traumatic optic neuropathy

• foreign body
• globe
• guns
• gunshot wounds
• orbit
• periocular soft tissue injury
• sclopetaria
• trauma

Traumatic optic neuropathy (TON) is the most feared visual consequence of head and ocular trauma in both military and civilian communities, for which standard treatment does not exist. Animal models are critical for the development of novel TON therapies as well as the understanding of TON pathophysiology. However, the models currently used for TON have some limitations regarding consistency and mirroring the exact pathological progression of TON in closed ocular trauma. In this study, we modified the model of controlled cortical impact and adapted it for studying TON.

We defined new standardized procedures to induce TON in mice, wherein the optic nerve is reproducibly exposed to a graded controlled impact of known velocity to produce a graded deficit in retinal ganglion cell (RGC) electrophysiological functions.

The key results of validating this newly modified model, “controlled orbital impact (COI),” included (1) the injury parameters (velocity as well as contusion depth and time), which were quantifiable and manageable to generate a wide range of TON severities; (2) a reproducible endpoint of diminished positive scotopic threshold response (pSTR) has been achieved without the interference of surgical variability and destruction of surrounding tissues; (3) the contralateral eyes showed no significant difference to the eyes of naïve mice, allowing them to be used as an internal control to minimize interindividual variability among mice; and (4) the occurrence of injury-associated mortality and/or ocular comorbidity was rare.

Taken together, this model overcomes some limitations of prior TON mouse models and provides an innovative platform to identify therapeutic targets for neuroprotection and/or neurorestoration following traumatic ocular injury.

• electrophysiological examination
• ganglion cell complex
• magnetic resonance imaging
• traumatic lesion of the optic nerve

Axonal injury is a common feature of central nervous system insults. Upregulation of amyloid precursor protein (APP) is observed following central nervous system neurotrauma and is regarded as a marker of central nervous system axonal injury. However, the underlying mechanism by which APP mediates neuronal death remains to be elucidated. Here, we used mouse optic nerve axotomy (ONA) to model central nervous system axonal injury replicating aspects of retinal ganglion cell (RGC) death in optic neuropathies. APP and APP intracellular domain (AICD) were upregulated in retina after ONA and APP knockout reduced Tuj1⁺ RGC loss. Pathway analysis of microarray data combined with chromatin immunoprecipitation and a luciferase reporter assay demonstrated that AICD interacts with the JNK3 gene locus and regulates JNK3 expression. Moreover, JNK3 was found to be upregulated after ONA and to contribute to Tuj1⁺ RGC death. APP knockout reduced the ONA-induced enhanced expression of JNK3 and phosphorylated JNK (pJNK). Gamma-secretase inhibitors prevented production of AICD, reduced JNK3 and pJNK expression similarly, and protected Tuj1⁺ RGCs from ONA-induced cell death. Together these data indicate that ONA induces APP expression and that gamma-secretase cleavage of APP releases AICD, which upregulates JNK3 leading to RGC death. This pathway may be a novel target for neuronal protection in optic neuropathies and other forms of neurotrauma.

Traumatic optic neuropathy (TON) is a devastating cause of permanent visual loss following blunt injury to the head. Animal models for TON exist, but most fail to recapitulate the clinical scenario of closed head indirect trauma to the nerve and subsequent neurodegeneration. Thus, we developed a clinically-relevant animal model for TON using a novel ultrasonic pulse injury modality (sonication-induced TON; SI-TON). To trigger TON, a microtip probe sonifier was placed on the supraorbital ridge directly above the entrance of the optic nerve into the bony canal. An ultrasonic pulse was then delivered to the optic nerve. After injury, the number of RGCs in the retina as well as visual function measured by PERG steadily decreased over a two-week period. In the optic nerve, pro-inflammatory markers were upregulated within 6 hours following injury. Immunohistochemistry showed activation of microglia and infiltration of CD45-positive leukocytes in the optic nerve and initiation of a gliotic response. The SI-TON model is capable of delivering a non-contact concussive injury to the optic nerve and induce TON in mice. Thus, our data indicate that the SI-TON model reliably recapitulates the pathophysiology and progressive neurodegeneration seen in the human manifestation.

Retinal and optic nerve diseases are degenerative ocular pathologies which lead to irreversible visual loss. Since the advanced therapies availability, cell-based therapies offer a new all-encompassing approach. Advances in the knowledge of neuroprotection, immunomodulation and regenerative properties of mesenchymal stem cells (MSCs) have been obtained by several preclinical studies of various neurodegenerative diseases. It has provided the opportunity to perform the translation of this knowledge to prospective treatment approaches for clinical practice. Since 2008, several first steps projecting new treatment approaches, have been taken regarding the use of cell therapy in patients with neurodegenerative pathologies of optic nerve and retina. Most of the clinical trials using MSCs are in I/II phase, recruiting patients or ongoing, and they have as main objective the safety assessment of MSCs using various routes of administration. However, it is important to recognize that, there is still a long way to go to reach clinical trials phase III-IV. Hence, it is necessary to continue preclinical and clinical studies to improve this new therapeutic tool. This paper reviews the latest progress of MSCs in human clinical trials for retinal and optic nerve diseases.

• Mesenchymal stem cells
• Cell therapy
• Optic nerve diseases
• Clinical trials
• Retinal diseases

• cantholysis
• canthotomy
• decompression
• maxillofacial
• orbital compartment syndrome
• retrobulbar
• trauma

• Acetazolamide/administration & dosage
• Aged
• Compartment Syndromes/drug therapy
• Compartment Syndromes/surgery
• Decompression, Surgical
• Diuretics/administration & dosage
• Emergencies
• Humans
• Male
• Mannitol/administration & dosage
• Orbit/injuries
• Orbit/surgery
• Orbital Diseases/drug therapy
• Orbital Diseases/surgery
• Retrobulbar Hemorrhage
• Steroids/administration & dosage