Radial optic neurotomy: a new surgical approach for glaucoma treatment?

Glaucoma is a leading cause of blindness worldwide, characterised by specific visual field defects due to the degeneration of retinal ganglion cells and damage to the optic nerve head (ONH). Elevated intraocular pressure (IOP) is the most important risk factor for glaucoma development. One of the clinical hallmarks of glaucomatous optic neuropathy is the excavation of the ONH, which consists of a progressive posterior displacement of the ONH surface and excavation of the pre-laminar tissues beneath the anterior-most aspect of the scleral canal, known as the anterior scleral ring. Radial optic neurotomy (RON) is a surgical technique that has been proposed for treating central retinal vein occlusion. While the original rationale of RON was the relief of increased tissue pressure within the optic nerve that results from occlusion of the central retinal vein, recent results are discussed here which suggest that by relaxing of the scleral ring of the prelaminar and laminar regions of the ONH, RON may alleviate the IOP-related connective tissue stress, and in turn, prevent the onset and reduce the progression of glaucomatous neuropathy.Fil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; ArgentinaFil: Belforte, Nicolás Adalberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentin

Early NMDA receptor ablation in interneurons causes an activity-dependent E/I imbalance in vivo in prefrontal cortex pyramidal neurons of a mouse model useful for the study of schizophrenia

Altered Excitatory/Inhibitory (E/I) balance of cortical synaptic inputs has been proposed as a central pathophysiological factor for psychiatric neurodevelopmental disorders, including schizophrenia (SZ). However, direct measurement of E/I synaptic balance have not been assessed in vivo for any validated SZ animal model. Using a mouse model useful for the study of SZ we show that a selective ablation of NMDA receptors (NMDAr) in cortical and hippocampal interneurons during early postnatal development results in an E/I imbalance in vivo, with synaptic inputs to pyramidal neurons shifted towards excitation in the adult mutant medial prefrontal cortex (mPFC). Remarkably, this imbalance depends on the cortical state, only emerging when theta and gamma oscillations are predominant in the network. Additional brain slice recordings and subsequent 3D morphological reconstruction showed that E/I imbalance emerges after adolescence concomitantly with significant dendritic retraction and dendritic spine re-localization in pyramidal neurons. Therefore, early postnatal ablation of NMDAr in cortical and hippocampal interneurons developmentally impacts on E/I imbalance in vivo in an activity-dependent manner.Fil: Pafundo, Diego Esteban. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Pretell Annan, Carlos Alfredo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Fulginiti, Nicolás Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; ArgentinaFil: Belforte, Juan Emilio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Fisiología y Biofísica Bernardo Houssay. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Fisiología y Biofísica Bernardo Houssay; Argentin

Effect of chondroitin sulfate on intraocular pressure in rats

PURPOSE: To study the effect of intracameral injections of chondroitin sulfate (CS) on intraocular pressure (IOP), retinal function, and histology in rats. METHODS: Acute or chronic injections of CS were performed unilaterally in the rat anterior chamber, whereas the contralateral eye was injected with vehicle. IOP was daily or weekly assessed by a tonometer. Retinal function was assessed by scotopic electroretinography (ERG) and the visual pathway by flash visual evoked potentials (VEPs), whereas the retinal and optic nerve head structure were examined by histologic analysis. RESULTS: A single injection of 8 mg (but not 2 or 4 mg) CS induced a significant increase of IOP. The increase of IOP induced by a single injection of 8 mg CS lasted for 7 days, whereas chronic (weekly) administration during 10 weeks induced a significant and sustained increase in IOP compared with eyes injected with vehicle. A significant decrease of scotopic ERG a- and b- wave amplitude was observed after 6 and 10 weeks of CS administration. Moreover, a significant decrease in scotopic flash VEP N2-P2 component amplitude was observed in eyes treated with CS for 6 and 10 weeks. A significant loss of ganglion cell layer cells and optic nerve axons was observed in eyes receiving CS for 10 weeks. CONCLUSIONS: These results suggest that exogenous CS simulates the accumulation of CS in primary open-angle glaucoma and that increased amounts of CS could play a key role in the IOP dysregulation characteristic of glaucoma.Fil: Belforte, Nicolás Adalberto. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Sande Casal, Pablo Horacio. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: de Zavalia, Nuria Maria Asuncion. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Knepper, Paul A.. University of Illinois; Estados UnidosFil: Rosenstein, Ruth Estela. Universidad de Buenos Aires. Facultad de Medicina. Laboratorio de Neuroquímica Retiniana y Oftalmología Experimental; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentin

Oligodendrogenesis in iron-deficient rats: Effect of apotransferrin

In rats, iron deficiency produces an alteration in myelinformation. However, there is limited information on theeffects of this condition on oligodendroglial cell (OLGc)proliferation and maturation. In the present study, wefurther analyzed the hypomyelination associated withiron deficiency by studying the dynamics of oligodendrogenesis.Rats were fed control (40 mg Fe/kg) oriron-deficient (4 mg Fe/kg) diets from gestation day 5until postnatal day 3 (P3) or 11 (P11). OLGc proliferation,migration and differentiation were investigatedbefore and after an intracranial injection of apotransferrinat 3 days of age (P3). The proliferating cell populationwas evaluated at P3. Iron-deficient (ID) animalsshowed an increase in the oligodendrocyte precursorscell (OPC) population in comparison with controls. Theoverall pattern of migration of cells labeled with BrdUwas investigated at P11. Iron deficiency increased theamount of BrdU1 cells in the corpus callosum (CC) anddecreased OLGc maturation and myelin formation.Changes in nerve conduction were analyzed by measuringvisual evoked potentials. Latency and amplitudewere significantly disturbed in ID rats compared withcontrols. Both parameters were substantially normalizedwhen animals were treated with a single intracranialinjection of 350 ng apotransferrin (aTf). The currentresults give support to the idea that iron deficiencyincreases the number of proliferating and undifferentiatedcells in the CC compared with the control. Treatmentwith aTf almost completely reverted the effects ofiron deficiency, both changing the migration patternand increasing the number of mature cells in the CCand myelin formation.Fil: Rosato Siri, María Victoria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Badaracco, M. E.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Ortiz, E. H.. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Belforte, Nicolás Adalberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Guardia Clausi, Mariano. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Soto, Eduardo Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; ArgentinaFil: Bernabeu, Ramon Oscar. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Biología Celular y Neurociencia "Prof. Eduardo de Robertis". Universidad de Buenos Aires. Facultad de Medicina. Instituto de Biología Celular y Neurociencia; ArgentinaFil: Pasquini, Juana Maria. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas "Prof. Alejandro C. Paladini". Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Instituto de Química y Físico-Química Biológicas; Argentin

Therapeutic Benefit of Radial Optic Neurotomy in a Rat Model of Glaucoma

Radial optic neurotomy (RON) has been proposed as a surgical treatment to alleviate the neurovascular compression and to improve the venous outflow in patients with central retinal vein occlusion. Glaucoma is characterized by specific visual field defects due to the loss of retinal ganglion cells and damage to the optic nerve head (ONH). One of the clinical hallmarks of glaucomatous neuropathy is the excavation of the ONH. The aim of this work was to analyze the effect of RON in an experimental model of glaucoma in rats induced by intracameral injections of chondroitin sulfate (CS). For this purpose, Wistar rats were bilaterally injected with vehicle or CS in the eye anterior chamber, once a week, for 10 weeks. At 3 or 6 weeks of a treatment with vehicle or CS, RON was performed by a single incision in the edge of the neuro-retinal ring at the nasal hemisphere of the optic disk in one eye, while the contralateral eye was submitted to a sham procedure. Electroretinograms (ERGs) were registered under scotopic conditions and visual evoked potentials (VEPs) were registered with skull-implanted electrodes. Retinal and optic nerve morphology was examined by optical microscopy. RON did not affect the ocular hypertension induced by CS. In eyes injected with CS, a significant decrease of retinal (ERG a- and b-wave amplitude) and visual pathway (VEP N2-P2 component amplitude) function was observed, whereas RON reduced these functional alterations in hypertensive eyes. Moreover, a significant loss of cells in the ganglion cell layer, and Thy-1-, NeuN- and Brn3a- positive cells was observed in eyes injected with CS, whereas RON significantly preserved these parameters. In addition, RON preserved the optic nerve structure in eyes with chronic ocular hypertension. These results indicate that RON reduces functional and histological alterations induced by experimental chronic ocular hypertension

Ischemic Tolerance Protects the Rat Retina from Glaucomatous Damage

Glaucoma is a leading cause of acquired blindness which may involve an ischemic-like insult to retinal ganglion cells and optic nerve head. We investigated the effect of a weekly application of brief ischemia pulses (ischemic conditioning) on the rat retinal damage induced by experimental glaucoma. Glaucoma was induced by weekly injections of chondroitin sulfate (CS) in the rat eye anterior chamber. Retinal ischemia was induced by increasing intraocular pressure to 120 mmHg for 5 min; this maneuver started after 6 weekly injections of vehicle or CS and was weekly repeated in one eye, while the contralateral eye was submitted to a sham procedure. Glaucoma was evaluated in terms of: i) intraocular pressure (IOP), ii) retinal function (electroretinogram (ERG)), iii) visual pathway function (visual evoked potentials, (VEPs)) iv) histology of the retina and optic nerve head. Retinal thiobarbituric acid substances levels were assessed as an index of lipid peroxidation. Ischemic conditioning significantly preserved ERG, VEPs, as well as retinal and optic nerve head structure from glaucomatous damage, without changes in IOP. Moreover, ischemia pulses abrogated the increase in lipid peroxidation induced by experimental glaucoma. These results indicate that induction of ischemic tolerance could constitute a fertile avenue for the development of new therapeutic strategies in glaucoma treatment

Development of new therapeutic strategies for glaucoma treatment

En este Trabajo de Tesis se demostró que la hipertensión ocular inducida por inyecciones semanales intracamerales de ácido hialurónico provocó un aumento significativo en la actividad del sistema nitrérgico retiniano. La melatonina moduló los sistemas glutamatérgico, GABAérgico, nitrérgico y antioxidante endógeno retinianos en forma opuesta a la inducida por la hipertensión ocular crónica. Un tratamiento crónico con melatonina disminuyó las alteraciones funcionales e histológicas provocadas por el glaucoma experimental. Hemos desarrollado un modelo de glaucoma experimental a través de la administración semanal de condroitín sulfato (CS) en la cámara anterior del ojo de rata que reproduce características centrales del glaucoma humano. La inducción de tolerancia isquémica provocó una preservación significativa en la función retiniana y en la estructura de la retina y del nervio óptico en ojos con hipertensión ocular inducida por la administración de CS. Asimismo, hemos demostrado que la neurotomía óptica radial, que no provocó daño per se, previno y redujo los cambios inducidos por el glaucoma experimental, tanto a nivel funcional como histológico.In this Thesis, we have demonstrated that ocular hypertension induced by weekly intracameral injections of hyaluronic acid provoked a significant increase in the retinal nitridergic pathway activity. Melatonin modulated the retinal glutamatergic, GABAergic, nitridergic and endogenous antioxidant systems in an opposite way to that induced by chronic ocular hypertension. Moreover, a chronic treatment with melatonin decreased functional and histological alterations provoked by experimental glaucoma. We have developed an experimental model of glaucoma in rats induced by weekly injections of chondroitin sulfate (CS) in the eye anterior chamber, which reproduces central features of human glaucoma. The induction of ischemic tolerance provoked a significant preservation of retinal function and retinal and optic nerve structure in eyes with ocular hypertension induced by CS. In addition, we have demonstrated that radial optic neurotomy, which did not cause damage per se, prevented and reduced functional and histological alterations in the retina induced by experimental glaucoma.Fil:Belforte, Nicolás Adalberto. Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales; Argentina

Early histological and functional study of radial optic neurotomy outcomes in normal rat eyes

BACKGROUND: Radial optic neurotomy (RON) has been proposed as a treatment for central retinal vein occlusion. However, it is still under debate whether RON would be an adequate treatment or a dangerous procedure, and persuasive animal studies are lacking. The aim of this study was to analyze the early histologic and functional outcomes of RON in normal rat eyes. METHODS: Radial optic neurotomy was performed by cutting into the optic nerve edge at the nasal hemisphere, while the contralateral eye underwent a sham procedure. The retinal function was assessed by scotopic electroretinography, and the visual pathway was assessed by flash visual evoked potentials. Intraocular pressure was assessed with a tonometer, the pupillary light reflex was measured after exposing eyes to a 30-second light flash, whereas the optic nerve head structure was examined by histologic analysis. RESULTS: In normal rat eyes, RON provoked minor histologic alterations at the optic nerve head level and a transient decrease in the electroretinography. No changes in visual evoked potentials, intraocular pressure, and pupillary light reflex were observed in rat eyes submitted to RON. CONCLUSION: To our knowledge, this is the first study describing the early histopathologic and functional consequences of RON in normal rat eyes.Fil: Belforte, Nicolás Adalberto. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Sande Casal, Pablo Horacio. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; ArgentinaFil: Dorfman, Damián. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; ArgentinaFil: Croxatto, Juan Oscar. Fundación Oftalmología Argentina "J. Malbrán"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Rosenstein, Ruth Estela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Centro de Estudios Farmacológicos y Botánicos. Universidad de Buenos Aires. Facultad de Medicina. Centro de Estudios Farmacológicos y Botánicos; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Departamento de Bioquímica Humana; Argentin