PARIN5, a Novel Thrombin Receptor Antagonist Modulates a Streptozotocin Mice Model for Diabetic Encephalopathy.
Animals
Mice
Diabetes Mellitus, Experimental
/ complications
Disease Models, Animal
Inflammation
/ metabolism
Mice, Inbred C57BL
Prothrombin
/ metabolism
Receptor, PAR-1
/ antagonists & inhibitors
Receptors, Thrombin
/ metabolism
RNA, Messenger
/ metabolism
Streptozocin
Thrombin
/ metabolism
Tumor Necrosis Factor-alpha
/ metabolism
NfL
PAR1
TNF-α
behavioral tests
diabetes mellitus
diabetic encephalopathy
thrombin
Journal
International journal of molecular sciences
ISSN: 1422-0067
Titre abrégé: Int J Mol Sci
Pays: Switzerland
ID NLM: 101092791
Informations de publication
Date de publication:
19 Jan 2023
19 Jan 2023
Historique:
received:
28
12
2022
revised:
16
01
2023
accepted:
17
01
2023
entrez:
11
2
2023
pubmed:
12
2
2023
medline:
15
2
2023
Statut:
epublish
Résumé
Diabetic encephalopathy (DE) is an inflammation-associated diabetes mellitus (DM) complication. Inflammation and coagulation are linked and are both potentially modulated by inhibiting the thrombin cellular protease-activated receptor 1 (PAR1). Our aim was to study whether coagulation pathway modulation affects DE. Diabetic C57BL/6 mice were treated with PARIN5, a novel PAR1 modulator. Behavioral changes in the open field and novel object recognition tests, serum neurofilament (NfL) levels and thrombin activity in central and peripheral nervous system tissue (CNS and PNS, respectively), brain mRNA expression of tumor necrosis factor α (TNF-α), Factor X (FX), prothrombin, and PAR1 were assessed. Subtle behavioral changes were detected in diabetic mice. These were accompanied by an increase in serum NfL, an increase in central and peripheral neural tissue thrombin activity, and TNF-α, FX, and prothrombin brain intrinsic mRNA expression. Systemic treatment with PARIN5 prevented the appearance of behavioral changes, normalized serum NfL and prevented the increase in peripheral but not central thrombin activity. PARIN5 treatment prevented the elevation of both TNF-α and FX but significantly elevated prothrombin expression. PARIN5 treatment prevents behavioral and neural damage in the DE model, suggesting it for future clinical research.
Identifiants
pubmed: 36768341
pii: ijms24032021
doi: 10.3390/ijms24032021
pmc: PMC9917200
pii:
doi:
Substances chimiques
Prothrombin
9001-26-7
Receptor, PAR-1
0
Receptors, Thrombin
0
RNA, Messenger
0
Streptozocin
5W494URQ81
Thrombin
EC 3.4.21.5
Tumor Necrosis Factor-alpha
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Déclaration de conflit d'intérêts
The authors, E.S.S. and J.C., hold a patent to the compound PARIN5.
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