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 γ-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 dopaminer...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-11672-w |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849344293137809408 |
|---|---|
| author | Sijoon Lee Munki Kim Soo-Eun Sung Gonsup Kim Chungkil Won |
| author_facet | Sijoon Lee Munki Kim Soo-Eun Sung Gonsup Kim Chungkil Won |
| author_sort | Sijoon Lee |
| collection | DOAJ |
| description | Abstract Dopamine (DA) plays an essential role in regulating γ-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. |
| format | Article |
| id | doaj-art-cb2df482b0aa4a738215fc9c47616fe8 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-cb2df482b0aa4a738215fc9c47616fe82025-08-20T03:42:41ZengNature PortfolioScientific Reports2045-23222025-07-0115111110.1038/s41598-025-11672-wSKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegenerationSijoon Lee0Munki Kim1Soo-Eun Sung2Gonsup Kim3Chungkil Won4Preclinical Research Center, Daegu-Gyeongbuk Medical Innovation FoundationDepartment of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National UniversityPreclinical Research Center, Daegu-Gyeongbuk Medical Innovation FoundationDepartment of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National UniversityDepartment of Veterinary Medicine & Institute of Animal Medicine, Gyeongsang National UniversityAbstract Dopamine (DA) plays an essential role in regulating γ-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.https://doi.org/10.1038/s41598-025-11672-wDopamine receptorsGAD67SKF38393Heparanase-1Tyrosine hydroxylase |
| spellingShingle | Sijoon Lee Munki Kim Soo-Eun Sung Gonsup Kim Chungkil Won SKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegeneration Scientific Reports Dopamine receptors GAD67 SKF38393 Heparanase-1 Tyrosine hydroxylase |
| title | SKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegeneration |
| title_full | SKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegeneration |
| title_fullStr | SKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegeneration |
| title_full_unstemmed | SKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegeneration |
| title_short | SKF-38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase-1 in 6-hydroxydopamine-induced neurodegeneration |
| title_sort | skf 38393 regulates the expression of glutamic acid decarboxylase 67 via heparanase 1 in 6 hydroxydopamine induced neurodegeneration |
| topic | Dopamine receptors GAD67 SKF38393 Heparanase-1 Tyrosine hydroxylase |
| url | https://doi.org/10.1038/s41598-025-11672-w |
| work_keys_str_mv | AT sijoonlee skf38393regulatestheexpressionofglutamicaciddecarboxylase67viaheparanase1in6hydroxydopamineinducedneurodegeneration AT munkikim skf38393regulatestheexpressionofglutamicaciddecarboxylase67viaheparanase1in6hydroxydopamineinducedneurodegeneration AT sooeunsung skf38393regulatestheexpressionofglutamicaciddecarboxylase67viaheparanase1in6hydroxydopamineinducedneurodegeneration AT gonsupkim skf38393regulatestheexpressionofglutamicaciddecarboxylase67viaheparanase1in6hydroxydopamineinducedneurodegeneration AT chungkilwon skf38393regulatestheexpressionofglutamicaciddecarboxylase67viaheparanase1in6hydroxydopamineinducedneurodegeneration |