SKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegeneration

Abstract

Dopamine (DA) plays an essential role in regulating gamma-aminobutyric acid (GABA) neurons in the brain. This study aimed to investigate the effects of DA receptor agonists on the expression of glutamic acid decarboxylase 67 (GAD67) in the context of 6-hydroxydopamine (6-OHDA)-induced dopaminergic neurodegeneration. To explore the potential involvement of DA receptor agonists in modulating GAD67 expression, these agonists were administered to primary cultured neurons and the substantia nigra in a mouse model with 6-OHDA-induced lesions. The GAD67 expression was subsequently assessed via Western blotting and immunohistochemistry analysis. Results revealed an increased GAD67 expression in in vitro and in vivo models induced by 6-OHDA. Interestingly, treatment with the D1-like receptor agonist SKF38393 led to a decrease in the GAD67 expression. Meanwhile, treatment with the D2-like receptor agonist quinpirole resulted in an increase in the GAD67 expression. Further, the inhibitory effect of SKF38393 on GAD67 was negated when the D1 receptor-selective antagonist LE300 was administered. Conversely, the expression of tyrosine hydroxylase was not affected by the DA receptor agonists SKF38393 or quinpirole. Subsequently, the association between heparanase-1 and the increased expression of GAD67 was examined. The GAD67 and heparanase-1 expression levels increased due to 6-OHDA treatment. However, they decreased when SKF38393 was administered. In contrast, treatment with the heparanase inhibitor suramin led to a reduction in the GAD67 expression. Therefore, the DA D1-like receptor agonist SKF38393 can modulate GAD67 expression under DA degenerative conditions by interacting with heparanase-1.