Funciones no visuales de la retina: Razones para cuidar la retina en la ceguera total

La retina es una porción del sistema nervioso central formada por una red de neuronas especializadas que se localiza tapizando el interior del globo ocular. En este tejido, los estímulos luminosos desencadenan respuestas eléctricas y químicas que activan diferentes vías paralelas de transmisión de la información hacia distintas áreas del sistema nervioso. La vía clásica visual, “formadora de imágenes”, se inicia con el proceso de transformación de las señales luminosas en impulsos eléctricos a nivel de los fotorreceptores clásicos, conos y bastones. Las células ganglionares de la retina son las encargadas de enviar la información desde la retina al cerebro a través de sus axones, que forman el nervio óptico

THE EFFECT OF A HAMSTRING STRECHING PROTOCOL ON HAMSTRING EXTENSIBIITY IN ADOLESCENT STUDENTS: INFLUENCE OF THE CLASS SESSION WEEKLY DISTRIBUTION

Introducción: la realización de estiramientos de la musculatura isquiosural, dos sesiones por semana en días alternos, produce mejoras significativas en escolares. Objetivo: comparar los efectos de un programa de estiramientos de la musculatura isquiosural realizado en las clases de educación física en dos grupos de adolescentes, en función de la distribución semanal de sus sesiones de clase (sesiones alternas vs. sesiones consecutivas). Metodología: cincuenta y ocho estudiantes adolescentes realizaron un programa de estiramientos estático-activos de la musculatura isquiosural durante cinco semanas, ejecutados al comienzo de dos clases semanales de educación física, con una duración total de cinco minutos. Los alumnos fueron divididos en dos grupos: el grupo A, formado por 30 alumnos, tenían las clases en días consecutivos (lunes-martes) y el grupo B, compuesto por 29 alumnos, en días no consecutivos (martes-viernes). La extensibilidad de la musculatura isquiosural se evalúo mediante el test sit-and-reach antes del inicio del programa (pre-test) y tras finalizar el mismo (post-test). Resultados y discusión: se encontró una mejora significativa de la distancia alcanzada en el test sit-and-reach tanto en el grupo A (+2,15 cm) (p = 0,003) como en el grupo B (+2,31 cm) (p 0,05). Conclusiones: la aplicación de un programa de intervención con una duración de cinco semanas y una frecuencia de dos sesiones semanales produce mejoras en la extensibilidad isquiosural en escolares. La distribución semanal de las sesiones no influye en los resultados encontrados.Introduction: students who do hamstring stretching exercises, twice per week on alternate days, have showed significant increases on extensibility. Objetive: to compare the effects of a hamstring stretching program includes in the physical education classes in booth groups of adolescent, which had a different class session weekly distribution (non-consecutive sessions vs. consecutive sessions). Method: fifty-eight adolescent students did a static-active stretching program on hamstring in the warm-up of both weekly physical education sessions for five weeks. The total duration of the stretching was five minutes. Students were divided in two groups: group A, with 30 students, had consecutive sessions (monday-tuesday), and the group B, with 29 students, had non-consecutive sessions (tuesday-friday). Hamstring extensibility was evaluated with the sit-and-reach test before (pre-test) and after (post-test) the intervention program. Results and discussion: there was found a significant increase in the sit-and-reach score in the group A (+2,15 cm) (p = 0.003) and in the group B (+2,31 cm) (p 0.05). Conclusions: the implementation of an intervention program for five weeks, twice sessions a week, induded increases on hamstring extensibility in students. The class session weekly distribution does not affect the results.Actividad Física y Deport

Neuroprotective Effects of Tauroursodeoxicholic Acid Involves Vascular and Glial Changes in Retinitis Pigmentosa Model

Purpose: Retinitis pigmentosa is primarily characterized by a massive photoreceptor loss. But a global retinal remodeling occurs in later stages of the disease. At that phase, glial cells and retinal vasculature are also strongly affected. The main aim of the present work is to assess if the bile acid Tauroursodeoxicholic acid (TUDCA), which has a demonstrated neuroprotective effect in numerous neurodegenerative diseases, is able to prevent glial and vascular degeneration in the P23H rat retina. Methods: Homozygous P23H (line 3) animals were injected weekly with a TUDCA (500 mg/kg, i.p.) or vehicle solution, from the postnatal day (P) 21 to P120. Sprague-Dawley rats (SD) were used as control. Retinal cross-sections and wholemounts were immunostained using different glial and vascular markers and visualized with confocal microscopy. Retinal blood vessels were stained with nicotinamide adenine dinucleotide phosphate (NADPH) diaphorase histochemistry and retinal vascular networks were drawn by hand using a camera lucida. Results: At P120, the photoreceptor degeneration observed in P23H rats was accompanied by a reduction in the vascular network density and complexity at the deep capillary plexus. In addition, astrocytes showed gliotic features and the outer processes of Müller cells displayed an aberrant distribution in ring-shaped structures. When treated with TUDCA, P23H rats displayed better-preserved vessels and capillary loops in the deep capillary plexus which are associated with the partial preservation of photoreceptors. TUDCA treatment also increased the number of astrocytes and reduced the presence of Müller cell process clusters in the outer retina. Conclusion: This work suggests that, besides its neuroprotective effect on photoreceptor cells, TUDCA treatment also protects from vascular and glial degeneration, a fact that encourages the use of TUDCA as a powerful therapy for neurodegenerative diseases.The authors also acknowledge support from grants funded by the Spanish Ministry of Science and Innovation (FEDER-PID2019-106230RB-I00), Spanish Ministry of Universities (FPU18/02964), National Institute of Health Carlos III (RETICS-FEDER RD16/0008/0016), and Generalitat Valenciana (IDIFEDER/2017/064, PROMETEO/2021/024, GV/2020/028, and APOSTD/2020/245)

Natural Compounds from Saffron and Bear Bile Prevent Vision Loss and Retinal Degeneration

All retinal disorders, regardless of their aetiology, involve the activation of oxidative stress and apoptosis pathways. The administration of neuroprotective factors is crucial in all phases of the pathology, even when vision has been completely lost. The retina is one of the most susceptible tissues to reactive oxygen species damage. On the other hand, proper development and functioning of the retina requires a precise balance between the processes of proliferation, differentiation and programmed cell death. The life-or-death decision seems to be the result of a complex balance between pro- and anti-apoptotic signals. It has been recently shown the efficacy of natural products to slow retinal degenerative process through different pathways. In this review, we assess the neuroprotective effect of two compounds used in the ancient pharmacopoeia. On one hand, it has been demonstrated that administration of the saffron constituent safranal to P23H rats, an animal model of retinitis pigmentosa, preserves photoreceptor morphology and number, the capillary network and the visual response. On the other hand, it has been shown that systemic administration of tauroursodeoxycholic acid (TUDCA), the major component of bear bile, to P23H rats preserves cone and rod structure and function, together with their contact with postsynaptic neurons. The neuroprotective effects of safranal and TUDCA make these compounds potentially useful for therapeutic applications in retinal degenerative diseases.This research was supported by grants from the Spanish Ministry of Economy and Competitiveness-FEDER (BFU2012-36845), Instituto de Salud Carlos III (RETICS RD12/0034/0010), Asociación Retina Asturias, Fundación Jesús Gangoiti, Organización Nacional de Ciegos Españoles (ONCE) and FUNDALUCE

Persistent inflammatory state after photoreceptor loss in an animal model of retinal degeneration

Microglia act as the resident immune cells of the central nervous system, including the retina. In response to damaging stimuli microglia adopt an activated state, which can progress into a phagocytic phenotype and play a potentially harmful role by eliciting the expression and release of pro-inflammatory cytokines. The aim of the present study was to assess longitudinal changes in microglia during retinal degeneration in the homozygous P23H rat, a model of dominant retinitis pigmentosa. Microglial phenotypes, morphology and density were analyzed by immunohistochemistry, flow cytometry, and cytokine antibody array. In addition, we performed electroretinograms to evaluate the retinal response. In the P23H retina, sclera, choroid and ciliary body, inflammatory cells increased in number compared with the control at all ages analyzed. As the rats became older, a higher number of amoeboid MHC-II+ cells were observed in the P23H retina, which correlated with an increase in the expression of pro-inflammatory cytokines. These findings suggest that, in the P23H model, retinal neuroinflammation persists throughout the rat’s life span even after photoreceptor depletion. Therefore, the inclusion of anti-inflammatory drugs at advanced stages of the neurodegenerative process may provide better retinal fitness so the remaining cells could still be used as targets of cellular or gene therapies.This work was supported by grants from the Spanish Ministry of the Economy and Competitiveness-FEDER (BFU2012-36845, BFU2015-67139-R), Instituto de Salud Carlos III (RETICS-FEDER RD12/0034/0010), Organización Nacional de Ciegos Españoles (ONCE), Asociación Retina Asturias, FUNDALUCE and Fundación Jesús de Gangoiti Barrera

Combined drug triads for synergic neuroprotection in retinal degeneration

This review focuses on retina degeneration occurring during glaucoma, age-related macular degeneration (AMD), diabetic retinopathy (DR), and retinitis pigmentosa (RP), and on the potential therapeutic use of triads of repositioned medicines, addressed to distinct but complementary targets, to prevent, delay or stop retina cell death. Although myriad pathogenic mechanisms have been implicated in these disorders, common signaling pathways leading to apoptotic cell death to all of them, and to all neurodegenerative diseases are (i) calcium dyshomeostasis/excitotoxicity; (ii) oxidative stress/mitochondrial dysfunction, and (iii) neuroinflammation/P2X7 receptor activation. From a therapeutic point of view, it is relevant to consider the multitarget approach based on the use of combined medicines acting on complementary pathogenic mechanisms that has been highly successful in the treatment of chronic diseases such as cancer, AIDS, pain, hypertension, Parkinson’s disease, cardiac failure, depression, or the epilepsies as the basic mechanisms of cell death do not differ between the different CNS degenerative diseases. We suggest the multi-target therapy approach could be more effective compared with single-drug treatments. Used at doses lower than standard, these triads may also be safer and more efficient. After the establishment of a proof-of-concept in animal models of retinal degeneration, potential successful preclinical trials of such combinations may eventually drive to test this concept in clinical trials in patients, first to evaluate the safety and efficacy of the drug combinations in humans and then their therapeutic advantages, if any, seeking the prevention and/or the delay of retina degeneration and blindness.We thank the support received from the EU Horizon 2020 Research and Innovation Program under Maria Slodowska‐Curie, Grant/Award Number: Grant Agreement N. 766124; Fundación Teófilo Hernando; Spanish Ministry of Science and Innovation (FEDER-PID2019-106230RB-I00) and Generalitat Valenciana (IDIFEDER/2017/064, PROMETEO/2021/024)

Loss of Melanopsin-Expressing Ganglion Cell Subtypes and Dendritic Degeneration in the Aging Human Retina

In mammals, melanopsin-expressing retinal ganglion cells (mRGCs) are, among other things, involved in several non-image-forming visual functions, including light entrainment of circadian rhythms. Considering the profound impact of aging on visual function and ophthalmic diseases, here we evaluate changes in mRGCs throughout the life span in humans. In 24 post-mortem retinas from anonymous human donors aged 10–81 years, we assessed the distribution, number and morphology of mRGCs by immunostaining vertical retinal sections and whole-mount retinas with antibodies against melanopsin. Human retinas showed melanopsin immunoreactivity in the cell body, axon and dendrites of a subset of ganglion cells at all ages tested. Nearly half of the mRGCs (51%) were located within the ganglion cell layer (GCL), and stratified in the outer (M1, 12%) or inner (M2, 16%) margin of the inner plexiform layer (IPL) or in both plexuses (M3, 23%). M1 and M2 cells conformed fairly irregular mosaics, while M3 cell distribution was slightly more regular. The rest of the mRGCs were more regularly arranged in the inner nuclear layer (INL) and stratified in the outer margin of the IPL (M1d, 49%). The quantity of each cell type decrease after age 70, when the total number of mRGCs was 31% lower than in donors aged 30–50 years. Moreover, in retinas with an age greater than 50 years, mRGCs evidenced a decrease in the dendritic area that was both progressive and age-dependent, as well as fewer branch points and terminal neurite tips per cell and a smaller Sholl area. After 70 years of age, the distribution profile of the mRGCs was closer to a random pattern than was observed in younger retinas. We conclude that advanced age is associated with a loss in density and dendritic arborization of the mRGCs in human retinas, possibly accounting for the more frequent occurrence of circadian rhythm disorders in elderly persons.This research was supported by grants from the Spanish Ministry of Economy and Competitiveness (MINECO-FEDER BFU2015-67139-R), Instituto de Salud Carlos III (RETICS-FEDER RD16/0008/0016) and Generalitat Valenciana (PROMETEO/2016/158)

Neuroprotective Effect of Tauroursodeoxycholic Acid on N-Methyl-D-Aspartate-Induced Retinal Ganglion Cell Degeneration

Retinal ganglion cell degeneration underlies the pathophysiology of diseases affecting the retina and optic nerve. Several studies have previously evidenced the anti-apoptotic properties of the bile constituent, tauroursodeoxycholic acid, in diverse models of photoreceptor degeneration. The aim of this study was to investigate the effects of systemic administration of tauroursodeoxycholic acid on N-methyl-D-aspartate (NMDA)-induced damage in the rat retina using a functional and morphological approach. Tauroursodeoxycholic acid was administered intraperitoneally before and after intravitreal injection of NMDA. Three days after insult, full-field electroretinograms showed reductions in the amplitudes of the positive and negative-scotopic threshold responses, scotopic a- and b-waves and oscillatory potentials. Quantitative morphological evaluation of whole-mount retinas demonstrated a reduction in the density of retinal ganglion cells. Systemic administration of tauroursodeoxycholic acid attenuated the functional impairment induced by NMDA, which correlated with a higher retinal ganglion cell density. Our findings sustain the efficacy of tauroursodeoxycholic acid administration in vivo, suggesting it would be a good candidate for the pharmacological treatment of degenerative diseases coursing with retinal ganglion cell loss.This work was supported by project grants from Spanish Ministerio de Economía y Competitividad-FEDER (http://www.mineco.gob.es) #BFU2012‐36845, Instituto de Salud Carlos III RETICS (http://www.oftared.com) #RD12/0034/0010 and Organización Nacional de Ciegos Españoles (http://www.once.es) to NC; Ministerio de Ciencia e Innovación #JCI‐2009‐05224 to VGV; Universidad de Alicante (http://www.ua.es) #2010-48536273 to GE; Instituto de Salud Carlos III (http://www.isciii.es) #PI13/02098 and RETICS #RD12/0034/0006 to PdV; and FUNDALUCE

Retinitis pigmentosa is associated with shifts in the gut microbiome

The gut microbiome is known to influence the pathogenesis and progression of neurodegenerative diseases. However, there has been relatively little focus upon the implications of the gut microbiome in retinal diseases such as retinitis pigmentosa (RP). Here, we investigated changes in gut microbiome composition linked to RP, by assessing both retinal degeneration and gut microbiome in the rd10 mouse model of RP as compared to control C57BL/6J mice. In rd10 mice, retinal responsiveness to flashlight stimuli and visual acuity were deteriorated with respect to observed in age-matched control mice. This functional decline in dystrophic animals was accompanied by photoreceptor loss, morphologic anomalies in photoreceptor cells and retinal reactive gliosis. Furthermore, 16S rRNA gene amplicon sequencing data showed a microbial gut dysbiosis with differences in alpha and beta diversity at the genera, species and amplicon sequence variants (ASV) levels between dystrophic and control mice. Remarkably, four fairly common ASV in healthy gut microbiome belonging to Rikenella spp., Muribaculaceace spp., Prevotellaceae UCG-001 spp., and Bacilli spp. were absent in the gut microbiome of retinal disease mice, while Bacteroides caecimuris was significantly enriched in mice with RP. The results indicate that retinal degenerative changes in RP are linked to relevant gut microbiome changes. The findings suggest that microbiome shifting could be considered as potential biomarker and therapeutic target for retinal degenerative diseases.This study was funded by the Spanish Ministry of Economy Industry and Competitiveness (MINECO-FEDER BFU2015-67139-R and RTI2018-094248-B-I00), Spanish Ministry of Science and Innovation (MICINN-FEDER PID2019-106230RB-I00), Instituto de Salud Carlos III co-financed by European Regional Development funds (RETICS-FEDER RD16/0008/0016), Asociación Retina Asturias (ASOCIACIONRETINA1-20I), FARPE-FUNDALUCE (FUNDALUCE18-01), Generalitat Valenciana (FEDER IDIFEDER/2017/064) and Alicante’s University (UAIND18-05A)

Age-related changes in photosensitive melanopsin-expressing retinal ganglion cells correlate with circadian rhythm impairments in sighted and blind rats

The melanopsin system consists of intrinsically photosensitive retinal ganglion cells containing the photopigment melanopsin (mRGCs). These mRGCs mediate several non-image-forming visual functions, including light entrainment of circadian rhythms. Here we evaluate age-related alterations of the melanopsin system and circadian rhythms in P23H line 1 (P23H-1) rats, a rodent model of retinitis pigmentosa (RP). In homozygous P23H-1 rats and wild-type control rats from the same genetic background (Sprague-Dawley), body temperature and locomotor activity were continuously monitored at 10-min intervals for 7 days, once every 4-5 weeks, between 2 and 24 months of age, using a telemetry transmitter. The distribution and number of mRGCs were assessed in control rats at 12, 18, and 24 months of age and in P23H-1 rats aged 12, 18, 24, and 30 months by immunostaining whole-mount retinas with antibodies against melanopsin. The mean density of mRGCs in control rats showed no significant variations when evaluated at 12 and 18 months of age, and fell by approximately 56% between 18 and 24 months of age. Meanwhile, a significant decrease in the mean number of mRGCs was found in 18-month-old P23H-1 rats as compared to 18-month-old control rats (81% decrease). Parametric and non-parametric analyses of the records showed a gradual age-dependent weakening of body temperature and locomotor activity circadian rhythms robustness in both control and P23H-1 rats from 2 to 24 months of age. However, body temperature and locomotor activity circadian patterns were less robust throughout the experiment in P23H-1 as compared to control rats, with lower amplitude, weaker coupling strength to environmental zeitgebers and higher fragmentation of the rhythms. The present study shows that the degeneration of photoreceptors and inner retinal neurons, characteristic of RP, has age-related degenerative effects on the melanopsin system and is associated with weaker circadian patterns