Inherited Retinal Degeneration: Towards the Development of a Combination Therapy Targeting Histone Deacetylase, Poly (ADP-Ribose) Polymerase, and Calpain

• Published in: Biomolecules (Basel, Switzerland) Vol. 13; no. 4; p. 581
• Main Authors: Dong, Yujie, Yan, Jie, Yang, Ming, Xu, Wenrong, Hu, Zhulin, Paquet-Durand, François, Jiao, Kangwei
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23-03-2023; MDPI
• Subjects: Animal welfare; Animals; Apoptosis; Calpain; Calpain - metabolism; Care and treatment; Cell death; cGMP; Combination therapy; Enzymes; Genetic aspects; Health aspects; Histone deacetylase; Histone Deacetylases; Histones; Kinases; Mice; photoreceptor cell death; Photoreceptor Cells, Vertebrate; Photoreceptors; Physiological aspects; PKG; Point mutation; Poly(ADP-ribose) polymerase; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Poly(ADP-ribose) Polymerase Inhibitors - therapeutic use; Poly(ADP-ribose) Polymerases - metabolism; Retina; Retinal degeneration; Retinal Degeneration - drug therapy; Retinal Degeneration - genetics; retinitis pigmentosa; Ribose - pharmacology; Ribose - therapeutic use; Vorinostat - pharmacology; Vorinostat - therapeutic use; China; New York; Sweden; United Kingdom > UK; United States > US; Germany; photoreceptor cell death; retinitis pigmentosa; cGMP; PKG
• ISSN: 2218-273X; 2218-273X
• DOI: 10.3390/biom13040581

Inherited retinal degeneration (IRD) represents a diverse group of gene mutation-induced blinding diseases. In IRD, the loss of photoreceptors is often connected to excessive activation of histone-deacetylase (HDAC), poly-ADP-ribose-polymerase (PARP), and calpain-type proteases (calpain). Moreover, the inhibition of either HDACs, PARPs, or calpains has previously shown promise in preventing photoreceptor cell death, although the relationship between these enzyme groups remains unclear. To explore this further, organotypic retinal explant cultures derived from wild-type mice and
mice as a model for IRD were treated with different combinations of inhibitors specific for HDAC, PARP, and calpain. The outcomes were assessed using in situ activity assays for HDAC, PARP, and calpain, immunostaining for activated calpain-2, and the TUNEL assay for cell death detection. We confirmed that inhibition of either HDAC, PARP, or calpain reduced
mouse photoreceptor degeneration, with the HDAC inhibitor Vorinostat (SAHA) being most effective. Calpain activity was reduced by inhibition of both HDAC and PARP whereas PARP activity was only reduced by HDAC inhibition. Unexpectedly, combined treatment with either PARP and calpain inhibitors or HDAC and calpain inhibitors did not produce synergistic rescue of photoreceptors. Together, these results indicate that in
photoreceptors, HDAC, PARP, and calpain are part of the same degenerative pathway and are activated in a sequence that begins with HDAC and ends with calpain.