Prothrombin kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation

Kim, Sang Ryong; Chung, Eun Sook; Bok, Eugene; Baik, Hyung Hwan; Chung, Young Cheul; Won, So Yoon; Joe, Eunhye; Kim, Tae Hyong; Kim, Soung Soo; Jin, Min Young; Choi, Sang Ho; Jin, Byung Kwan

doi:10.1002/jnr.22318

Cited by 43Neuroinflammation and Neurodegeneration MechanismsParkinson's Disease Mechanisms and TreatmentsNuclear Receptors and Signaling

Prothrombin kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation

Kim, Sang Ryong, Chung, Eun Sook, Bok, Eugene, Baik, Hyung Hwan, Chung, Young Cheul, Won, So Yoon, Joe, Eunhye, Kim, Tae Hyong +4 more·2010·Journal of Neuroscience Research

DOI 10.1002/jnr.22318

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Abstract

We have shown that prothrombin kringle-2 (pKr-2), a domain of human prothrombin distinct from thrombin could activate cultured rat brain microglia in vitro. However, little is known whether pKr-2-induced microglial activation could cause neurotoxicity on dopaminergic (DA) neurons in vivo. To address this question, pKr-2 was injected into the rat substantia nigra (SN). Tyrosine hydroxylase (TH) immunohistochemistry experiments demonstrate significant loss of DA neurons seven days after injection of pKr-2. In parallel, pKr-2-activated microglia were detected in the SN with OX-42 and OX-6 immunohistochemistry. Reverse transcription PCR and double-label immunohistochemistry revealed that activated microglia in vivo exhibit early and transient expression of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and several proinflammatory cytokines. The pKr-2-induced loss of SN DA neurons was partially inhibited by the NOS inhibitor N(G)-nitro-L-arginine methyl ester hydrochloride, and the COX-2 inhibitor DuP-697. Extracellular signal-regulated kinase 1/2, c-Jun N-terminal kinase and p38 mitogen-activated protein kinase were activated in the SN as early as 1 hr after pKr-2 injection, and localized within microglia. Inhibition of these kinases led to attenuation of mRNA expression of iNOS, COX-2 and several proinflammatory cytokines, and rescue of DA neurons in the SN. Intriguingly, following treatment with pKr-2 in vitro, neurotoxicity was detected exclusively in co-cultures of mesencephalic neurons and microglia, but not microglia-free neuron-enriched mesencephalic cultures, indicating that microglia are required for pKr-2 neurotoxicity. Our results strongly suggest that microglia activated by endogenous compound(s), such as pKr-2, are implicated in the DA neuronal cell death in the SN.

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pKr-2 induced DA neuronal death in an experimental PD model.
“Also, pKr-2 induced DA neuronal death in an experimental PD model (Kim et al., 2010).”
From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Kim et al., 2010

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Thrombin-induced microglial activation contributes to the degeneration of nigral dopaminergic neurons in vivo
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Authors: Kim, S. R., Chung, E. S., Bok, E., Baik, H. H., Chung, Y. C., Won, S. Y., Joe, E., Kim, T. H., Kim, S. S., Jin, M. Y., Choi, S. H., & Jin, B. K.
Affiliations: Ajou University (KR)
Kyung Hee University (KR)
Yonsei University (KR)
Corresponding author: Jin, Byung Kwan
ORCID: Kim, Sang Ryong
Bok, Eugene
Chung, Young Cheul
Won, So Yoon
Jin, Min Young
Jin, Byung Kwan
Venue: Journal of Neuroscience Research
Publisher: Wiley
Published: 2009-12-18
Volume: 88
Issue: 7
Pages: 1537-1548
ISSN: 0360-4012 (ISSN-L)
1097-4547
DOI: 10.1002/jnr.22318
OpenAlex: W1996966804
Cited by: 43
References: 48
Citations by year: 2026: 3 · 2023: 3 · 2022: 3 · 2021: 5 · 2020: 3 · 2019: 3 · 2018: 3 · 2017: 3 · 2016: 3 · 2015: 6 · 2014: 4 · 2013: 1
FWCI: 0.64
Type: journal article
Language: en
Open access: closed
Licence: onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations: Journal of Neuroscience Research (publishedVersion)
PubMed (publishedVersion)
AJOU Open Repository (Ajou University) (submittedVersion)
Topics: Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Nuclear Receptors and Signaling
Keywords: microglial activation, dopaminergic neuron death, substantia nigra, neuroinflammation, inducible nitric oxide synthase, cyclooxygenase-2, inflammatory cytokines, MAPK signaling, ERK1/2, JNK, p38 MAPK, nitric oxide synthase inhibitors, COX-2 inhibitors, neurotoxicity, mesencephalic neurons, Parkinson's disease
MeSH terms: Animals, Cells, Cultured, Dopamine, Female, Gliosis, Neurons, Parkinson Disease, Prothrombin, RNA, Messenger, Substantia Nigra, Rats, Sprague-Dawley, Microglia, Kringles, Inflammation Mediators, Coculture Techniques, Nitric Oxide Synthase, MAP Kinase Signaling System, CD11b Antigen, Rats, Cyclooxygenase 2, Cyclooxygenase 2 Inhibitors, Nitric Oxide Synthase Type II

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Prothrombin kringle-2 induces death of mesencephalic dopaminergic neurons in vivo and in vitro via microglial activation

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