# Intravitreal Administration of a Selective HDAC6 Inhibitor Prevents Retinal Damage Progression in the Acute Ocular Toxoplasmosis Model

## TL;DR

A new treatment using a selective HDAC6 inhibitor prevents retinal damage in a model of ocular toxoplasmosis.

## Contribution

Intravitreal administration of Tubastatin A, an HDAC6 inhibitor, is shown to prevent retinal damage in an acute ocular toxoplasmosis model.

## Key findings

- Tubastatin A prevents retinal lesion progression in infected mice.
- Tubastatin A reduces inflammation and regulates glial activation in the retina.
- Combining Tubastatin A with antifolates may improve treatment outcomes for ocular toxoplasmosis.

## Abstract

Ocular toxoplasmosis
(OT), caused by Toxoplasma
gondii, is the leading cause of retinochoroiditis
worldwide, with particularly severe cases in Brazil. The treatment
used for OT is the combination of cotrimoxazole and corticosteroids.
However, this therapy includes prolonged treatment, resistance to
circulating strains, and cytotoxic effects for patients. The intensification
of the inflammatory response against T. gondii can exacerbate retinal tissue damage. In this study, the HDAC6 inhibitor
Tubastatin A was evaluated by intravitreal injection in the murine
ocular toxoplasmosis model. Tubastatin A has presented anti-T. gondii activity and an interesting potential for
immunoregulation in the approach to eye disease. The inhibition of
HDAC6 interferes with the establishment of infection by blocking the
recruitment of the host cell cytoskeleton, which is necessary for
the active entry of tachyzoites. After 5 days of treatment, Tubastatin
A prevented the progression of lesions in the infected retina from
the 10th postinfection day. Tubastatin A restored retinal tissue barriers
and regulated the HDAC6-Hsp90 pathway, leading to decreased VEGF and
HSF1 expression, which may help prevent neovascularization observed
in OT patients. A single intravitreal dose of Tubastatin A established
an anti-inflammatory microenvironment that supported retinal tissue
homeostasis. Tubastatin regulated micro- and macroglial activation,
reduced immunolabeling of Iba1 and GFAP (glial fibrillary acidic),
and decreased the secretion of IL-12, IL-4, and IL-17A, key cytokines
associated with OT pathology. The combination of Tubastatin A with
antifolates may be a viable new treatment regimen to protect retinal
tissue and prevent blindness in patients.