Neuroprotective actions of progesterone in an in vivo model of retinitis pigmentosa

Sánchez-Vallejo, Violeta; Benlloch-Navarro, Soledad; López‐Pedrajas, Rosa; Romero, Francisco J.; Miranda, María

doi:10.1016/j.phrs.2015.06.019

Cited by 39 publications

(42 citation statements)

References 78 publications

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“…A group of researchers in Spain revealed that rd1 mice orally administered with progesterone (100 mg/kg body weight) at postnatal day 7 (P7) exhibited significantly decreased number of apoptotic cells in ONL in the far peripheral retina and increased amplitude of ERG b-wave at P15, but no Protecting the Aging Retina DOI: http://dx.doi.org/10.5772/intechopen.82330 significant change was observed at P17. There was also a transient reduced gliosis in the treated rd1 mice [73]. Similar results were observed with oral administration of synthetic progestin, known as the FDA-approved Norgestrel, showing reduction of photoreceptor death by 70 and 75% in light-damaged mouse model and rd10 mice, respectively [74].…”

Section: Studies In Animal Modelssupporting

confidence: 76%

Protecting the Aging Retina

Shen¹,

Lo²

2019

Neuroprotection

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Aging retina, notably the aging macula, is prone to develop degenerative diseases, such as age-related macular degeneration (AMD), the leading cause of visual loss in individuals aged 65 or above in developed countries. However, current treatments are very limited. Since degeneration, dysfunction, and death of retinal neurons are demonstrated in the pathogenesis of AMD, neuroprotective strategies could serve as a possible way to treat AMD. In this chapter, we will briefly introduce risk factors, pathophysiology, affected neurons, classification, clinical manifestation, and current treatments of AMD. Finally, neuroprotection in both AMD animal models and patients will be discussed. Neuroprotection 2 Anatomy and function of the retinaThe eye is composed of three layers, which are the inner retina layer, middle vascular choroid layer, and outer fibrous sclera layer, respectively. Retina, the innermost layer of the eye, consists of two parts: the inner transparent neurosensory retina and outer pigmented epithelial layer-the retinal pigment epithelium (RPE). There is a potential space between neural retina and RPE, called subretinal space. In the neural retina, the neural cell bodies are situated in three layers (Figure 1), including the outer nuclear layer (ONL) occupied with nuclei of photoreceptors; the inner nuclear layer (INL) filled with nuclei of horizontal, bipolar, and most of the amacrine cells; as well as ganglion cell layer (GCL) containing nuclei of retinal ganglion cells and the rest of displaced amacrine cells. Additionally, axons and dendrites of these retinal neurons constitute two synaptic layers: the inner plexiform layer (IPL) and outer plexiform layer (OPL) [8]. The RPE cells form a continuous polarized cell monolayer with its apical surface adjacent to the outer segment apices of the photoreceptors and its basal aspect lying on supportive substrate Bruch's membrane.Retinal neurons are mainly distributed in three layers: ONL with nuclei of photoreceptors; INL with nuclei of horizontal, bipolar, and most of the amacrine cells; and GCL with nuclei of retinal ganglion cells and the rest of displaced amacrine cells. Additionally, axons and dendrites of these retinal neurons constitute two synaptic layers, including IPL and OPL [8].Photoreceptors are divided into two types: rods, which are dominated in the peripheral retina and responsible for dim light vision and detecting movement and contrast, and cones, which are dominated in the macula, especially the fovea (only cones), and are responsible for bright light vision and sensing color vision Figure 1. Retinal layers of the human eye.Protecting the Aging Retina DOI: http://dx.doi.org/10.5772/intechopen.82330 and resolution. Outer segments of the photoreceptor are generated by the cell body, and the distal parts of outer segments are phagocytosed by RPE every day. There are abundant mitochondria in inner segments to supply energy for these cells with high metabolic rate. Bruch's membrane, where the RPE cells are tightly attached, consists of five la...

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Section: Studies In Animal Modelssupporting

confidence: 76%

Protecting the Aging Retina

Shen¹,

Lo²

2019

Neuroprotection

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“…Pregnenolone can be further metabolized to progesterone and allopregnanolone that are both potent neuroprotective and anti-inflammatory molecules [ 53 – 55 ]. When orally applied to rd1 mice with inherited retinal degeneration, progesterone potently reduced oxidative stress levels, diminished gliosis, and provided a temporal improvement in photoreceptor function [ 56 ].…”

Section: Discussionmentioning

confidence: 99%

Targeting translocator protein (18 kDa) (TSPO) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration

Scholz

Caramoy

Bhuckory

et al. 2015

J Neuroinflammation

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BackgroundReactive microglia are commonly seen in retinal degenerative diseases, and neurotoxic microglia responses can contribute to photoreceptor cell death. We and others have previously shown that translocator protein (18 kDa) (TSPO) is highly induced in retinal degenerations and that the selective TSPO ligand XBD173 (AC-5216, emapunil) exerts strong anti-inflammatory effects on microglia in vitro and ex vivo. Here, we investigated whether targeting TSPO with XBD173 has immuno-modulatory and neuroprotective functions in two mouse models of acute retinal degeneration using bright white light exposure.MethodsBALB/cJ and Cx3cr1GFP/+ mice received intraperitoneal injections of 10 mg/kg XBD173 or vehicle for five consecutive days, starting 1 day prior to exposure to either 15,000 lux white light for 1 h or 50,000 lux focal light for 10 min, respectively. The effects of XBD173 treatment on microglia and Müller cell reactivity were analyzed by immuno-stainings of retinal sections and flat mounts, fluorescence-activated cell sorting (FACS) analysis, and mRNA expression of microglia markers using quantitative real-time PCR (qRT-PCR). Optical coherence tomography (OCT), terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) stainings, and morphometric analyses were used to quantify the extent of retinal degeneration and photoreceptor apoptosis.ResultsFour days after the mice were challenged with bright white light, a large number of amoeboid-shaped alerted microglia appeared in the degenerating outer retina, which was nearly completely prevented by treatment with XBD173. This treatment also down-regulated the expression of TSPO protein in microglia but did not change the TSPO levels in the retinal pigment epithelium (RPE). RT-PCR analysis showed that the microglia/macrophage markers Cd68 and activated microglia/macrophage whey acidic protein (Amwap) as well as the pro-inflammatory genes Ccl2 and Il6 were reduced after XBD173 treatment. Light-induced degeneration of the outer retina was nearly fully blocked by XBD173 treatment. We further confirmed these findings in an independent mouse model of focal light damage. Retinas of animals receiving XBD173 therapy displayed significantly more ramified non-reactive microglia and more viable arrestin-positive cone photoreceptors than vehicle controls.ConclusionsTargeting TSPO with XBD173 effectively counter-regulates microgliosis and ameliorates light-induced retinal damage, highlighting a new pharmacological concept for the treatment of retinal degenerations.

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“…These effects mediated by XBD173 were prevented upon blocking the enzymatic conversion of cholesterol to pregnenolone (Fig ), which can be converted to progesterone, a potent neurosteroid with pleiotropic neuroprotective properties (Pettus et al, ; Guennoun et al, ; Cai et al, ). In rd 1 mice, a model for retinitis pigmentosa, oral progesterone treatment decreased gliosis and cell death leading to improved retinal function (Sanchez‐Vallejo et al, ). Similarly, TTN stimulation of microglia increased levels of dehydroepiandrosterone, an effective anti‐inflammatory neurosteroid (Wang et al, ), and the TSPO ligand Ro5‐4864 effectively reduced diabetic neuropathy through a local increase in neurosteroids (Giatti et al, ).…”

Section: Targeting Mononuclear Phagocytes In Retinal Degenerative Dismentioning

confidence: 99%

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

et al. 2018

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This review highlights the role of three key immune pathways in the pathophysiology of major retinal degenerative diseases including diabetic retinopathy, age‐related macular degeneration, and rare retinal dystrophies. We first discuss the mechanisms how loss of retinal homeostasis evokes an unbalanced retinal immune reaction involving responses of local microglia and recruited macrophages, activity of the alternative complement system, and inflammasome assembly in the retinal pigment epithelium. Presenting these key mechanisms as complementary targets, we specifically emphasize the concept of immunomodulation as potential treatment strategy to prevent or delay vision loss. Promising molecules are ligands for phagocyte receptors, specific inhibitors of complement activation products, and inflammasome inhibitors. We comprehensively summarize the scientific evidence for this strategy from preclinical animal models, human ocular tissue analyses, and clinical trials evolving in the last few years.

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Neuroprotective actions of progesterone in an in vivo model of retinitis pigmentosa

Cited by 39 publications

References 78 publications

Protecting the Aging Retina

Protecting the Aging Retina

Targeting translocator protein (18 kDa) (TSPO) dampens pro-inflammatory microglia reactivity in the retina and protects from degeneration

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

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