Valproic Acid Reduces Neuroinflammation to Provide Retinal Ganglion Cell Neuroprotection in the Retina Axotomy Model

Abstract

Neuroinflammation is a critical and targetable pathogenic component of neurodegenerative diseases, including glaucoma, the leading cause of irreversible blindness. Valproic acid has previously been demonstrated to reduce neuroinflammation and is neuroprotective in a number of experimental settings. To determine whether valproic acid can limit retinal neuroinflammation and protect retinal neurons we used an ex vivo retina explant (axotomy) model to isolate resident glial responses from blood-derived monocytes. Neuroinflammatory status was defined using high resolution confocal imaging with 3D morphological reconstruction and cytokine protein arrays. Valproic acid significantly reduced microglia and astrocyte morphological changes, consistent with a reduction in pro-inflammatory phenotypes. Cytokine profiling demonstrated that valproic acid significantly attenuated or prevented expression of pro-inflammatory cytokines in injured retina. This identifies that the retinal explant model as a useful tool to explore resident neuroinflammation in a rapid timescale whilst maintaining a complex system of cell interactions and valproic acid as a useful drug to further explore anti-neuroinflammatory strategies in retinal disease.

Oxidative Stress: A Suitable Therapeutic Target for Optic Nerve Diseases?

“…In murine models of NTG, VPA has been found to decrease oxidative stress and enhance RGC survival through a pathway associated with ERK [311]. Additionally, a recent Swedish study using retina explant models suggested that VPA possesses anti-inflammatory properties by reducing the expression of pro-inflammatory cytokines and attenuating microglial changes, highlighting its potential as an anti-neuroinflammatory drug in retinal diseases [312]. A randomized controlled trial assessing the effectiveness of VPA in glaucoma patients reported an improvement of visual acuity among patients with advanced glaucoma [313].…”

Oxidative Stress: A Suitable Therapeutic Target for Optic Nerve Diseases?

“…In murine models of NTG, VPA has been found to decrease oxidative stress and enhance RGC survival through a pathway associated with ERK [302]. Additionally, a recent Swedish study using retina explant models suggested that VPA possesses anti-inflammatory properties by reducing the expression of proinflammatory cytokines and attenuating microglial changes, highlighting its potential as an antineuroinflammatory drug in retinal diseases [303]. A randomized controlled trial assessing the effectiveness of VPA in glaucoma patients reported an improvement in visual acuity among patients with advanced glaucoma [304].…”

Epigenetics in Glaucoma

“…The elucidations of such mechanisms could be crucial. The experimental inhibition of retinal HDAC activity with specific agents such as valproic acid (VPA) has been proven to be successful as neuroprotective treatment [ 41 , 42 , 43 , 44 , 45 ].…”

“…Specifically, VPA is an inhibitor of the activity of HDAC enzymes, particularly HDAC1, and is involved in the regulation of gene expression by modifying the acetylation status of histones [ 44 , 45 ].…”