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

Ocular toxoplasmosis (OT), caused by <i>Toxoplasma gondii</i>, 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 <i>T. gondii</i> 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-<i>T. gondii</i> 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.