Browsing by Subject "BDNF"
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- PublicationOpen AccessApoptotic 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 MedicinaPurpose: 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.
- PublicationRestrictedBrain derived neurotrophic factor maintains Brn3a expression in axotomized rat retinal ganglion cells(Elsevier, 2009-08-16) Sánchez Migallón, María del Cielo; Nadal-Nicolás, Francisco Manuel; Jiménez López, Manuel; Sobrado Calvo, Paloma; Vidal Sanz, Manuel; Agudo Barriuso, Marta; Oftalmología, Optometría, Otorrinolaringología y Anatomía Patológica; Facultades de la UMU::Facultad de MedicinaThe transcription factor Brn3a has been reported to be a good marker for adult rat retinal ganglion cells in control and injured retinas. However, it is still unclear if Brn3a expression declines progressively by the injury itself or otherwise its expression is maintained in retinal ganglion cells that, though being injured, are still alive, as might occur when assessing neuroprotective therapies. Therefore, we have automatically quantified the whole population of surviving Brn3a positive retinal ganglion cells in retinas subjected to intraorbital optic nerve transection and treated with either brain derived neurotrophic factor or vehicle. Brain derived neurotrophic factor is known to delay retinal ganglion cell death after axotomy. Thus, comparison of both groups would inform of the suitability of Brn3a as a retinal ganglion cell marker when testing neuroprotective molecules. As internal control, retinal ganglion cells were, as well, identified in all retinas by retrogradely tracing them with fluorogold. Our data show that at all the analyzed times post-lesion, the numbers of Brn3a positive retinal ganglion cells and of fluorogold positive retinal ganglion cells are significantly higher in the brain derived neurotrophic factor-treated retinas compared to the vehicle-treated ones. Moreover, detailed isodensity maps of the surviving Brn3a positive retinal ganglion cells show that a single injection of brain derived neurotrophic factor protects retinal ganglion cells throughout the entire retina. In conclusion, Brn3a is a reliable retinal ganglion cell marker that can be used to accurately measure the potential effect of a given neuroprotective therapy.
- PublicationRestrictedEffects 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 PsicobiologíaWe 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.
- PublicationOpen AccessMaternal exposure to the environmental pollutant "BDE-47" impairs the postnatal development of rat cerebellar cortex by modulating neuronal proliferation, synaptogenesis, NGF and BDNF pathways(Universidad de Murcia, Departamento de Biologia Celular e Histiologia, 2022) Mandour, Dalia A.; Tolba, Asmaa M; El Bestawy, Emtethal M.. 2,2’,4,4’-Tetrabromodiphenyl ether (BDE47) is an environmental contaminant that crosses the blood placental barrier and interferes with the homeostasis of fetal thyroid hormones. Aim of work. This study was designed to investigate the perinatal effect of BDE-47 exposure on the postnatal development of the rat cerebellar cortex. Materials and methods. This study was carried out on 20 pregnant rats and 36 of their offspring. The pregnant rats were divided equally into control and BDE-47 treated mother groups; supplemented orally with BDE-47 (0.2 mg/kg/day from day 8 of gestation until the day of weaning). The offspring of both mother groups were subdivided, according to their developmental age, into three subgroups; PND14, PND21and PND42. SerumT3, T4 and TSH were assessed for dams and their offspring. Testing the motor coordination of the offspring via the rotarod test was conducted. Sections of the cerebellar cortex from offspring subgroups were stained with hematoxylin and eosin alongside immunohistochemical reactions and optical density of nerve growth factor (NGF), brain derived neurotrophic factor (BDNF), proliferating cell nuclear antigen (PCNA) and synaptophysin (SYN) were assessed. Also, the thickness of different layers of the cerebellar cortex was histomorphometrically measured. Results. BDE-47 treated mothers and their offspring subgroups showed a significant decrease in the serum free T3, T4 and increased TSH. The BDE-47 offspring displayed incoordination of the motor activity together with disturbed cytoarchitecture of the cerebellar cortical layers, and impaired migration of its germinative neuronal zones, particularly on PND14 and PND21. Moreover, these offspring displayed a decrease of the immune-expression and optical density of NGF, BDNF in the cerebellar cortical layers with impaired proliferation, and synaptogenesis. Conclusion. Maternal exposure to BDE-47 during pregnancy and lactation effectuated a potential deleterious retarding effect on the postnatal development of the rat cerebellar cortex mostly via modulating neuronal proliferation, synaptogenesis, NGF and BDNF pathways secondary to its hypothyroid effect.
- PublicationOpen AccessMorphological alterations in the hippocampus of the Ts65Dn mouse model for Down syndrome correlate with structural plasticity markers(Universidad de Murcia. Departamento de Biología Celular e Histología, 2018) Villarroya, Olga; Ballestín, Raúl; López Hidalgo, Rosa; Mulet, Maria; Blasco Ibáñez, José Miguel; Crespo, Carlos; Nacher, Juan; Gilabert Juan, Javier; Varea, EmilioDown syndrome (DS) is the most common chromosomal aneuploidy. Although trisomy on chromosome 21 can display variable phenotypes, there is a common feature among all DS individuals: the presence of intellectual disability. This condition is partially attributed to abnormalities found in the hippocampus of individuals with DS and in the murine model for DS, Ts65Dn. To check if all hippocampal areas were equally affected in 4-5 month adult Ts65Dn mice, we analysed the morphology of dentate gyrus granule cells and cornu ammonis pyramidal neurons using Sholl method on Golgi-Cox impregnated neurons. Structural plasticity has been analysed using immunohistochemistry for plasticity molecules followed by densitometric analysis (Brain Derived Neurotrophic Factor (BDNF), Polysialylated form of the Neural Cell Adhesion Molecule (PSA-NCAM) and the Growth Associated Protein 43 (GAP43)). We observed an impairment in the dendritic arborisation of granule cells, but not in the pyramidal neurons in the Ts65Dn mice. When we analysed the expression of molecules related to structural plasticity in trisomic mouse hippocampus, we observed a reduction in the expression of BDNF and PSA-NCAM, and an increment in the expression of GAP43. These alterations were restricted to the regions related to dentate granule cells suggesting an interrelation. Therefore the impairment in dendritic arborisation and molecular plasticity is not a general feature of all Down syndrome principal neurons. Pharmacological manipulations of the levels of plasticity molecules could provide a way to restore granule cell morphology and function.
- PublicationOpen AccessSystemic 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 PsicobiologíaHere, 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.