Neuroprotective effect of peroxiredoxin 6 against hypoxia-induced retinal ganglion cell damage

Background  

The ability to respond to changes in the extra-intracellular environment is prerequisite for cell survival. Cellular responses to the environment include elevating defense systems, such as the antioxidant defense system. Hypoxia-evoked reactive oxygen species (ROS)-driven oxidative stress is an underlying mechanism of retinal ganglion cell (RGC) death that leads to blinding disorders. The protein peroxiredoxin 6 (PRDX6) plays a pleiotropic role in negatively regulating death signaling in response to stressors, and thereby stabilizes cellular homeostasis.     

Both systemic and local application of Granulocyte-colony stimulating factor (G-CSF) is neuroprotective after retinal ganglion cell axotomy

Background  

The hematopoietic Granulocyte-Colony Stimulating Factor (G-CSF) plays a crucial role in controlling the number of neutrophil progenitor cells. Its function is mediated via the G-CSF receptor, which was recently found to be expressed also in the central nervous system. In addition, G-CSF provided neuroprotection in models of neuronal cell death. Here we used the retinal ganglion cell (RGC) axotomy model to compare effects of local and systemic application of neuroprotective molecules.     

Dominant inheritance of retinal ganglion cell resistance to optic nerve crush in mice

Background  

Several neurodegenerative diseases are influenced by complex genetics that affect an individual's susceptibility, disease severity, and rate of progression. One such disease is glaucoma, a chronic neurodegenerative condition of the eye that targets and stimulates apoptosis of CNS neurons called retinal ganglion cells. Since ganglion cell death is intrinsic, it is reasonable that the genes that control this process may contribute to the complex genetics that affect ganglion cell susceptibility to disease. To determine if genetic background influences susceptibility to optic nerve damage, leading to ganglion cell death, we performed optic nerve crush on 15 different inbred lines of mice and measured ganglion cell loss. Resistant and susceptible strains were used in a reciprocal breeding strategy to examine the inheritance pattern of the resistance phenotype. Because earlier studies had implicated Bax as a susceptibility allele for ganglion cell death in the chronic neurodegenerative disease glaucoma, we conducted allelic segregation analysis and mRNA quantification to assess this gene as a candidate for the cell death phenotype.     

<Emphasis Type="Italic">Rgcs1</Emphasis>, a dominant QTL that affects retinal ganglion cell death after optic nerve crush in mice

Background  

Intrinsic apoptosis of neuronal somas is one aspect of neurodegenerative diseases that can be influenced by genetic background. Genes that affect this process may act as susceptibility alleles that contribute to the complex genetic nature of these diseases. Retinal ganglion cell death is a defining feature of the chronic and genetically complex neurodegenerative disease glaucoma. Previous studies using an optic nerve crush procedure in inbred mice, showed that ganglion cell resistance to crush was affected by the Mendelian-dominant inheritance of 1–2 predicted loci. To assess this further, we bred and phenotyped a large population of F2 mice derived from a resistant inbred strain (DBA/2J) and a susceptible strain (BALB/cByJ).     

Progressive ganglion cell loss and optic nerve degeneration in DBA/2J mice is variable and asymmetric

Background  

Glaucoma is a chronic neurodegenerative disease of the retina, characterized by the degeneration of axons in the optic nerve and retinal ganglion cell apoptosis. DBA/2J inbred mice develop chronic hereditary glaucoma and are an important model system to study the molecular mechanisms underlying this disease and novel therapeutic interventions designed to attenuate the loss of retinal ganglion cells. Although the genetics of this disease in these mice are well characterized, the etiology of its progression, particularly with respect to retinal degeneration, is not. We have used two separate labeling techniques, post-mortem DiI labeling of axons and ganglion cell-specific expression of the βGeo reporter gene, to evaluate the time course of optic nerve degeneration and ganglion cell loss, respectively, in aging mice.     

Inducible nitric oxide synthase, <Emphasis Type="Italic">Nos2</Emphasis>, does not mediate optic neuropathy and retinopathy in the DBA/2J glaucoma model

Background  

Nitric oxide synthase 2 (NOS2) contributes to neural death in some settings, but its role in glaucoma remains controversial. NOS2 is implicated in retinal ganglion cell degeneration in a rat glaucoma model in which intraocular pressure (IOP) is experimentally elevated by blood vessel cauterization, but not in a rat glaucoma model where IOP was elevated by injection of hypertonic saline. To test the importance of NOS2 for an inherited glaucoma, in this study we both genetically and pharmacologically decreased NOS2 activity in the DBA/2J mouse glaucoma model.     

Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis

Background  

Silencing of normal gene expression occurs early in the apoptosis of neurons, well before the cell is committed to the death pathway, and has been extensively characterized in injured retinal ganglion cells. The causative mechanism of this widespread change in gene expression is unknown. We investigated whether an epigenetic change in active chromatin, specifically histone H4 deacetylation, was an underlying mechanism of gene silencing in apoptotic retinal ganglion cells (RGCs) following an acute injury to the optic nerve.     

Roles of PI3K and JAK pathways in viability of retinal ganglion cells after acute elevation of intraocular pressure in rats with different autoimmune backgrounds

Background  

We recently showed that whereas inhibition of PI3K/akt or JAK/STAT pathway promoted retinal ganglion cell (RGC) survival after optic nerve (ON) injury in Fischer 344 (F344) rats, the same inhibition resulted in aggravated RGC loss after acute intraocular pressure (IOP) elevation in Sprague Dawley (SPD) rats. In addition, the responses of macrophages to ON injury and acute IOP elevation were different between F344 and Lewis rats, i.e., different autoimmune profiles. Using an acute IOP elevation paradigm in this study, we investigated 1) whether autoimmune background influences PI3K/akt and JAK/STAT functions by examining the effect of PI3K/akt and JAK/STAT pathway inhibition on RGC survival in F344 and Lewis rats, and 2) whether differential actions of macrophages occur in PI3K/akt and JAK/STAT pathways-dependent modulation of RGC survival. IOP elevation was performed at 110 mmHg for 2 hours. PI3K/akt and JAK/STAT pathway inhibitors were applied intravitreally to block their respective pathway signaling transduction. Because macrophage invasion was seen in the eye after the pathway inhibition, to examine the role of these pathways independent of macrophages, macrophages in the retina were removed by intravitreal application of clodronate liposomes. Viable RGCs were retrogradely labelled by FluoroGold 40 hours before animal sacrifice.     

Neurotrophin and Trk expression by cells of the human lamina cribrosa following oxygen-glucose deprivation

Background  

Ischemia within the optic nerve head (ONH) may contribute to retinal ganglion cell (RGC) loss in primary open angle glaucoma (POAG). Ischemia has been reported to increase neurotrophin and high affinity Trk receptor expression by CNS neurons and glial cells. We have previously demonstrated neurotrophin and Trk expression within the lamina cribrosa (LC) region of the ONH. To determine if ischemia alters neurotrophin and Trk protein expression in cells from the human LC, cultured LC cells and ONH astrocytes were exposed to 48 hours of oxygen-glucose deprivation (OGD). Also cells were exposed to 48 hours of OGD followed by 24 hours of recovery in normal growth conditions. Cell number, neurotrophin and Trk receptor protein expression, neurotrophin secretion, and Trk receptor activation were examined.     

Differential production of superoxide by neuronal mitochondria

Background  

Mitochondrial DNA (mtDNA) mutations, which are present in all mitochondria-containing cells, paradoxically cause tissue-specific disease. For example, Leber's hereditary optic neuropathy (LHON) results from one of three point mutations mtDNA coding for complex I components, but is only manifested in retinal ganglion cells (RGCs), a central neuron contained within the retina. Given that RGCs use superoxide for intracellular signaling after axotomy, and that LHON mutations increase superoxide levels in non-RGC transmitochondrial cybrids, we hypothesized that RGCs regulate superoxide levels differently than other neuronal cells. To study this, we compared superoxide production and mitochondrial electron transport chain (METC) components in isolated RGC mitochondria to mitochondria isolated from cerebral cortex and neuroblastoma SK-N-AS cells.     

Sperry versus Hebb: Topographic mapping in Isl2/EphA3 mutant mice

Background  

In wild-type mice, axons of retinal ganglion cells establish topographically precise projection to the superior colliculus of the midbrain. This means that axons of neighboring retinal ganglion cells project to the proximal locations in the target. The precision of topographic projection is a result of combined effects of molecular labels, such as Eph receptors and ephrins, and correlated neural activity. In the Isl2/EphA3 mutant mice the expression levels of molecular labels are changed. As a result the topographic projection is rewired so that the neighborhood relationships between retinal cell axons are disrupted.     

Midkine,heparin-binding growth factor,blocks kainic acid-induced seizure and neuronal cell death in mouse hippocampus

Background  

Midkine (MK), a member of the heparin-binding growth factor family, which includes MK and pleiotrophin, is known to possess neurotrophic and neuroprotective properties in the central nervous system. Previous studies have shown that MK is an effective neuroprotective agent in reducing retinal degeneration caused by excessive light and decreasing hippocampal neuronal death in ischemic gerbil brain. The present study was undertaken to investigate whether MK acts as an anticonvulsant in kainic acid (KA)-induced seizure in mouse and blocks KA-mediated neuronal cell death in hippocampus.     

Neuroprotective effects of bis(7)-tacrine against glutamate-induced retinal ganglion cells damage

Background  

Glutamate-mediated excitotoxicity, primarily through N-methyl-D-aspartate (NMDA) receptors, may be an important cause of retinal ganglion cells (RGCs) death in glaucoma and several other retinal diseases. Bis(7)-tacrine is a noncompetitive NMDA receptors antagonist that can prevent glutamate-induced hippocampal neurons damage. We tested the effects of bis(7)-tacrine against glutamate-induced rat RGCs damage in vitro and in vivo.     

Pigment epithelium-derived factor protects retinal ganglion cells

Background  

Retinal ganglion cells (RGCs) are responsible for the transmission of visual signals to the brain. Progressive death of RGCs occurs in glaucoma and several other retinal diseases, which can lead to visual impairment and blindness. Pigment epithelium-derived factor (PEDF) is a potent antiangiogenic, neurotrophic and neuroprotective protein that can protect neurons from a variety of pathologic insults. We tested the effects of PEDF on the survival of cultured adult rat RGCs in the presence of glaucoma-like insults, including cytotoxicity induced by glutamate or withdrawal of trophic factors.     

GT1b-induced neurotoxicity is mediated by the Akt/GSK-3/tau signaling pathway but not caspase-3 in mesencephalic dopaminergic neurons

Background  

Gangliosides, sialic acid-containing glycosphingolipids exist in mammalian cell membranes particularly neuronal membranes. The trisialoganglioside (GT1b) is one of the major brain gangliosides and acts as an endogenous regulator in the brain. We previously showed GT1b induces mesencephalic dopaminergic (DA) neuronal death, both in vivo and in vitro. We further investigate the underlying mechanisms of GT1b neurotoxicity.     

Polysialylated-neural cell adhesion molecule (PSA-NCAM) in the human trigeminal ganglion and brainstem at prenatal and adult ages

Background  

The polysialylated neuronal cell adhesion molecule (PSA-NCAM) is considered a marker of developing and migrating neurons and of synaptogenesis in the immature vertebrate nervous system. However, it persists in the mature normal brain in some regions which retain a capability for morphofunctional reorganization throughout life. With the aim of providing information relevant to the potential for dynamic changes of specific neuronal populations in man, this study analyses the immunohistochemical occurrence of PSA-NCAM in the human trigeminal ganglion (TG) and brainstem neuronal populations at prenatal and adult age.     

Foxo3a induces motoneuron death through the Fas pathway in cooperation with JNK

Background  

Programmed cell death of motoneurons in the developing spinal cord is thought to be regulated through the availability of target-derived neurotrophic factors. When deprived of trophic support, embryonic spinal motoneurons in vitro over-express FasL, a ligand activating a Fas-mediated death pathway. How trophic factors regulate the expression of FasL is presently unclear, but two regulators of FasL, FOXO3a (FKHRL1) and JNK have been described to play a role in other cell types. Thus, their potential function in motoneurons was investigated in this study.     

An analysis of the dependence of saccadic latency on target position and target characteristics in human subjects

Background  

Predictions from conduction velocity data for primate retinal ganglion cell axons indicate that the conduction time to the lateral geniculate nucleus for stimulation of peripheral retina should be no longer than for stimulation of central retina. On this basis, the latency of saccadic eye movements should not increase for more peripherally located targets. However, previous studies have reported relatively very large increases, which has the implication of a very considerable increase in central processing time for the saccade-generating system.     

Structural effects and potential changes in growth factor signalling in penis-projecting autonomic neurons after axotomy

Background  

The responses of adult parasympathetic ganglion neurons to injury and the neurotrophic mechanisms underlying their axonal regeneration are poorly understood. This is especially relevant to penis-projecting parasympathetic neurons, which are vulnerable to injury during pelvic surgery such as prostatectomy. We investigated the changes in pelvic ganglia of adult male rats in the first week after unilateral cavernous (penile) nerve axotomy (cut or crush lesions). In some experiments FluoroGold was injected into the penis seven days prior to injury to allow later identification of penis-projecting neurons. Neurturin and glial cell line-derived neurotrophic factor (GDNF) are neurotrophic factors for penile parasympathetic neurons, so we also examined expression of relevant receptors, GFRα1 and GFRα2, in injured pelvic ganglion neurons.     

Expression of ionotropic glutamate receptors in the retina of the rdta transgenic mouse

Background  

The expression of retinal CaMKII is up-regulated in the retina of the rdta mouse in which rod photoreceptors are genetically ablated. As ionotropic glutamate receptors are known substrates of CAMKII, this study set out to determine if the protein levels of ionotropic glutamate receptors in the rdta mouse retina are also affected.