[Pathogenetic basis of optic nerve atrophy in methanol poisoning]. / Patogeneticheskie osnovy razvitiya atrofii zritel'nogo nerva pri toksicheskom porazhenii metanolom.

Optic nerve atrophy is a pathomorphological consequence of diseases of the peripheral neuron of the visual pathway, manifested as atrophy of nerve fibers of varying severity. The toxic effect of methanol is mainly associated with formic acid and formaldehyde, which suppress the cytochrome system, inhibit oxidative phosphorylation, and thereby cause a deficiency of adenosine triphosphoric acid, to which brain and retinal tissues are especially susceptible. When formiate accumulates, tissue respiration is disrupted, leading to pronounced tissue hypoxia. As a result of such methanol metabolism, metabolic acidosis occurs. Tissue hypoxia develops in the first few hours as a result of the action of formic acid on the respiratory enzyme chain at the cytochrome oxidase level. Hypoxia and, as a consequence, a decrease in energy supply lead to a disruption of biological oxidation and the development of apoptosis in the optic nerve fibers. Understanding the process of optic nerve atrophy development at the pathogenetic level in methyl alcohol intoxication will help make a correct early diagnosis and prescribe timely treatment.

The Protective Effects of n-Butylidenephthalide on Retinal Ganglion Cells during Ischemic Injury.

Clinically, acute ischemic symptoms in the eyes are one of the main causes of vision loss, with the associated inflammatory response and oxidative stress being the key factors that cause injury. Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common type of ischemic optic neuropathy (ION); however, there are still no effective or safe treatment options to date. In this study, we investigated the neuroprotective effects of n-butylidenephthalide (BP) treatment in an experimental NAION rodent model (rAION). BP (10 mg/kg) or PBS (control group) were administered on seven consecutive days in the rAION model. Rats were evaluated for visual function by flash visual evoked potentials (FVEPs) at 4 weeks after NAION induction. The retina and optic nerve were removed for histological examination after the rats were euthanized. The molecular machinery of BP treatment in the rAION model was analyzed using Western blotting. We discovered that BP effectively improves retinal ganglion cell survival rates by preventing apoptotic processes after AION induction and reducing the inflammatory response through which blood-borne macrophages infiltrate the optic nerve. In addition, BP significantly preserved the integrity of the myelin sheath in the rAION model, demonstrating that BP can prevent the development of demyelination. Our immunoblotting results revealed the molecular mechanism through which BP mitigates the neuroinflammatory response through inhibition of the NF-κB signaling pathway. Taken together, these results demonstrate that BP can be used as an exceptional neuroprotective agent for ischemic injury.

Methanol-induced optic neuropathy: a still-present problem.

Methanol-induced optic neuropathy (Me-ION) is a serious condition that may result in long-term or irreversible visual impairment or even blindness secondary to damage and loss of function of the optic nerve and retina. Me-ION shows a tendency to occur as mass poisonings around the world with a clear predilection for poor societies in developing countries. The main mechanism underlying the molecular basis of Me-ION is the inhibition of the mitochondrial oxidative phosphorylation process through the binding of the toxic metabolite of methanol-formic acid-with the key enzyme of this process-cytochrome c oxidase. However, other mechanisms, including damage to the eye tissues by oxidative stress causing the intensification of the oxidative peroxidation process with the formation of cytotoxic compounds, as well as an increase in the synthesis of pro-inflammatory cytokines and influence on the expression of key proteins responsible for maintaining cell homeostasis, also play an important role in the pathogenesis of Me-ION. Histopathological changes in the eye tissues are mainly manifested as the degeneration of axons and glial cells of the optic nerve, often with accompanying damage of the retina that may involve all its layers. Despite the development of therapeutic approaches, persistent visual sequelae are seen in 30-40% of survivors. Thus, Me-ION continues to be an important problem for healthcare systems worldwide.

Axonal Protection by Netarsudil, a ROCK Inhibitor, Is Linked to an AMPK-Autophagy Pathway in TNF-Induced Optic Nerve Degeneration.

Purpose: Netarsudil, a Rho kinase inhibitor with norepinephrine transport inhibitory effect, lowers intraocular pressure, however, its effect on axon damage remains to be elucidated. The aim of the current study was to investigate the effect of netarsudil on TNF-induced axon loss and to examine whether it affects phosphorylated-AMP-activated kinase (p-AMPK) and autophagy in the optic nerve. Methods: Intravitreal administration of TNF or TNF with netarsudil was carried out on rats and quantification of axon number was determined. Electron microscopy determined autophagosome numbers. Localization of p-AMPK expression was examined by immunohistochemistry. The changes in p62, LC3-II, and p-AMPK levels were estimated in the optic nerve by immunoblot analysis. The effect of an AMPK activator A769662 or an AMPK inhibitor dorsomorphin on axon number was evaluated. Results: Morphometric analysis revealed apparent protection by netarsudil against TNF-induced axon degeneration. Netarsudil increased autophagosome numbers inside axons. Netarsudil treatment significantly upregulated optic nerve LC3-II levels in both the TNF-treated eyes and the control eyes. Increased p62 protein level induced by TNF was significantly ameliorated by netarsudil. The netarsudil administration alone lessened p62 levels. Netarsudil significantly upregulated the optic nerve p-AMPK levels. A769662 exhibited obvious axonal protection against TNF-induced damage. A769662 treatment upregulated LC3-II levels and the increment of p62 level induced by TNF was significantly ameliorated by A769662. Immunohistochemical analysis revealed that p-AMPK is present in axons. Netarsudil-mediated axonal protection was significantly suppressed by dorsomorphin administration. Conclusions: Netarsudil upregulated p-AMPK and autophagy. Netarsudil-mediated axonal protection may be associated with upregulated p-AMPK.

Early Intervention and Lifelong Treatment with GLP1 Receptor Agonist Liraglutide in a Wolfram Syndrome Rat Model with an Emphasis on Visual Neurodegeneration, Sensorineural Hearing Loss and Diabetic Phenotype.

Wolfram syndrome (WS), also known as a DIDMOAD (diabetes insipidus, early-onset diabetes mellitus, optic nerve atrophy and deafness) is a rare autosomal disorder caused by mutations in the Wolframin1 (WFS1) gene. Previous studies have revealed that glucagon-like peptide-1 receptor agonist (GLP1 RA) are effective in delaying and restoring blood glucose control in WS animal models and patients. The GLP1 RA liraglutide has also been shown to have neuroprotective properties in aged WS rats. WS is an early-onset, chronic condition. Therefore, early diagnosis and lifelong pharmacological treatment is the best solution to control disease progression. Hence, the aim of this study was to evaluate the efficacy of the long-term liraglutide treatment on the progression of WS symptoms. For this purpose, 2-month-old WS rats were treated with liraglutide up to the age of 18 months and changes in diabetes markers, visual acuity, and hearing sensitivity were monitored over the course of the treatment period. We found that treatment with liraglutide delayed the onset of diabetes and protected against vision loss in a rat model of WS. Therefore, early diagnosis and prophylactic treatment with the liraglutide may also prove to be a promising treatment option for WS patients by increasing the quality of life.

Neuroprotective Effect of Statins in a Rat Model of Chronic Ocular Hypertension.

Glaucoma is an optic neuropathy in which the degeneration of retinal ganglion cells (RGCs) results in irreversible vison loss. Therefore, neuroprotection of RGCs from glaucomatous afflictions is crucial for glaucoma treatment. In this study, we aimed to investigate the beneficial effects of statins in the protection of RGCs using a rat model. Glaucomatous injury was induced in rats by chronic ocular hypertension (OHT) achieved after performing a circumlimbal suture. The rats were given either statins such as simvastatin and atorvastatin or a solvent weekly for 6 weeks. Retina sections underwent hematoxylin and eosin, Brn3a, or cleaved casepase-3 staining to evaluate RGC survival. In addition, modulation of glial activation was assessed. While the retinas without statin treatment exhibited increased RGC death due to chronic OHT, statins promoted the survival of RGCs and reduced apoptosis. Statins also suppressed chronic OHT-mediated glial activation in the retina. Our results demonstrate that statins exert neuroprotective effects in rat retinas exposed to chronic OHT, which may support the prospect of statins being a glaucoma treatment.

Long-term corticosteroid-induced chronic glaucoma model produced by intracameral injection of dexamethasone-loaded PLGA microspheres.

PURPOSE: To evaluate a new chronic glaucoma model produced by intracameral injection of dexamethasone-loaded poly lactic-co-glycolic acid microspheres (Dex-PLGA-Ms) over six months. METHODS: Healthy rats received two injections (at baseline and Week 4) of Dex-PLGA-Ms into the anterior chamber of the right eye. Clinical signs and intraocular pressure (IOP) were weekly recorded. The structure of the retina and optic nerve was in vivo evaluated using optical coherence tomography (OCT) every two weeks and functionally using dark- and light-adapted electroretinography at 0-12-24 weeks. Histological studies were also performed. RESULTS: IOP progressively increased up to hypertension (23.22 ± 3.63 mmHg) in both eyes but did so later in left eyes. OCT quantified a decrease in full-thickness retina posterior pole (R), retinal-nerve-fiber layer (RNFL), and ganglion-cell layer (GCL) thickness up to 24 weeks. Right eyes showed higher neuroretinal thickness loss up to week 8. RNFL experienced the highest percentage thickness loss at the inferior-superior axis, while in GCL the inner sectors of the horizontal axis (Nasal-Temporal) suffered the greatest decrease in thickness. Retinal ganglion cell, photoreceptor, and intermediate cell functionality decreased over time. Increased deposition of collagen IV was also found in zonular fibers and the ciliary body. CONCLUSIONS: This work shows the usefulness of drug delivery systems, not to treat pathology but to induce it. Only two injections of Dex-PLGA-Ms in the anterior chamber of rat eyes were enough to progressively create ocular hypertension and subsequent functional and structural neuroretinal degeneration, at least over 6 months.

Therapeutic Neuroprotection by an Engineered Neurotrophin that Selectively Activates Tropomyosin Receptor Kinase (Trk) Family Neurotrophin Receptors but Not the p75 Neurotrophin Receptor.

The neurotrophin growth factors bind and activate two types of cell surface receptors: the tropomyosin receptor kinase (Trk) family and p75. TrkA, TrkB, and TrkC are bound preferentially by nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 (NT3), respectively, to activate neuroprotective signals. The p75 receptors are activated by all neurotrophins, and paradoxically in neurodegenerative disease p75 is upregulated and mediates neurotoxic signals. To test neuroprotection strategies, we engineered NT3 to broadly activate Trk receptors (mutant D) or to reduce p75 binding (mutant RK). We also combined these features in a molecule that activates TrkA, TrkB, and TrkC but has reduced p75 binding (mutant DRK). In neurodegenerative disease mouse models in vivo, the DRK protein is a superior therapeutic agent compared with mutant D, mutant RK, and wild-type neurotrophins and protects a broader range of stressed neurons. This work rationalizes a therapeutic strategy based on the biology of each type of receptor, avoiding activation of p75 toxicity while broadly activating neuroprotection in stressed neuronal populations expressing different Trk receptors. SIGNIFICANCE STATEMENT: The neurotrophins nerve growth factor, brain-derived neurotrophic factor, and neurotrophin 3 each can activate a tropomyosin receptor kinase (Trk) A, TrkB, or TrkC receptor, respectively, and all can activate a p75 receptor. Trks and p75 mediate opposite signals. We report the engineering of a protein that activates all Trks, combined with low p75 binding, as an effective therapeutic agent in vivo.

In vitro inhibitory effect of obtusofolin on the activity of CYP3A4, 2C9, and 2E1.

BACKGROUND: Obtusofolin is the major active ingredient of Catsia tora L., which possesses the activity of improving eyesight and protecting the optic nerve. Investigation on the interaction of obtusofolin with cytochrome P450 enzymes (CYP450s) could provide a reference for the clinical application of obtusofolin. METHODS: The effect of obtusofolin on the activity of CYP450s was investigated in the presence of 100 µM obtusofolin in pooled human liver microsomes (HLMs) and fitted with the Lineweaver-Burk plots to characterize the specific inhibition model and kinetic parameters. RESULTS: Obtusofolin was found to significantly inhibited the activity of CYP3A4, 2C9, and 2E1. In the presence of 0, 2.5, 5, 10, 25, 50, and 100 µM obtusofolin, the inhibition of these CYP450s showed a dose-dependent manner with the IC50 values of 17.1 ± 0.25, 10.8 ± 0.13, and 15.5 ± 0.16 µM, respectively. The inhibition of CYP3A4 was best fitted with the non-competitive inhibition model with the Ki value of 8.82 µM. While the inhibition of CYP2C9 and 2E1 was competitive with the Ki values of 5.54 and 7.79 µM, respectively. After incubating for 0, 5, 10, 15, and 30 min, the inhibition of CYP3A4 was revealed to be time-dependent with the KI value of 4.87 µM- 1 and the Kinact value of 0.0515 min- 1. CONCLUSIONS: The in vitro inhibitory effect of obtusofolin implying the potential drug-drug interaction between obtusofolin and corresponding substrates, which needs further in vivo validations.

Elezanumab, a clinical stage human monoclonal antibody that selectively targets repulsive guidance molecule A to promote neuroregeneration and neuroprotection in neuronal injury and demyelination models.

Repulsive guidance molecule A (RGMa) is a potent inhibitor of axonal growth and a regulator of neuronal cell death. It is up-regulated following neuronal injury and accumulates in chronic neurodegenerative diseases. Neutralizing RGMa has the potential to promote neuroregeneration and neuroprotection. Previously we reported that a rat anti-N terminal RGMa (N-RGMa) antibody r5F9 and its humanized version h5F9 (ABT-207) promote neuroprotection and neuroregeneration in preclinical neurodegenerative disease models. However, due to its cross-reactivity to RGMc/hemojuvelin, ABT-207 causes iron accumulation in vivo, which could present a safety liability. Here we report the generation and characterization of a novel RGMa-selective anti-N-RGMa antibody elezanumab, which is currently under Phase 2 clinical evaluation in multiple disease indications. Elezanumab, a human monoclonal antibody generated by in vitro PROfusion mRNA display technology, competes with ABT-207 in binding to N-RGMa but lacks RGMc cross-reactivity with no impact on iron metabolism. It neutralizes repulsive activity of soluble RGMa in vitro and blocks membrane RGMa mediated BMP signaling. In the optic nerve crush and optic neuritis models, elezanumab promotes axonal regeneration and prevents retinal nerve fiber layer degeneration. In the spinal targeted experimental autoimmune encephalomyelitis (EAE) model, elezanumab promotes axonal regeneration and remyelination, decreases inflammatory lesion area and improves functional recovery. Finally, in the mouse cuprizone model, elezanumab reduces demyelination, which is consistent with its inhibitory effect on BMP signaling. Taken together, these preclinical data demonstrate that elezanumab has neuroregenerative and neuroprotective activities without impact on iron metabolism, thus providing a compelling rationale for its clinical development in neurodegenerative diseases.

Decorin-An Antagonist of TGF-ß in Astrocytes of the Optic Nerve.

During the pathogenesis of glaucoma, optic nerve (ON) axons become continuously damaged at the optic nerve head (ONH). This often is associated with reactive astrocytes and increased transforming growth factor (TGF-ß) 2 levels. In this study we tested the hypothesis if the presence or absence of decorin (DCN), a small leucine-rich proteoglycan and a natural inhibitor of several members of the TGF family, would affect the expression of the TGF-ßs and connective tissue growth factor (CTGF/CCN2) in human ONH astrocytes and murine ON astrocytes. We found that DCN is present in the mouse ON and is expressed by human ONH and murine ON astrocytes. DCN expression and synthesis was significantly reduced after 24 h treatment with 3 nM CTGF/CCN2, while treatment with 4 pM TGF-ß2 only reduced expression of DCN significantly. Conversely, DCN treatment significantly reduced the expression of TGF-ß1, TGF-ß2 and CTGF/CCN2 vis-a-vis untreated controls. Furthermore, DCN treatment significantly reduced expression of fibronectin (FN) and collagen IV (COL IV). Notably, combined treatment with DCN and triciribine, a small molecule inhibitor of protein kinase B (AKT), attenuated effects of DCN on CTGF/CCN2, TGF-ß1, and TGF-ß2 mRNA expression. We conclude (1) that DCN is an important regulator of TGF-ß and CTGF/CCN2 expression in astrocytes of the ON and ONH, (2) that DCN thereby regulates the expression of extracellular matrix (ECM) components and (3) that DCN executes its negative regulatory effects on TGF-ß and CTGF/CCN2 via the pAKT/AKT signaling pathway in ON astrocytes.

Protection against experimental cisplatin-induced optic nerve toxicity using resveratrol: A rat model study.

AIM: To investigate the effects of resveratrol on oxidative stress and inflammation parameters and histological alterations in cisplatin-induced optic nerve damage in a mouse model. MATERIAL AND METHOD: Thirty-six albino Wistar male rats were divided into three groups as control, 5 mg/kg cisplatin-administered (Cis) and 5 mg/kg cisplatin + 25 mg/kg resveratrol-administered (Cis + Res) animals. At the end of the experimental period, the rats were sacrificed with high-dose (50 mg/kg) thiopental sodium, and their optic nerves were dissected. Malondialdehyde (MDA), total glutathione (tGSH), total oxidant status (TOS), total antioxidant status (TAS), tumour necrosis factor alpha (TNF-α), nuclear factor kappa B (NF-KB) levels, and histopathological findings were assessed using the optic nerve tissues. RESULTS: In the Cis + Res group, the MDA, TOS, OSI, TNF-a and NFK-B levels were significantly lower and the tGSH and TAS levels were significantly higher compared with the Cis group (P = 0.001). In histological evaluations, there were dilated and congested blood vessels, destruction, oedema, degeneration, haemorrhage, and proliferating capillaries indicating the presence of inflammation and damage only in the Cis-administered group. However, in the Cis + Res group, the histological findings were very similar to the healthy controls. CONCLUSION: Resveratrol is a promising neuroprotective agent for cisplatin-induced optic nerve toxicity with its anti-oxidant and anti-inflammatory effects. Further investigations are needed to evaluate the possible therapeutic effects on other optic nerve toxicities.

Matrine treatment reduces retinal ganglion cell apoptosis in experimental optic neuritis.

Inflammatory demyelination and axonal injury of the optic nerve are hallmarks of optic neuritis (ON), which often occurs in multiple sclerosis and is a major cause of visual disturbance in young adults. Although a high dose of corticosteroids can promote visual recovery, it cannot prevent permanent neuronal damage. Novel and effective therapies are thus required. Given the recently defined capacity of matrine (MAT), a quinolizidine alkaloid derived from the herb Radix Sophorae flavescens, in immunomodulation and neuroprotection, we tested in this study the effect of matrine on rats with experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. MAT administration, started at disease onset, significantly suppressed optic nerve infiltration and demyelination, with reduced numbers of Iba1+ macrophages/microglia and CD4+ T cells, compared to those from vehicle-treated rats. Increased expression of neurofilaments, an axon marker, reduced numbers of apoptosis in retinal ganglion cells (RGCs). Moreover, MAT treatment promoted Akt phosphorylation and shifted the Bcl-2/Bax ratio back towards an antiapoptotic one, which could be a mechanism for its therapeutic effect in the ON model. Taken as a whole, our results demonstrate that MAT attenuated inflammation, demyelination and axonal loss in the optic nerve, and protected RGCs from inflammation-induced cell death. MAT may therefore have potential as a novel treatment for this disease that may result in blindness.

Citicoline Modulates Glaucomatous Neurodegeneration Through Intraocular Pressure-Independent Control.

Glaucoma is a neurodegenerative disease that causes progressive, irreversible vision loss. Currently, intraocular pressure (IOP) is the only modifiable risk factor for glaucoma. However, glaucomatous degeneration may continue despite adequate IOP control. Therefore, there exists a need for treatment that protects the visual system, independent of IOP. This study sought, first, to longitudinally examine the neurobehavioral effects of different magnitudes and durations of IOP elevation using multi-parametric magnetic resonance imaging (MRI), optokinetics and histology; and, second, to evaluate the effects of oral citicoline treatment as a neurotherapeutic in experimental glaucoma. Eighty-two adult Long Evans rats were divided into six groups: acute (mild or severe) IOP elevation, chronic (citicoline-treated or untreated) IOP elevation, and sham (acute or chronic) controls. We found that increasing magnitudes and durations of IOP elevation differentially altered structural and functional brain connectivity and visuomotor behavior, as indicated by decreases in fractional anisotropy in diffusion tensor MRI, magnetization transfer ratios in magnetization transfer MRI, T1-weighted MRI enhancement of anterograde manganese transport, resting-state functional connectivity, visual acuity, and neurofilament and myelin staining along the visual pathway. Furthermore, 3 weeks of oral citicoline treatment in the setting of chronic IOP elevation significantly reduced visual brain integrity loss and visual acuity decline without altering IOP. Such effects sustained after treatment was discontinued for another 3 weeks. These results not only illuminate the close interplay between eye, brain, and behavior in glaucomatous neurodegeneration, but also support a role for citicoline in protecting neural tissues and visual function in glaucoma beyond IOP control.

Dynamics of Central Remyelination and Treatment Evolution in a Model of Multiple Sclerosis with Optic Coherence Tomography.

The need for remyelinating drugs is essential for healing disabling diseases such as multiple sclerosis (MS). One of the reasons for the lack of this class of therapies is the impossibility to monitor remyelination in vivo, which is of utmost importance to perform effective clinical trials. Here, we show how optical coherence tomography (OCT), a cheap and non-invasive technique commonly used in ophthalmology, may be used to assess remyelination in vivo in MS patients. Our pioneer approach validates OCT as a technique to study remyelination of the optic nerve and reflects what is occurring in non-accessible central nervous system (CNS) structures, like the spinal cord. In this study we used the orally bioavailable small molecule VP3.15, confirming its therapeutical potential as a neuroprotective, anti-inflammatory, and probably remyelinating drug for MS. Altogether, our results confirm the usefulness of OCT to monitor the efficacy of remyelinating therapies in vivo and underscore the relevance of VP3.15 as a potential disease modifying drug for MS therapy.

How curcumin affects hyperglycemia-induced optic nerve damage: A short review.

Considered to be one of the most important non-contagious systemic diseases worldwide, diabetes mellitus is still a topical issue on the health agenda with the problems it causes. Exposure to long-term hyperglycemia causes diabetic complications (diabetic neuropathy, nephropathy and retinopathy). The optic nerve can suffer damage by both diabetic retinopathy and neuropathy during diabetes, both because it is formed by axons of retinal ganglion cells and these axons belong to the central nervous system. The issue of hyperglycemia on the optic nerve have been described as diabetic papillopathy, posterior ischemic optic neuropathy, nonarteritic anterior ischemic optic neuropathy and optic atrophy in clinical studies. Experimental studies indicated axon-myelin degeneration in addition to microvascular and ultrastructural changes caused by the hyperglycemia-induced optic nerve damage. Although there are several proposed biochemical mechanisms to cause these damages, oxidative stress emerges as an important factor among them. Oxidative stress leads to pathological state on the nerve cells by affecting the DNA, protein and lipids at different levels. These are causing deterioration on nerve conduction velocity, myelin sheath and nerve structure, neurotrophic support system, glial cells and nerve function. Curcumin, as an important antioxidant, can be an ideal prophylactic agent to eliminate damages on optic nerve. Curcumin helps to regulate the balance of antioxidant and reactive oxygen species by targeting various molecules (NF-κB, STAT3, MAPK, Mfn2, Nrf2, pro-inflammatory cytokines). In addition, it shows healing or preventive effects on myelin sheath damage via regulating ferritin protein in oligodendrocytes. It is also effective in preventing neurovascular damage.

Cholesterol synthesis inhibition promotes axonal regeneration in the injured central nervous system.

Neuronal regeneration in the injured central nervous system is hampered by multiple extracellular proteins. These proteins exert their inhibitory action through interactions with receptors that are located in cholesterol rich compartments of the membrane termed lipid rafts. Here we show that cholesterol-synthesis inhibition prevents the association of the Neogenin receptor with lipid rafts. Furthermore, we show that cholesterol-synthesis inhibition enhances axonal growth both on inhibitory -myelin and -RGMa substrates. Following optic nerve injury, lowering cholesterol synthesis with both drugs and siRNA-strategies allows for robust axonal regeneration and promotes neuronal survival. Cholesterol inhibition also enhanced photoreceptor survival in a model of Retinitis Pigmentosa. Our data reveal that Lovastatin leads to several opposing effects on regenerating axons: cholesterol synthesis inhibition promotes regeneration whereas altered prenylation impairs regeneration. We also show that the lactone prodrug form of lovastatin has differing effects on regeneration when compared to the ring-open hydroxy-acid form. Thus the association of cell surface receptors with lipid rafts contributes to axonal regeneration inhibition, and blocking cholesterol synthesis provides a potential therapeutic approach to promote neuronal regeneration and survival in the diseased Central Nervous System. SIGNIFICANCE STATEMENT: Statins have been intensively used to treat high levels of cholesterol in humans. However, the effect of cholesterol inhibition in both the healthy and the diseased brain remains controversial. In particular, it is unclear whether cholesterol inhibition with statins can promote regeneration and survival following injuries. Here we show that late stage cholesterol inhibition promotes robust axonal regeneration following optic nerve injury. We identified distinct mechanisms of action for activated vs non-activated Lovastatin that may account for discrepancies found in the literature. We show that late stage cholesterol synthesis inhibition alters Neogenin association with lipid rafts, thereby i) neutralizing the inhibitory function of its ligand and ii) offering a novel opportunity to promote CNS regeneration and survival following injuries.

Effects of sevoflurane and propofol on the optic nerve sheath diameter in patients undergoing laparoscopic gynecological surgery: a randomized controlled clinical studies.

BACKGROUND: The results of studies on changes in intracranial pressure in patients undergoing laparoscopic surgery are inconsistent. Meanwhile, previous neurosurgery studies have suggested that propofol and sevoflurane have inconsistent effects on cerebral blood flow and cerebrovascular self-regulation. The purpose of this study is to compare changes in the optic nerve sheath diameter in patients undergoing laparoscopic gynecological surgery under anesthetic maintenance with propofol versus sevoflurane. METHODS: This study included 110 patients undergoing laparoscopic gynecological surgery with an estimated operative time of more than 2 h under general anesthesia. The study was a randomized controlled study. The optic nerve sheath diameter (ONSD) at various time points was measured by ultrasound, including when the patients entered the operating room (Tawake), after successful anesthesia induction and endotracheal intubation (Tinduction), when the body position was adjusted to the Trendelenburg position and the CO2 pneumoperitoneum pressure reached 14 mmHg, which was recorded as T0. Then, measurements were conducted every 15 min for the first 1 h and then once every hour until the end of the surgery (T15, T30, T45, T1h, T2h …), after the end of surgery and the tracheal tube was removed (Tend), and before the patients were transferred to the ward (Tpacu). RESULTS: A significant difference in optic nerve sheath diameter was found between two groups at T15, T30, T45 (4.64 ± 0.48 mm and 4.50 ± 0.29 mm, respectively, p = 0.031;4.77 ± 0.45 mm and 4.62 ± 0.28 mm, respectively, p = 0.036;4.84 ± 0.46 mm and 4.65 ± 0.30 mm, respectively, p = 0.012), while there was no significant difference at Tawake and other time points. CONCLUSION: During laparoscopic gynecological surgery lasting more than 2 h, the optic nerve sheath diameter was slightly larger in the propofol group than that in the sevoflurane group in the first 45 min. No significant difference was observed between the two groups 1 h after surgery. TRIAL REGISTRATION: clinicaltrials.gov, NCT03498235 . Retrospectively registered 1 March 2018. The manuscript adheres to CONSORT guidelines.

Liraglutide, 7,8-DHF and their co-treatment prevents loss of vision and cognitive decline in a Wolfram syndrome rat model.

Wolfram syndrome (WS) is a monogenic progressive neurodegenerative disease and is characterized by various neurological symptoms, such as optic nerve atrophy, loss of vision, cognitive decline, memory impairment, and learning difficulties. GLP1 receptor agonist liraglutide and BDNF mimetic 7,8-dihydroxyflavone (7,8-DHF) have had protective effect to visual pathway and to learning and memory in different rat models of neurodegenerative disorders. Although synergistic co-treatment effect has not been reported before and therefore the aim of the current study was to investigate liraglutide, 7,8-DHF and most importantly for the first time their co-treatment effect on degenerative processes in WS rat model. We took 9 months old WS rats and their wild-type (WT) control animals and treated them daily with liraglutide, 7,8-DHF or with the combination of liraglutide and 7,8-DHF up to the age of 12.5 months (n = 47, 5-8 per group). We found that liraglutide, 7,8-DHF and their co-treatment all prevented lateral ventricle enlargement, improved learning in Morris Water maze, reduced neuronal inflammation, delayed the progression of optic nerve atrophy, had remyelinating effect on optic nerve and thereby improved visual acuity in WS rats compared to WT controls. Thus, the use of the liraglutide, 7,8-DHF and their co-treatment could potentially be used as a therapeutic intervention to induce neuroprotection or even neuronal regeneration.

Prospective study to evaluate incidence and indicators for early detection of ethambutol toxicity.

AIMS: To evaluate incidence of toxic optic neuropathy in patients receiving ethambutol (EMB) for 6 months and to identify its early indicators. METHODS: We included 50 patients on anti-tubercular therapy (ATT) including EMB (HRE regimen) based on total body weight for 6 months. Best-corrected visual acuity (ETDRS), colour vision (Ishihara pseudo-isochromatic plates), contrast sensitivity (Pelli-Robson chart), Humphrey visual field analysis (HVF 30-2 SITA FAST), pattern visual evoked response (VER) and spectral-domain optical coherence tomography (SDOCT) for ganglion cell inner plexiform layer (GCIPL) and retinal nerve fibre layer (RNFL) analysis were assessed at baseline and at 2, 4 and 6 months after starting ATT. RESULTS: Mean age of the patients was 36.5±14.7 years with male:female ratio of 2.5:1. Mean daily dosage of EMB was 17.5±1.3 mg/kg/day. No significant change was observed in visual acuity, contrast sensitivity, color vision and mean or pattern SD on HVF at 6 months. Significant increase in VER latency of >2 SD (>125 ms) was observed in 46% eyes on follow-up indicating subclinical toxicity. Significant loss of mean RNFL (from 100.79±16.05 µm to 89.96±13.79 µm) and GCIPL thickness (from 83.1±5.60 µm to 79.85±6.45 µm) was observed at 6 months (p=0.001 for both). Patients with subclinical toxicity had significantly greater damage in temporal RNFL quadrant, supero-nasal and infero-nasal GCIPL sectors compared with others. CONCLUSION: The incidence of clinical EMB optic neuropathy was <2%, though subclinical damage in the form of increase in VER latency, and decrease in RNFL and GCIPL on OCT was seen in 46% eyes.