scholarly journals Redefining the role of Ca2+-permeable channels in photoreceptor degeneration using diltiazem

2022 ◽  
Vol 13 (1) ◽  
Author(s):  
Soumyaparna Das ◽  
Valerie Popp ◽  
Michael Power ◽  
Kathrin Groeneveld ◽  
Jie Yan ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Strong Increase ◽  
Channel Blockers ◽  
Photoreceptor Degeneration ◽  
Therapy Development ◽  
Hypertensive Drug ◽  
Future Therapy

AbstractHereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were very effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pore of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced the activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.

scholarly journals Redefining the role of Ca2+-permeable channels in hereditary photoreceptor degeneration using the D- and L-cis enantiomers of diltiazem

2020 ◽  
Author(s):  
Soumyaparna Das ◽  
Valerie Popp ◽  
Michael Power ◽  
Kathrin Groeneveld ◽  
Christian Melle ◽  
...  
Keyword(s):  
Cell Death ◽  
Photoreceptor Cell ◽  
Strong Increase ◽  
Channel Blockers ◽  
Photoreceptor Degeneration ◽  
Therapy Development ◽  
Hypertensive Drug ◽  
Future Therapy ◽  
Reduced Activity

ABSTRACTHereditary degeneration of photoreceptors has been linked to over-activation of Ca2+-permeable channels, excessive Ca2+-influx, and downstream activation of Ca2+-dependent calpain-type proteases. Unfortunately, after more than 20 years of pertinent research, unequivocal evidence proving significant and reproducible photoreceptor protection with Ca2+-channel blockers is still lacking. Here, we show that both D- and L-cis enantiomers of the anti-hypertensive drug diltiazem were highly effective at blocking photoreceptor Ca2+-influx, most probably by blocking the pores of Ca2+-permeable channels. Yet, unexpectedly, this block neither reduced activity of calpain-type proteases, nor did it result in photoreceptor protection. Remarkably, application of the L-cis enantiomer of diltiazem even led to a strong increase in photoreceptor cell death. These findings shed doubt on the previously proposed links between Ca2+ and retinal degeneration and are highly relevant for future therapy development as they may serve to refocus research efforts towards alternative, Ca2+-independent degenerative mechanisms.

scholarly journals Minocycline decreases CCR2-positive monocytes in the retina and ameliorates photoreceptor degeneration in a mouse model of retinitis pigmentosa

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0239108
Author(s):  
Ryo Terauchi ◽  
Hideo Kohno ◽  
Sumiko Watanabe ◽  
Saburo Saito ◽  
Akira Watanabe ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Fluorescent Protein ◽  
Outer Nuclear Layer ◽  
Inhibitory Effect ◽  
Subretinal Space ◽  
Photoreceptor Degeneration ◽  
Retinal Inflammation ◽  
Green Fluorescent

Retinal inflammation accelerates photoreceptor cell death caused by retinal degeneration. Minocycline, a semisynthetic broad-spectrum tetracycline antibiotic, has been previously reported to rescue photoreceptor cell death in retinal degeneration. We examined the effect of minocycline on retinal photoreceptor degeneration using c-mer proto-oncogene tyrosine kinase (Mertk)−/−Cx3cr1GFP/+Ccr2RFP/+ mice, which enabled the observation of CX3CR1-green fluorescent protein (GFP)- and CCR2-red fluorescent protein (RFP)-positive macrophages by fluorescence. Retinas of Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice showed photoreceptor degeneration and accumulation of GFP- and RFP-positive macrophages in the outer retina and subretinal space at 6 weeks of age. Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice were intraperitoneally administered minocycline. The number of CCR2-RFP positive cells significantly decreased after minocycline treatment. Furthermore, minocycline administration resulted in partial reversal of the thinning of the outer nuclear layer and decreased the number of apoptotic cells, as assessed by the TUNEL assay, in Mertk−/−Cx3cr1GFP/+Ccr2RFP/+ mice. In conclusion, we found that minocycline ameliorated photoreceptor cell death in an inherited photoreceptor degeneration model due to Mertk gene deficiency and has an inhibitory effect on CCR2 positive macrophages, which is likely to be a neuroprotective mechanism of minocycline.

scholarly journals High dose expression of heme oxigenase-1 induces retinal degeneration through ER stress-related DDIT3

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Huirong Li ◽  
Bo Liu ◽  
Lili Lian ◽  
Jiajia Zhou ◽  
Shengjin Xiang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cell Death ◽  
Retinal Degeneration ◽  
Knockout Mice ◽  
Photoreceptor Cell ◽  
Heme Oxygenase 1 ◽  
High Dose ◽  
Photoreceptor Degeneration ◽  
Expression Levels ◽  
High Level

Abstract Background Oxidative stress is a common cause of neurodegeneration and plays a central role in retinal degenerative diseases. Heme oxygenase-1 (HMOX1) is a redox-regulated enzyme that is induced in neurodegenerative diseases and acts against oxidative stress but can also promote cell death, a phenomenon that is still unexplained in molecular terms. Here, we test whether HMOX1 has opposing effects during retinal degeneration and investigate the molecular mechanisms behind its pro-apoptotic role. Methods Basal and induced levels of HMOX1 in retinas are examined during light-induced retinal degeneration in mice. Light damage-independent HMOX1 induction at two different expression levels is achieved by intraocular injection of different doses of an adeno-associated virus vector expressing HMOX1. Activation of Müller glial cells, retinal morphology and photoreceptor cell death are examined using hematoxylin-eosin staining, TUNEL assays, immunostaining and retinal function are evaluated with electroretinograms. Downstream gene expression of HMOX1 is analyzed by RNA-seq, qPCR examination and western blotting. The role of one of these genes, the pro-apoptotic DNA damage inducible transcript 3 (Ddit3), is analyzed in a line of knockout mice. Results Light-induced retinal degeneration leads to photoreceptor degeneration and concomitant HMOX1 induction. HMOX1 expression at low levels before light exposure prevents photoreceptor degeneration but expression at high levels directly induces photoreceptor degeneration even without light stress. Photoreceptor degeneration following high level expression of HMOX1 is associated with a mislocalization of rhodopsin in photoreceptors and an increase in the expression of DDIT3. Genetic deletion of Ddit3 in knockout mice prevents photoreceptor cell degeneration normally resulting from high level HMOX1 expression. Conclusion The results reveal that the expression levels determine whether HMOX1 is protective or deleterious in the retina. Furthermore, in contrast to the protective low dose of HMOX1, the deleterious high dose is associated with induction of DDIT3 and endoplasmic reticulum stress as manifested, for instance, in rhodopsin mislocalization. Hence, future applications of HMOX1 or its regulated targets in gene therapy approaches should carefully consider expression levels in order to avoid potentially devastating effects.

scholarly journals The role of cGMP-signalling and calcium-signalling in photoreceptor cell death: perspectives for therapy development

2021 ◽  
Author(s):  
Soumyaparna Das ◽  
Yiyi Chen ◽  
Jie Yan ◽  
Gustav Christensen ◽  
Soumaya Belhadj ◽  
...  
Keyword(s):  
Cell Death ◽  
Photoreceptor Cell ◽  
Second Messengers ◽  
Calcium Signalling ◽  
Clinical Applications ◽  
Photoreceptor Degeneration ◽  
Therapeutic Approaches ◽  
Cgmp Signalling ◽  
Key Aspects

AbstractThe second messengers, cGMP and Ca2+, have both been implicated in retinal degeneration; however, it is still unclear which of the two is most relevant for photoreceptor cell death. This problem is exacerbated by the close connections and crosstalk between cGMP-signalling and calcium (Ca2+)-signalling in photoreceptors. In this review, we summarize key aspects of cGMP-signalling and Ca2+-signalling relevant for hereditary photoreceptor degeneration. The topics covered include cGMP-signalling targets, the role of Ca2+ permeable channels, relation to energy metabolism, calpain-type proteases, and how the related metabolic processes may trigger and execute photoreceptor cell death. A focus is then put on cGMP-dependent mechanisms and how exceedingly high photoreceptor cGMP levels set in motion cascades of Ca2+-dependent and independent processes that eventually bring about photoreceptor cell death. Finally, an outlook is given into mutation-independent therapeutic approaches that exploit specific features of cGMP-signalling. Such approaches might be combined with suitable drug delivery systems for translation into clinical applications.

Photoreceptor Cell Death Mechanisms in Inherited Retinal Degeneration

2008 ◽  
Vol 38 (3) ◽  
pp. 253-269 ◽  
Author(s):  
Javier Sancho-Pelluz ◽  
Blanca Arango-Gonzalez ◽  
Stefan Kustermann ◽  
Francisco Javier Romero ◽  
Theo van Veen ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Cell Death Mechanisms ◽  
Inherited Retinal Degeneration

Inhibition of LOX-1 prevents inflammation and photoreceptor cell death in retinal degeneration

2020 ◽  
Vol 80 ◽  
pp. 106190
Author(s):  
Xinran Gao ◽  
Ruilin Zhu ◽  
Jiantong Du ◽  
Wenbo Zhang ◽  
Wenna Gao ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell

scholarly journals Excessive phospholipid peroxidation distinguishes ferroptosis from other cell death modes including pyroptosis

2020 ◽  
Vol 11 (10) ◽  
Author(s):  
Bartosz Wiernicki ◽  
Hanne Dubois ◽  
Yulia Y. Tyurina ◽  
Behrouz Hassannia ◽  
Hülya Bayir ◽  
...  
Keyword(s):  
Reactive Oxygen Species ◽  
Cell Death ◽  
The Other ◽  
Strong Increase ◽  
Oxygen Species ◽  
Membrane Rupture ◽  
Regulated Cell Death ◽  
Phospholipid Peroxidation ◽  
Differential Involvement

Abstract Lipid peroxidation (LPO) drives ferroptosis execution. However, LPO has been shown to contribute also to other modes of regulated cell death (RCD). To clarify the role of LPO in different modes of RCD, we studied in a comprehensive approach the differential involvement of reactive oxygen species (ROS), phospholipid peroxidation products, and lipid ROS flux in the major prototype modes of RCD viz. apoptosis, necroptosis, ferroptosis, and pyroptosis. LC-MS oxidative lipidomics revealed robust peroxidation of three classes of phospholipids during ferroptosis with quantitative predominance of phosphatidylethanolamine species. Incomparably lower amounts of phospholipid peroxidation products were found in any of the other modes of RCD. Nonetheless, a strong increase in lipid ROS levels was detected in non-canonical pyroptosis, but only during cell membrane rupture. In contrast to ferroptosis, lipid ROS apparently was not involved in non-canonical pyroptosis execution nor in the release of IL-1β and IL-18, while clear dependency on CASP11 and GSDMD was observed. Our data demonstrate that ferroptosis is the only mode of RCD that depends on excessive phospholipid peroxidation for its cytotoxicity. In addition, our results also highlight the importance of performing kinetics and using different methods to monitor the occurrence of LPO. This should open the discussion on the implication of particular LPO events in relation to different modes of RCD.

scholarly journals AAV-miR-204 Protects from Retinal Degeneration by Attenuation of Microglia Activation and Photoreceptor Cell Death

2020 ◽  
Vol 19 ◽  
pp. 144-156 ◽  
Author(s):  
Marianthi Karali ◽  
Irene Guadagnino ◽  
Elena Marrocco ◽  
Rossella De Cegli ◽  
Annamaria Carissimo ◽  
...  
Keyword(s):  
Cell Death ◽  
Retinal Degeneration ◽  
Photoreceptor Cell ◽  
Microglia Activation
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