In the eyes, limited evidence suggests the involvement of HDACs in retina degeneration. For example; mRNA expression of HDAC 1, 2, and 3 was increased in acute optic nerve injury.
6,19 Genetic ablation of HDAC 3 does not seem to play a large role in early gene silencing in RGCs, but HDAC 3 knockdown has been shown to stop histones deacetylation and attenuate subsequent RGC death after axonal injury.
19 The class I and II HDAC inhibitor VPA reduces RGC death by day 8 after acute optic nerve injury.
44 Additionally, TSA attenuated RGC soma degeneration in DBA/2J mouse model without any axonal degeneration.
45 VPA and sodium butyrate (SB) reduces RGC death in vitro via reduction of HDAC activity.
46 Pharmacological inhibition of HDAC 3 specific activity by RGFP966 was able to preserve histone H4 acetylation and RGC survival after acute optic nerve injury.
47 HDAC 3 has been reported to translocate to the nucleus from the cytoplasm of RGCs following injury in both the optic nerve crush and NMDC-induced excitotoxicity rodent models.
19 Selective inhibitors of HDAC 1, 2, and 3 (MS-275) protect RGCs in optic nerve injury model.
48 Overexpression of HDAC 2 resulted in increased in glial cell activity (e.g. expression of GFAP, Iba-1, and iNOS) in the ischemic retina.
49 Genetic and pharmacological methods have shown that inhibition of HDAC 6 promotes the survival and regeneration of neurons in neurodegenerative disease.
50 HDAC 6 deacetylates its substrates, including α-tubulin, Hsp90, and cortactin, and then forms a complex with other partner proteins and involved in numerous biological processes, such as cell migration and cell to cell interaction.
51 These published reports provide useful information regarding neurodegenerative roles of HDACs, however, it remains in question that how and which subtype of HDAC plays a crucial role in RGC degeneration in glaucoma. Overall, studies using HDAC inhibitors or genetic ablation do not provide similar outcomes, which indicate that genetic deletion of certain HDACs may be compensated by other HDACs. Hence, it remains unclear how each HDAC plays a crucial role in the silencing of genes and/or function of proteins that are detrimental for RGC during glaucoma. Overall, we have seen relatively small but statistically significant changes in class I and IIb HDACs activities and expression in the retina of ocular hypertensive animals. These findings indicated the involvement of other epigenetic events, such as DNA methylation, which could also be parallelly active for RGC death in glaucoma. Another factor could be the study duration, we focused our study for 6 weeks and there is a possibility that HDAC expression and RGC function may deteriorate further beyond 6 weeks. We might see more appreciable changes in the HDAC activities and expression beyond 6 weeks in ocular hypertensive animals. It is also important to emphasize that we have used young animals (2–3 months old), however, glaucoma is an age-dependent disease. This is very likely that young animals are more resistant to ocular insult and strong endogenous compensatory neuroprotective pathways counteract to mitigate occur hypertension-induced injury. These are some of the possibilities for mild changes and open a wide array of unanswered questions. These critical questions will require additional studies using current glaucoma model for the young and old animals for a longer duration study (i.e. 12 weeks or longer), and a different age-dependent glaucoma model (i.e. DBA/2J). In addition, other epigenetic events, such as DNA methylation, is equally important and its role in RGC death remains unknown. Future studies should also be focusing to understand the role of DNA methylation in RGC death and if they are also regulated by δ-opioids.