trichostatin-a and Retinal-Degeneration

Cone photoreceptor cell death as it occurs in certain hereditary retinal diseases is devastating, with the affected patients suffering from a loss of accurate and colour vision. Regrettably, these hereditary cone diseases are still untreatable to date. Thus, the identification of substances able to block or restrain cone cell death is of primary importance. We studied the neuroprotective effects of a histone deacetylase inhibitor, Trichostatin A (TSA), in a mouse model of inherited, primary cone degeneration (cpfl1). We show that HDAC inhibition protects cpfl1 cones in vitro, in retinal explant cultures. More importantly, in vivo, a single intravitreal TSA injection significantly increased cone survival for up to 16 days post-injection. In addition, the abnormal, incomplete cone migration pattern in the cpfl1 retina was significantly improved by HDAC inhibition. These findings suggest a crucial role for HDAC activity in primary cone degeneration and highlight a new avenue for future therapy developments for cone dystrophies and retinal diseases associated with impaired cone migration.

Topics: Animals; Disease Models, Animal; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Neuroprotective Agents; Retinal Cone Photoreceptor Cells; Retinal Degeneration

Neuroretinal ischemic injury contributes to several degenerative diseases in the eye and the resulting pathogenic processes involving a series of necrotic and apoptotic events. This study investigates the time and extent of changes in acetylation, and whether this influences function and survival of neuroretinal cells following injury. Studies evaluated the time course of changes in histone deacetylase (HDAC) activity, histone-H3 acetylation and caspase-3 activation levels as well as retinal morphology and function (electroretinography) following ischemia. In addition, the effect of two HDAC inhibitors, trichostatin-A and valproic acid were also investigated. In normal eyes, retinal ischemia produced a significant increase in HDAC activity within 2 h that was followed by a corresponding significant decrease in protein acetylation by 4 h. Activated caspase-3 levels were significantly elevated by 24 h. Treatment with HDAC inhibitors blocked the early decrease in protein acetylation and activation of caspase-3. Retinal immunohistochemistry demonstrated that systemic administration of trichostatin-A or valproic acid, resulted in hyperacetylation of all retinal layers after systemic treatment. In addition, HDAC inhibitors provided a significant functional and structural neuroprotection at seven days following injury relative to vehicle-treated eyes. These results provide evidence that increases in HDAC activity is an early event following retinal ischemia, and are accompanied by corresponding decreases in acetylation in advance of caspase-3 activation. In addition to preserving acetylation status, the administration of HDAC inhibitors suppressed caspase activation and provided structural and functional neuroprotection in model of ischemic retinal injury. Taken together these data provide evidence that decrease in retinal acetylation status is a central event in ischemic retinal injury, and the hyperacetylation induced by HDAC inhibition can provide acute neuroprotection.

Topics: Acetylation; Animals; Blotting, Western; Caspase 3; Cell Survival; Electroretinography; Female; Histone Deacetylase Inhibitors; Histone Deacetylases; Histones; Hydroxamic Acids; Lysine; Male; Neuroprotective Agents; Rats, Inbred BN; Reperfusion Injury; Retinal Degeneration; Retinal Neurons; Valproic Acid

Protein acetylation is an essential mechanism in regulating transcriptional and inflammatory events. Studies have shown that nonselective histone deacetylase (HDAC) inhibitors can protect the retina from ischemic injury in rats. However, the role of specific HDAC isoforms in retinal degenerative processes remains obscure. The purpose of this study was to investigate the role of HDAC2 isoform in a mouse model of ischemic retinal injury.. Localization of HDAC2 in mice retinas was evaluated by immunohistochemical analyses. To investigate whether selective reduction in HDAC2 activity can protect the retina from ischemic injury, Hdac2⁺/⁻ mice were utilized. Electroretinographic (ERG) and morphometric analyses were used to assess retinal function and morphology.. Our results demonstrated that HDAC2 is primarily localized in nuclei in inner nuclear and retinal ganglion cell layers, and HDAC2 activity accounted for approximately 35% of the total activities of HDAC1, 2, 3, and 6 in the retina. In wild-type mice, ERG a- and b-waves from ischemic eyes were significantly reduced when compared to pre-ischemia baseline values. Morphometric examination of these eyes revealed significant degeneration of inner retinal layers. In Hdac2⁺/⁻ mice, ERG a- and b-waves from ischemic eyes were significantly greater than those measured in ischemic eyes from wild-type mice. Morphologic measurements demonstrated that Hdac2⁺/⁻ mice exhibit significantly less retinal degeneration than wild-type mice.. This study demonstrated that suppressing HDAC2 expression can effectively reduce ischemic retinal injury. Our results support the idea that the development of selective HDAC2 inhibitors may provide an efficacious treatment for ischemic retinal injury.

Topics: Animals; Disease Models, Animal; Electroretinography; Histone Deacetylase 2; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Mice, Inbred C57BL; Mice, Knockout; Reperfusion Injury; Retina; Retinal Degeneration; Retinal Ganglion Cells