Intraperitoneal Administration of Adenosine A2A Receptor Antagonist Reduces Neuroinflammatory and Antioxidant Responses in GM2 Gangliosidosis Mouse Model.

Tay-Sachs disease (TSD) is a fatal lysosomal storage disorder characterized by neuronal GM2 ganglioside accumulation and progressive neurodegeneration. Neuroinflammation and oxidative stress are increasingly seen as key factors in disease progression. In this study, we evaluated the effects of istradefylline, a selective adenosine A2A receptor antagonist, in the Hexa-/-Neu3-/- mouse model, which closely recapitulates the neuropathological features of human TSD. Istradefylline treatment reduced the expression of several proinflammatory markers, including Ccl2, Ccl3, Ccl5, Cxcl10, Il1b, and Gfap, particularly in the cortex. Immunohistochemical analysis indicated reduced astrogliosis and microgliosis and increased CNPase-positive oligodendrocytes following treatment. The two-phase regimen also modulated antioxidant-response gene expression, including Sod2, Catalase, and Ttase1, and increased cortical APE1 protein abundance. Behavioral assessment demonstrated improved rotarod performance, particularly following two-stage treatment, whereas the open-field findings did not support a significant effect on anxiety-like behavior or locomotor activity. Istradefylline did not substantially reduce GM2 accumulation or restore neuronal density, indicating that it did not correct the primary storage pathology or prevent associated neuronal loss. Overall, istradefylline attenuated selected neuroinflammatory and glial alterations and modulated antioxidant-response markers in Hexa-/-Neu3-/- mice. These findings support further investigation of A2A receptor antagonism as an adjunctive symptomatic and anti-inflammatory strategy, potentially in combination with treatments that directly target the underlying enzymatic deficiency.