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A Novel Pyrazolo[3,4-d]pyrimidine Induces Heme Oxygenase-1 and Exerts Anti-Inflammatory and Neuroprotective Effects

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Abstract
--------e-pub(22.1.12)-----------
The anti-oxidant enzyme heme oxygenase-1 (HO-1) is known to exert anti-inflammatory effects. From a library of pyrazolo[3,4-d]pyrimidines, we identified a novel compound KKC080096 that upregulated HO-1 at the mRNA and protein levels in microglial BV-2 cells. KKC080096 exhibited antiinflammatory effects via suppressing nitric oxide, interleukin-1β (IL-1β), and iNOS production in lipopolysaccharide (LPS)-challenged cells. It inhibited the phosphorylation of IKK and MAP kinases (p38, JNK, ERK), which trigger inflammatory signaling, and whose activities are inhibited by HO-1. Further, KKC080096 upregulated anti-inflammatory marker (Arg1, YM1, CD206, IL-10, transforming growth factor-β [TGF-β]) expression. In 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridinetreated mice, KKC080096 lowered microglial activation, protected the nigral dopaminergic neurons, and nigral damage-associated motor deficits. Next, we elucidated the mechanisms by which KKC080096 upregulated HO-1. KKC080096 induced the phosphorylation of AMPK and its known upstream kinases LKB1 and CaMKKbeta, and pharmacological inhibition of AMPK activity reduced the effects of KKC080096 on HO-1 expression and LPS-induced NO generation, suggesting that KKC080096-induced HO-1 upregulation involves LKB1/AMPK and CaMKKbeta/AMPK pathway activation. Further, KKC080096 caused an increase in cellular Nrf2 level, bound to Keap1 (Nrf2 inhibitor protein) with high affinity, and blocked Keap1-Nrf2 interaction. This Nrf2 activation resulted in concurrent induction of HO-1 and other Nrf2-targeted antioxidant enzymes in BV- 2 and in dopaminergic CATH.a cells. These results indicate that KKC080096 is a potential therapeutic for oxidative stress and inflammation-related neurodegenerative disorders such as Parkinson’s disease.
Author(s)
이지애권영원김혜리신나리손효진정찬성김동진황온유
Issued Date
2021
Type
Article
Keyword
4-d]pyrimidineParkinson’s diseaseheme oxygenase-1neuroinflammationpyrazolo[3
DOI
10.14348/molcells.2021.0074
URI
https://oak.ulsan.ac.kr/handle/2021.oak/8483
https://ulsan-primo.hosted.exlibrisgroup.com/primo-explore/fulldisplay?docid=TN_cdi_crossref_primary_10_14348_molcells_2021_0074&context=PC&vid=ULSAN&lang=ko_KR&search_scope=default_scope&adaptor=primo_central_multiple_fe&tab=default_tab&query=any,contains,A%20Novel%20Pyrazolo%5B3,4-d%5Dpyrimidine%20Induces%20Heme%20Oxygenase-1%20and%20Exerts%20Anti-Inflammatory%20and%20Neuroprotective%20Effects&offset=0&pcAvailability=true
Publisher
MOLECULES AND CELLS
Location
대한민국
Language
영어
ISSN
1016-8478
Citation Volume
44
Citation Number
12
Citation Start Page
00
Citation End Page
00
Appears in Collections:
Medicine > Medicine
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