TUDCA Slows Retinal Degeneration in Two Different Mouse Models of Retinitis Pigmentosa and Prevents Obesity in Bardet-Biedl Syndrome Type 1 Mice

Drack, Arlene V.; Dumitrescu, Alina V.; Bhattarai, Sajag; Gratie, Daniel; Stone, Edwin M.; Mullins, Robert F.; Sheffield, Val C.

doi:10.1167/iovs.11-8544

Cited by 84 publications

(75 citation statements)

References 37 publications

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“…In addition, we show that in genetically normal rod photoreceptors there is bystander cell death mediated through a caspase-dependent mechanism. Our data may provide an explanation of why using single inhibitors of cell death have had limited rescue effects and poor longterm outcomes when tested in other retinal degeneration models, 36,37 because the rod and cone photoreceptors are dying by different mechanisms so eventually all the photoreceptors are lost. The significance of our findings is that combination therapy directed at the different cell death mechanisms would be crucial in designing effective treatment strategies.…”

Section: Discussionmentioning

confidence: 93%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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Achromatopsia is a progressive autosomal recessive retinal disease characterized by early loss of cone photoreceptors and later rod photoreceptor loss. In most cases, mutations have been identified in CNGA3, CNGB3, GNAT2, PDE6C or PDE6H genes. Owing to this genetic heterogeneity, mutation-independent therapeutic schemes aimed at preventing cone cell death are very attractive treatment strategies. In pde6c w59 mutant zebrafish, cone photoreceptors expressed high levels of receptor-interacting protein kinase 1 (RIP1) and receptor-interacting protein kinase 3 (RIP3) kinases, key regulators of necroptotic cell death. In contrast, rod photoreceptor cells were alternatively immunopositive for caspase-3 indicating activation of caspase-dependent apoptosis in these cells. Morpholino gene knockdown of rip3 in pde6c w59 embryos rescued the dying cone photoreceptors by inhibiting the formation of reactive oxygen species and by inhibiting second-order neuron remodelling in the inner retina. In rip3 morphant larvae, visual function was restored in the cones by upregulation of the rod phosphodiesterase genes (pde6a and pde6b), compensating for the lack of cone pde6c suggesting that cones are able to adapt to their local environment. Furthermore, we demonstrated through pharmacological inhibition of RIP1 and RIP3 activity that cone cell death was also delayed.Collectively, these results demonstrate that the underlying mechanism of cone cell death in the pde6c w59 mutant retina is through necroptosis, whereas rod photoreceptor bystander death occurs through a caspase-dependent mechanism. This suggests that targeting the RIP kinase signalling pathway could be an effective therapeutic intervention in retinal degeneration patients. As bystander cell death is an important feature of many retinal diseases, combinatorial approaches targeting different cell death pathways may evolve as an important general principle in treatment.

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Section: Discussionmentioning

confidence: 93%

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

et al. 2014

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“…Synthetic TUDCA has been shown to exhibit antiapoptotic properties in neurodegenerative diseases, including those affecting the retina. Systemic administration of TUDCA has been demonstrated to slow retinal degeneration in both the rd10 autosomal recessive RP mouse model (Boatright et al, 2006;Drack et al, 2012;Oveson et al, 2011;Phillips et al, 2008) and in a LIRD mouse model (Boatright et al, 2006;Oveson et al, 2011). In these two retinal degeneration models, TUDCA-treated animals were shown to maintain better visual function, thicker ONL and better preservation of outer segments than untreated animals.…”

Section: Tauroursodeoxycholic Acid (Tudca)mentioning

confidence: 99%

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

Cuenca

Fernández‐Sánchez

Campello

et al. 2014

Progress in Retinal and Eye Research

353

394

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“…21 Tauroursodeoxycholic acid also rescued ERG b-waves and the outer nuclear layer in an animal model of retinal degeneration. 31 The dosage used in most in vitro experiments is much lower; for example, 100 lM of TUDCA added to culture medium effectively protected retinal neural cell cultures from cell death induced by elevated glucose concentration, decreased the mito-nuclear translocation of apoptosis-inducing factor, 32 and suppressed expression of p-c-Jun and p-JNK in diabetic rat retinas and retinas exposed to high glucose. 33 However, little is known about the dosage and direct effects of TUDCA on the visual response properties of RGCs under excessive oxidative stress.…”

Section: Tudca Impact On Retinal Neurocircuitrymentioning

confidence: 99%

Effects of Tauroursodeoxycholic Acid and Alpha-Lipoic-Acid on the Visual Response Properties of Cat Retinal Ganglion Cells: An In Vitro Study

Xia

Huang

et al. 2015

Invest. Ophthalmol. Vis. Sci.

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Citation: Xia H, Nan Y, Huang X, Gao J, Pu M. Effects of tauroursodeoxycholic acid and alpha-lipoic-acid on the visual response properties of cat retinal ganglion cells: an in vitro study. Invest Ophthalmol Vis Sci. 2015;56:6638-6645. DOI:10.1167/iovs.15-17301 PURPOSE. To investigate the effects of tauroursodeoxycholic acid (TUDCA) and alpha-lipoicacid (ALA) on the visual response properties of cat retinal ganglion cells (RGCs) in wholemount retinas.METHODS. Young adult cats were divided into three groups: control, ALA, and TUDCA. In vitro single-unit extracellular recordings were performed on wholemount retinas to objectively evaluate the visual response properties of RGCs prior and post to antioxidant treatment. The visual responses properties of RGCs, including receptive field size, luminance threshold, and contrast sensitivity, were collected online and analyzed off-line with Axon Pclamp9. RESULTS.Most of the RF sizes were larger than those plotted prior to the 60 minutes dark adaptation. The luminance threshold was elevated in the control group (no treatment) but reduced post ALA treatment and significantly reduced post TUDCA treatment. The contrast threshold was significantly elevated in the control group (no treatment) and clearly elevated post ALA treatment but effectively sustained post TUCDA treatment. CONCLUSIONS.Retinal neurocircuitry deteriorates in wholemount retinas, resulting in abnormal visual response properties in RGCs. Alpha-lipoic-acid and TUDCA exerted beneficial neuroprotective effects by activating the antioxidant pathway, partially restoring the functionality of retinal neurocircuitry and significantly improving the visual response properties of RGCs. However, TUDCA appears to be more effective than ALA in reducing irradiance thresholds and improving contrast sensitivity.

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TUDCA Slows Retinal Degeneration in Two Different Mouse Models of Retinitis Pigmentosa and Prevents Obesity in Bardet-Biedl Syndrome Type 1 Mice

Cited by 84 publications

References 37 publications

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Rip3 knockdown rescues photoreceptor cell death in blind pde6c zebrafish

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

Effects of Tauroursodeoxycholic Acid and Alpha-Lipoic-Acid on the Visual Response Properties of Cat Retinal Ganglion Cells: An In Vitro Study

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