PARIN5, a Novel Thrombin Receptor Antagonist Modulates a Streptozotocin Mice Model for Diabetic Encephalopathy

Valery Golderman, Zehavit Goldberg, Shany Guly Gofrit, Amir Dori, Nicola Maggio, Joab Chapman, Ifat Sher, Ygal Rotenstreich, Efrat Shavit-Stein

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish
Article number2021
JournalInternational Journal of Molecular Sciences
Volume24
Issue number3
DOIs
StatePublished - Feb 2023

Keywords

  • NfL
  • PAR1
  • TNF-α
  • behavioral tests
  • diabetes mellitus
  • diabetic encephalopathy
  • thrombin

Fingerprint

Dive into the research topics of 'PARIN5, a Novel Thrombin Receptor Antagonist Modulates a Streptozotocin Mice Model for Diabetic Encephalopathy'. Together they form a unique fingerprint.

Cite this