DigitalUM :: Browsing by Subject "Neuroprotection"

Browsing by Subject "Neuroprotection"

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Open Access
Apoptotic retinal ganglion cell death after optic nerve transection or crush in mice: delayed RGC loss with BDNF or a Caspase 3 inhibitor
(Association for Research in Vision and Ophthalmology, 2016-01) Sánchez-Migallón, María C.; Valiente Soriano, Francisco Javier; Nadal-Nicolás, Francisco Manuel; Vidal Sanz, Manuel; Agudo Barriuso, Marta; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultad de Medicina
Purpose: To investigate retinal ganglion cell (RGC) survival and activation of caspase 3 after optic nerve crush (ONC) or transection (ONT) and treatment with brain-derived neurotrophic factor (BDNF) or Z-DEVD_fmk. Methods: In albino Swiss mice, the left optic nerve was severed or crushed at 0.5 mm from the optic head and retinas were analyzed from 1 to 10 days. Additional groups were treated intravitreally with a single injection of BDNF (2.5 μg) or Z-DEVD_fmk (125 ng) right after injury, or with Z-DEVD_fmk at day 2, or with multiple injections of Z-DEVD_fmk. As controls intact or vehicle-treated retinas were used. In all retinas, Brn3a (RGCs) and cleaved-caspase 3 (c-casp3) were immunodetected and their numbers quantified. In an additional group, c-casp3 expression was assessed in RGCs retrogradely labeled before axotomy. Results: The temporal loss of RGCs was the same after ONC or ONT and occurred in two phases with 65% loss during the first 7 days and an additional 4% loss from day 7 to 10. The appearance of c-casp3+RGCs is Gaussian, peaking at 4 days and declining thereafter. Brn3a down-regulates when RGCs start expressing c-casp3. Retinal ganglion cell rescue rate for BDNF or Z-DEVD_fmk is similar and both delay RGC loss by 1 day. Delayed treatment with Z-DEVD_fmk does not rescue RGCs, and several injections are not better than a single one at the time of the injury. Conclusions: Brn3a down-regulation marks the beginning of RGC death, which after axotomy occurs by caspase-dependent apoptosis in at least half of the RGCs. These data should be considered when designing neuroprotective strategies.
Open Access
Dock3-NMDA receptor interaction as a target for glaucoma therapy
(Universidad de Murcia. Departamento de Biología Celular e Histología, 2017) Kimura, Atsuko; Namekata, Kazuhiko; Guo, Xiaoli; Harada, Chikako; Harada, Takayuki
y. Glaucoma is a neurodegenerative disease of the eye and it is one of the major causes of blindness. Glaucoma is usually associated with elevated intraocular pressure (IOP) and the current therapy focuses on reduction of IOP. However, neuroprotective strategies could also be beneficial for treatment of glaucoma because the pathology of the disease involves retinal ganglion cell (RGC) death and damage to the optic nerve. Dedicator of cytokinesis 3 (Dock3) is an atypical guanine exchange factor (GEF) that belongs to a family of Dock proteins, Dock1-11. Dock3 exerts neuroprotective effects on the retina and optic nerve, and studies revealed that some of the Dock3-mediated effects are GEF-independent. One of these mechanisms is that Dock3 directly binds to the GluN2B subunit of the Nmethyl-D-aspartate (NMDA) receptor. Upon stimulation by NMDA or optic nerve crush, overexpression of Dock3 promotes internalization and degradation of the NMDA receptor in the retina in vivo. It is suggested that this process is mediated by inhibition of Fyn, a Src family tyrosine kinase. Reduction in NMDA receptor expression results in decreased excitotoxic damage and oxidative stress, thereby promoting RGC survival. In this review, we discuss the therapeutic potential of neuroprotection for glaucoma and the effects of Dock3 on NMDA receptors. We also discuss apoptosis signalregulating kinase 1 (ASK1), a member of mitogenactivated protein kinase kinase kinase that is a key regulator of cellular responses to oxidative stress, as an innovative therapeutic target for glaucoma.
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Effects of different neurotrophic factors on the survival of retinal ganglion cells after a complete intraorbital nerve crush injury: a quantitative in vivo study
(Elsevier, 2009-06-15) Parrilla Reverter, Guillermo; Agudo, Marta; Sobrado Calvo, Paloma; Villegas Pérez, María P.; Vidal Sanz, Manuel; Salinas Navarro, Manuel Ángel; Anatomía Humana y Psicobiología
We examined in adult Sprague Dawley rats the loss of retinal ganglion cells (RGCs) induced by complete intraorbital optic nerve crush (IONC) as well as the effects of several neurotrophic factors to prevent IONC-induced RGC loss. Completeness of the IONC lesion was assessed by investigating the orthograde and retrograde transport of neuronal tracers applied to the origin and termination of the retinotectal pathway. RGC survival after IONC alone or combined with intraocular injection of the neurotrophic factors NT-4, BDNF or CNTF was quantified at survival intervals ranging from 5 to 12 days post-lesion (dpl) by identifying RGCs that had been pre-labelled with fluorogold (FG). RGC loss first appeared at 7 dpl and by 12 dpl only 32% of the RGC population remained in the retina. Intraocular administration of NT-4, BDNF or CNTF resulted in almost a complete protection against IONC-induced RGC loss by 7 dpl, and the protection remained significant by 12 dpl only for NT-4 and BDNF. We have analyzed these results taking into account our previous studies on the loss of RGCs induced by intraorbital optic nerve transection (IONT) and concluded that RGC loss induced by IONC is slower and less severe than that following IONT. Moreover, as for IONT-induced RGC loss, IONC-induced RGC loss may also be prevented with administration of NT-4, BDNF or CNTF, though for NT-4 and CNTF their neuroprotective effects differ depending on the injury type. Overall this data underscore the importance of the type of ON injury on the pattern of RGC degeneration as well as in their response to neuroprotective treatments.
Open Access
Evaluation of the neuroprotective efficacy of the gramine derivative ITH12657 against NMDA-induced excitotoxicity in the rat retina
(Frontiers Media, 2024-02-13) Di Pierdomenico, Johnny; Gallego Ortega, Alejandro; Norte Muñoz, María; Vidal-Villegas, Beatriz; Bravo, Isaac; Boluda-Ruiz, María; Bernal-Garro, José Manuel; Fernández-Bueno, Iván; Pastor-Jimeno, Jose Carlos; Villegas Pérez, Maria Paz; Avilés Trigueros, Marcelino; Ríos, Cristobal de los; Vidal Sanz, Manuel; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultad de Óptica y Optometría
Purpose: The aim of this study was to investigate, the neuroprotective effects of a new Gramine derivative named: ITH12657, in a model of retinal excitotoxicity induced by intravitreal injection of NMDA. Methods: Adult Sprague Dawley rats received an intravitreal injection of 100 mM NMDA in their left eye and were treated daily with subcutaneous injections of ITH12657 or vehicle. The best dose–response, therapeutic window study, and optimal treatment duration of ITH12657 were studied. Based on the best survival of Brn3a + RGCs obtained from the above-mentioned studies, the protective effects of ITH12657 were studied in vivo (retinal thickness and full-field Electroretinography), and ex vivo by quantifying the surviving population of Brn3a + RGCs, αRGCs and their subtypes α-ONsRGCs, α-ONtRGCs, and α-OFFRGCs. Results: Administration of 10 mg/kg ITH12657, starting 12 h before NMDA injection and dispensed for 3 days, resulted in the best significant protection of Brn3a + RGCs against NMDA-induced excitotoxicity. In vivo, ITH12657-treated rats showed significant preservation of retinal thickness and functional protection against NMDA-induced retinal excitotoxicity. Ex vivo results showed that ITH12657 afforded a significant protection against NMDA-induced excitotoxicity for the populations of Brn3a + RGC, αRGC, and αONs-RGC, but not for the population of αOFF-RGC, while the population of α-ONtRGC was fully resistant to NMDA-induced excitotoxicity. Conclusion: Subcutaneous administration of ITH12657 at 10 mg/kg, initiated 12 h before NMDA-induced retinal injury and continued for 3 days, resulted in the best protection of Brn3a + RGCs, αRGC, and αONs-RGC against excitotoxicity-induced RGC death. The population of αOFF-RGCs was extremely sensitive while α-ONtRGCs were fully resistant to NMDA-induced excitotoxicity.
Open Access
Expression of activity-dependent neuroprotective protein in the brain of adult rats
(Murcia : F. Hernández, 2008) Gennet, N.; Herden, C.; Bubb, V.J.; Quinn, J.P.; Kipar, A.
Activity-dependent neuroprotective protein (ADNP) is a VIP-regulated gene, which is essential for brain development. A synthetic peptide (NAP) derived from the ADNP sequence is highly neuroprotective, therefore it has been hypothesised that ADNP has a similar role. ADNP contains classical transcription factor motifs and nuclear localisation domains, but it has also been reported to be secreted and to co-localise with microtubules, indicating that ADNP may have multiple functions. We investigated the pattern of ADNP expression by immunohistology in normal rat brain, in order to generate a framework for future studies examining changes in ADNP expression in response to noxious stimuli or in models of disease. We found widespread ADNP-like immunoreactivity in neurons throughout the rat brain, with the highest expression in the cerebellum, and strong expression in the thalamus, mesencephalon, pons and medulla oblongata. ADNPlike immunoreactivity was mainly observed in the cytoplasm of neurons, and fibre tracts were often strongly positive as well. In addition, positive neuronal nuclei were occasionally observed. ADNP-like immunoreactivity was lost in degenerating ‘dark’ neurons, the morphologically unaltered adjacent cells. Occasional astrocyte and microglial cells were also positive. We suggest that the widespread expression of ADNP may correlate with the wide-ranging protective effects of NAP, and that the cytoplasmic and axonal localisation of ADNP-like immunoreactivity suggests additional, nontranscriptional functions of ADNP
Open Access
Expression of EAAT1 reflects a possible neuroprotective function of reactive astrocytes and activated microglia following human traumatic brain injury
(Murcia : F. Hernández, 2007) Beschorner, R.; Dietz, K.; Schauer, N.; Mittelbronn, M.; Schluesener, H.J.; Trautmann, K.; Meyermann, R.; Simon, P.
Glutamate-mediated excitotoxicity is known to cause secondary brain damage following stroke and traumatic brain injury (TBI). However, clinical trials using NMDA antagonists failed. Thus, glial excitatory amino acid transporters (EAATs) might be a promising target for therapeutic intervention. Methods and Results. We examined expression of EAAT1 (GLAST) and EAAT2 (Glt-1) in 36 TBI cases by immunohistochemistry. Cortical expression of both EAATs decreased rapidly and widespread throughout the brain (in lesional, adjacent and remote areas) following TBI. In the white matter numbers of EAAT1+ parenchymal cells increased 39-fold within 24h (p<0.001) and remained markedly elevated till later stages in the lesion (90-fold, p<0.01) and in peri-lesional regions (86-fold, p<0.01). In contrast, EAAT2+ parenchymal cells and EAAT1+ or EAAT2+ perivascular cells did not increase significantly. Within the first days following TBI mainly activated microglia and thereafter mainly reactive astrocytes expressed EAAT1. Perivascular monocytes and foamy macrophages lacked EAAT1 immunoreactivity. We conclude that following TBI i) loss of cortical EAATs contributes to secondary brain damage, ii) glial EAAT1 expression reflects a potential neuroprotective function of microglia and astrocytes, iii) microglial EAAT1 expression is restricted to an early stage of activation, iv) blood-derived monocytes do not express EAAT1 and v) pharmacological modification of glial EAAT expression might further limit neuronal damage.
Open Access
Human Wharton’s jelly mesenchymal stem cells protect axotomized rat retinal ganglion cells via secretion of antiinflammatory and neurotrophic factors
(Springer Nature, 2018-11-02) Millán-Rivero, J.E; Sobrado-Calvo, P.; Blanquer, M.; Moraleda, J.M.; Vidal-Sanz, M.A.; Agudo-Barriuso, M.; Nadal-Nicolás, Francisco Manuel; García Bernal, David; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica
El artículo muestra los resultados del estudio de la capacidad neuroprotectora de las células mesenquimales derivadas de cordón umbilical (CMCU) sobre las células ganglionares de la retina (CGR) tras axotomía por aplastamiento del nervio óptico. Se quería saber, no solo si existía efecto neuroprotector, si no también si el trasplante de estas células tenía algún efecto tóxico en retina, y dilucidar los posibles mecanismos a través de los cuales se produjeran estos efectos. En una primera parte del estudio, demostramos que las CMCU suprimen la proliferación de células T e inhiben la producción de citocinas proinflamatorias, confirmando que su efecto inmunomodulador es mayor que el de las células mesequimales derivadas de médula ósea. También observamos que tras la inyección intravítrea de CMCU, estas se integran en la capa de CGR, extendiéndose por toda la retina, observándose una reducción importante a los 30 días, y no observando la formación de tumoración. En retinas intactas no se observó efecto tóxico sobre las CGR, si bien sí hubo alteración de la arquitectura de la retina por la infiltración masiva de células Iba1+ (microglía o macrófagos), que se reduce mucho a los 30 días y da señales de restauración de dicha arquitectura. Por otra parte, en retinas axotomizadas se encontró un aumento muy importante de la supervivencia de las CGR de los animales tratados.
Open Access
In vitro, in vivo, and in silico evidence for the use of plant pigments betalains as potential nutraceuticals against Alzheimer’s disease
(Wiley, 2024-07-24) Martínez-Rodriguez, Pedro; Henarejos Escudero, Paula; Hernández García, Samanta; Gandía Herrero, Fernando; Sánchez Ferrer, Álvaro; Bioquímica y Biología Molecular A
Anti-amyloidogenic properties of plant pigments betalains as potential nutraceuticals against Alzheimer’s disease have been screened using 24 pure molecules. Twenty-two betalains reduced amyloid aggregation in vitro, eight of them up to 100%, with IC 50values in the micromolar range. Atomic force and transmission electron microscopy images showed the typical fibrils associated with Alzheimer’s disease and how beta-lains avoid its formation. Neuroprotection after ingestion was supported by in vivo experiments with Caenorhabditis elegans. Indoline-betacyanin was the most effective molecule by significantly improving the chemotactic behavior of the CL2355 strain,a model of Alzheimer’s disease. Furthermore, in-depth molecular docking analyses revealed that the pigments interact with the N-terminal region of the amyloid pep-tide. This work is the most comprehensive study in the field and provides in vitro, in vivo, and in silico evidence for the use of betalains as nutraceuticals of relevance in theprevention of Alzheimer’s disease
Open Access
Intranasal administration: a potential solution for cross-BBB delivering neurotrophic factors
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Zhu, Juehua; Jiang, Yongjun; Xu, Gelin; Liu, Xinfeng
Neurotrophic factors (NTFs) are endogenous polypeptides that regulate the growth, survival, differentiation, and functioning of neurons. The neuroprotective effects of NTFs in experimental animals give strong rationale for developing therapies for neurological disorders. However, when NTFs are applied in clinical trials, great expectation leads to equal disappointment. NTFs are large molecular-weighted and hydrophilic proteins, which limits their access to the central nervous system (CNS) after systemic administration, principally due to poor blood-brain barrier (BBB) permeability and unfavorable pharmacokinetic profiles. Although intracerebral infusion may transport NTFs into the CNS, the invasiveness limits its clinical application. Intranasal administration has been under research for decades and presents promising outcomes in preclinical studies for brain delivering of NTFs. After intranasal delivery, NTFs gain direct and quick access into the CNS at concentrations high enough to elicit their biological effects, bypassing the BBB and minimizing systemic exposure. Due to its invasiveness and convenience, intranasal delivery is feasible for NTFs administration. Although direct evidence of nose-to-brain pathway in human is lacking due to ethical problems, the existence of the nose-to-cerebral spinal fluid pathway has been verified in men. Furthermore, there is abundant indirect evidence for the nose-to-brain pathway as determined by the efficacy of intranasally administered neuroproteins, such as insulin, oxytocin, and vasopressin in clinical trials. Based on the solid preclinical research supporting the efficacy of intranasal NTFs, and the successful clinical application of neuroproteins (not NTFs), it is time to evaluate clinical application of NTFs in treating both acute and chronic CNS diseases
Open Access
Ketorolac Administration Attenuates Retinal Ganglion Cell Death After Axonal Injury
(Association for Research in Vision and Ophthalmology., 2016-03) Nadal-Nicolás, Francisco Manuel; Rodríguez-Villagra, Esther; Bravo-Osuna, Irene; Sobrado-Calvo, Paloma; Molina-Martínez, Irene; Villegas Pérez, Maria Paz; Vidal Sanz, Manuel; Agudo Barriuso, Marta; Herrero-Vanrell, Rocío; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultad de Medicina
Purpose: To assess the neuroprotective effects of ketorolac administration, in solution or delivered from biodegradable microspheres, on the survival of axotomized retinal ganglion cells (RGCs). Methods: Retinas were treated intravitreally with a single injection of tromethamine ketorolac solution and/or with ketorolac-loaded poly(D,L-lactide-co-glycolide) (PLGA) microspheres. Ketorolac treatments were administered either 1 week before optic nerve crush (pre-ONC) or right after the ONC (simultaneous). In all cases, animals were euthanized 7 days after the ONC. As control, nonloaded microspheres or vehicle (balanced salt solution, BSS) were administered in parallel groups. All retinas were dissected as flat mounts; RGCs were immunodetected with brain-specific homeobox/POU domain protein 3A (Brn3a), and their number was automatically quantified. Results: The percentage of Brn3a+RGCs was 36% to 41% in all control groups (ONC with or without BSS or nonloaded microparticles). Ketorolac solution administered pre-ONC resulted in 63% survival of RGCs, while simultaneous administration promoted a 53% survival. Ketorolac-loaded microspheres were not as efficient as ketorolac solution (43% and 42% of RGC survival pre-ONC or simultaneous, respectively). The combination of ketorolac solution and ketorolac-loaded microspheres did not have an additive effect (54% and 55% survival pre-ONC and simultaneous delivery, respectively). Conclusions: Treatment with the nonsteroidal anti-inflammatory drug ketorolac delays RGC death triggered by a traumatic axonal insult. Pretreatment seems to elicit a better output than simultaneous administration of ketorolac solution. This may be taken into account when performing procedures resulting in RGC axonal injury.
Open Access
Melatonin and cannabinoids: mitochondrial-targeted molecules that may reduce inflammaging in neurodegenerative diseases
(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2020) García, Sebastián; Martín Giménez, Virna Margarita; Mocayar Marón, Feres José; Reiter, Russel J.; Manucha, Walter
Generally, the development and progression of neurodegenerative diseases are associated with advancing age, so they are usually diagnosed in late adulthood. A primary mechanism underlying the onset of neurodegenerative diseases is neuroinflammation. Based on this background, the concept of "neuroinflammaging" has emerged. In this deregulated neuroinflammatory process, a variety of immune cells participate, especially glial cells, proinflammatory cytokines, receptors, and subcellular organelles including mitochondria, which are mainly responsible for maintaining redox balance at the cellular level. Senescence and autophagic processes also play a crucial role in the neuroinflammatory disease associated with aging. Of particular interest, melatonin, cannabinoids, and the receptors of both molecules which are closely related, exert beneficial effects on the neuro- inflammatory processes that precede the onset of neurodegenerative pathologies such as Parkinson's and Alzheimer's diseases. Some of these neuroprotective effects are fundamentally related to its anti- inflammatory and antioxidative actions at the mitochondrial level due to the strategic functions of this organelle. The aim of this review is to summarize the most recent advances in the study of neuroinflammation and neurodegeneration associated with age and to consider the use of new mitochondrial therapeutic targets related to the endocannabinoid system and the pineal gland.
Open Access
Mesenchymal stromal cell therapy for damaged retinal ganglion cells, is gold all that glitters?
(Wolters Kluwer – Medknow Publications, 2019-11-01) Lucas Ruiz, Fernando; Galindo Romero, Caridad; García Bernal, David; Norte Muñoz, María; Rodríguez Ramírez, Kristy T.; Salinas Navarro, Manuel Ángel; Millán Rivero, José E.; Vidal Sanz, Manuel; Agudo Barriuso, Marta; Anatomía Humana y Psicobiología
Mesenchymal stromal cells are an excellent source of stem cells because they are isolated from adult tissues or perinatal derivatives, avoiding the ethical concerns that encumber embryonic stem cells. In preclinical models, it has been shown that mesenchymal stromal cells have neuroprotective and immunomodulatory properties, both of which are ideal for central nervous system treatment and repair. Here we will review the current literature on mesenchymal stromal cells, focusing on bone marrow mesenchymal stromal cells, adipose-derived mesenchymal stromal cells and mesenchymal stromal cells from the umbilical cord stroma, i.e., Wharton’s jelly mesenchymal stromal cells. Finally, we will discuss the use of these cells to alleviate retinal ganglion cell degeneration following axonal trauma.
Open Access
Optogenetic Stimulation of the Superior Colliculus Confers Retinal Neuroprotection in a Mouse Glaucoma Model
(Society for Neuroscience, 2019-03-20) Geeraerts, Emiel ; Claes, Marie ; Dekeyster, Eline; Salinas Navarro, Manuel Ángel; De Groef, Lies ; Van den Haute, Chris ; Scheyltjens, Isabelle ; Baekelandt, Veerle ; Arckens, Lutgarde ; Moons, Lieve ; Anatomía Humana y Psicobiología; Facultades de la UMU::Facultad de Medicina
Glaucoma is characterized by a progressive loss of retinal ganglion cells (RGCs) in the eye, which ultimately results in visual impairment or even blindness. Because current therapies often fail to halt disease progression, there is an unmet need for novel neuroprotective therapies to support RGC survival. Various research lines suggest that visual target centers in the brain support RGC functioning and survival. Here, we explored whether increasing neuronal activity in one of these projection areas could improve survival of RGCs in a mouse glaucoma model. Prolonged activation of an important murine RGC target area, the superior colliculus (SC), was established via a novel optogenetic stimulation paradigm. By leveraging the unique channel kinetics of the stabilized step function opsin (SSFO), protracted stimulation of the SC was achieved with only a brief light pulse. SSFO-mediated collicular stimulation was confirmed by immunohistochemistry for the immediate-early gene c-Fos and behavioral tracking, which both demonstrated consistent neuronal activity upon repeated stimulation. Finally, the neuroprotective potential of optogenetic collicular stimulation was investigated in mice of either sex subjected to a glaucoma model and a 63% reduction in RGC loss was found. This work describes a new paradigm for optogenetic collicular stimulation and a first demonstration that increasing target neuron activity can increase survival of the projecting neurons.
Open Access
Restorative potential of ciliary body cells in a retinal ganglion cell degeneration model
(Nature Research, 2025-05-03) Fernández-Nogales, Marta; Herrera, Macarena; Herrera, Eloisa ; Lucas Ruiz, Fernando; Valiente Soriano, Francisco Javier; Nadal-Nicolás, Francisco Manuel; Agudo Barriuso, Marta; Lucas Ruiz, Fernando; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultades de la UMU::Facultad de Medicina
The ciliary body (CB) has been proposed as a niche of neural stem cells because, in vitro, cells from this area are able to form neurospheres, proliferate and differentiate. Here, we explore the potential of CB cells to differentiate and replace degenerated retinal ganglion cells (RGCs) in vivo. CB cells and cells from the subventricular zone (SVZ) were isolated from adult or postnatal C57BL/6Tg(CAG-EGFP) mice, respectively, and intravitreally injected into intact retinas, immediately after optic nerve crush or 45 days after the lesion of adult C57/BL/6 mice. Retinas were analysed in whole mounts or cross sections at different time points. Controls were matched untreated retinas. Neither cell type caused gliosis or toxicity when injected into intact retinas. When CB or SVZ cells were injected right after axotomy, they formed an epimembrane without integrating in the retina. However, when CB cells were administered in retinas depleted of RGCs, they integrated into the ganglion cell layer and expressed RGC and neuronal markers. Although SVZ cells were also able to integrate into RGC depleted retinas they did so more slowly than CB cells. These results shed light in the long-standing question of whether cells in the CB have the potential to transdifferentiate in vivo and point to the CB as a suitable source of cells that could be used in cell-replacement therapies for neurodegenerative diseases of the retina.
Open Access
Role of Müller glia in neuroprotection and regeneration in the retina
(Murcia : F. Hernández, 2003) García, M.; Vecino, E.
Glial cells are thought to protect neurons from various neurological insults. When there is injury to retina, Müller cells, which are the predominant glial element in the retina, undergo significant morphological, cellular and molecular changes. Some of these changes reflect Müller cell involvement in protecting the retina from further damage. Müller cells express growth factors, neurotransmitter transporters and antioxidant agents that could have an important role in preventing excitotoxic damage to retinal neurons. Moreover, Müller cells contact to endothelial cells to facilitate the neovascularization process during hypoxic conditions. Finally, recent studies have pointed to a role of Müller cells in retina regeneration after damage, dedifferentiating to progenitor cells and then giving rise to different neuronal cell types. In this article we will review the role of Müller glia in neuroprotection and regeneration after damage in the retina.
Open Access
Systemic and Intravitreal Antagonism of the TNFR1 Signaling Pathway Delays Axotomy-Induced Retinal Ganglion Cell Loss
(Frontiers Media, 2019-10-15) Lucas Ruiz, Fernando; Galindo Romero, Caridad; Salinas Navarro, Manuel Ángel; González Riquelme, María Josefa; Vidal Sanz, Manuel; Agudo Barriuso, Marta; Anatomía Humana y Psicobiología
Here, we have blocked the signaling pathway of tumor necrosis factor α (TNFα) in a mouse model of traumatic neuropathy using a small cell permeable molecule (R7050) that inhibits TNFα/TNF receptor 1 (TNFR1) complex internalization. Adult pigmented mice were subjected to intraorbital optic nerve crush (ONC). Animals received daily intraperitoneal injections of R7050, and/or a single intravitreal administration the day of the surgery. Some animals received a combinatorial treatment with R7050 (systemic or local) and a single intravitreal injection of brain derived neurotrophic factor (BDNF). As controls, untreated animals were used. Retinas were analyzed for RGC survival 5 and 14 days after the lesion i.e., during the quick and slow phase of axotomy-induced RGC death. qPCR analyses were done to verify that Tnfr1 and TNFα were up-regulated after ONC. At 5 days post-lesion, R7050 intravitreal or systemic treatment neuroprotected RGCs as much as BDNF alone. At 14 days, RGC rescue by systemic or intravitreal administration of R7050 was similar. At this time point, intravitreal treatment with BDNF was significantly better than intravitreal R7050. Combinatory treatment was not better than BDNF alone, although at both time points, the mean number of surviving RGCs was higher. In conclusion, antagonism of the extrinsic pathway of apoptosis rescues axotomized RGCs as it does the activation of survival pathways by BDNF. However, manipulation of both pathways at the same time, does not improve RGC survival.
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Systemic treatment with 7,8-Dihydroxiflavone activates TtkB and affords protection of two different retinal ganglion cell populations against axotomy in adult rats
(Elsevier, 2021-07-08) Vidal-Villegas, Beatriz; Di Pierdomenico, Johnny; Gallego Ortega, Alejandro; Galindo Romero, Caridad; Martínez-de-la-Casa, José M.; García-Feijoo, Julián; Villegas Pérez, Maria Paz; Vidal Sanz, Manuel; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultad de Óptica y Optometría
Purpose: To analyze responses of different RGC populations to left intraorbital optic nerve transection (IONT) and intraperitoneal (i.p.) treatment with 7,8-Dihydroxyflavone (DHF), a potent selective TrkB agonist. Methods: Adult albino Sprague-Dawley rats received, following IONT, daily i.p. injections of vehicle (1%DMSO in 0.9%NaCl) or DHF. Group-1 (n = 58) assessed at 7days (d) the optimal DHF amount (1–25 mg/kg). Group-2, using freshly dissected naïve or treated retinas (n = 28), investigated if DHF treatment was associated with TrkB activation using Western-blotting at 1, 3 or 7d. Group-3 (n = 98) explored persistence of protection and was analyzed at survival intervals from 7 to 60d after IONT. Groups 2–3 received daily i.p. vehicle or DHF (5 mg/kg). Retinal wholemounts were immunolabelled for Brn3a and melanopsin to identify Brn3a+RGCs and m+RGCs, respectively. Results: Optimal neuroprotection was achieved with 5 mg/kg DHF and resulted in TrkB phosphorylation. The percentage of surviving Brn3a+RGCs in vehicle treated rats was 60, 28, 18, 13, 12 or 8% of the original value at 7, 10, 14, 21, 30 or 60d, respectively, while in DHF treated retinas was 94, 70, 64, 17, 10 or 9% at the same time intervals. The percentages of m+RGCs diminished by 7d–13%, and recovered by 14d–38% in vehicle-treated and to 48% in DHF-treated retinas, without further variations. Conclusions: DHF neuroprotects Brn3a + RGCs and m + RGCs; its protective effects for Brn3a+RGCs are maximal at 7 days but still significant at 21d, whereas for m+RGCs neuroprotection was significant at 14d and permanent.
Open Access
The action of 7,8-dihydroxyflavone preserves retinal ganglion cell survival and visual function via the TrkB pathway in NMDA-induced retinal excitotoxicity
(Elsevier, 2025-03-08) Gallego Ortega, Alejandro; Galindo Romero, Caridad; Vidal-Villegas, Beatriz; Bernal-Garro, José Manuel; Villa, Pedro de la; Avilés Trigueros, Marcelino; Vidal Sanz, Manuel; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultad de Óptica y Optometría
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The S1P1 receptor-selective agonist CYM-5442 protects retinal ganglion cells in endothelin-1 induced retinal ganglion cell loss
(Elsevier, 2017-08-04) Blanco, Román; Martínez Navarrete, Gema; Valiente Soriano, Francisco J.; Avilés Trigueros, Marcelino; Pérez Rico, Consuelo; Serrano Puebla, Ana; Boya, Patricia; Fernández, Eduardo; Vidal Sanz, Manuel; Villa, Pedro de la; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica
We investigated the feasibility and efficacy of using a specific sphingosine 1–phosphate (S1P1) receptor agonist, CYM-5442, to slow or block retinal ganglion cell (RGC) loss in endothelin-1 (ET-1) induced RGC loss. A single intravitreal injection of ET-1 (20pmol/ul), a potent vasoactive peptide that produces retinal vessels vasoconstriction, was used to induce and characterize RGC-specific cell death. CYM-5442 (1 mgr/kg) or vehicle was administered intraperitoneally for five consecutive days after ET-1-induced RGC loss. The functional extent of RGC loss injury was evaluated with pattern visual evoked potentials (VEP) and electroretinography. RGCs and retinal nerve fiber layer (RNFL) thickness were assessed in vivo using optical coherence tomography and ex vivo using Brn3a immunohistochemistry in flat-mounted retinas. ET-1 caused significant RGC loss and function loss one week after intravitreal injection. VEP showed preserved visual function after CYM-5442 administration compared to vehicle-treated animals (11.95 ± 0.86 μV vs 3.47 ± 1.20 μV, n = 12) (p < 0.05). RNFL was significantly thicker in the CYM treated-animals compared to the vehicle (93.62 ± 3.22 μm vs 77.72 ± 0.35 μm, n = 12) (p < 0.05). Furthermore, Brn3a immunohistochemistry validated this observation, showing significantly higher RGCs numbers in CYM treated rats than in the vehicle group (76,540 ± 303 vs 52,426 ± 1,932 cells/retina, n = 9) (p = 0.05). CYM-5442 administration was associated with significant retinal cleaved caspase-3 deactivation, indicating reduced apoptotic levels. The results of the present study further demonstrate the important role of S1P1 receptor agonists to lessen intravitreal ET-1 induced RGC loss.
Open Access
Toxicity of non-steroidal anti-inflammatory drugs: a review of melatonin and diclofenac sodium association
(F. Hernández y Juan F. Madrid. Universidad de Murcia: Departamento de Biología Celular e Histología, 2012) Aygün, Dursun; Kaplan, Süleyman; Odaci, Ersan; Onger, Mehmet E.; Altunkaynak, M. Eyüp
Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used for the purpose of anti-inflammation, antipyretic, and analgesia. For this aim, they are used for the alleviation of pain, fever, and inflammation associated with rheumatoid arthritis, sports injuries, and temporary pain. However, treatment with NSAIDs may be accompanied by adverse effects such as gastrointestinal damage and platelet dysfunction. As with the other NSAIDs, diclofenac sodium (sodium-(o-((2,6-dichlorophenyl)-amino)-phenyl)-acetate) (DS), an NSAID, has potent anti-inflammatory, analgesic, and antipyretic effects. However, treatment with DS may cause some adverse cerebral and cerebellar effects such as convulsions, disorientation, hallucination, and loss of consciousness. Melatonin (MLT) is a free-radical scavenger and possesses antioxidant properties. It has been reported to easily cross the blood-brain barrier, and is found in high concentrations in the brain after exogenous administration. It is also a neuroprotector in a wide range of conditions affecting the central nervous system CNS due to its free-radical scavenging activities and lipophilic-hydrophilic properties. Neuroprotective actions of MLT have been discovered in both in vitro and in vivo, and are a powerful scavenger of oxygen and nitrogen free radicals. Thus, MLT can protect the cell membrane, organelles, and core against free-radical damage. Therefore, it has been postulated that exogenous MLT acts as a neuroprotector contrary to DS neurotoxicity. In this review, we aimed to discuss the possible neuroprotective effects of MLT on DS toxicity