Transient early neurotrophin release and delayed inflammatory cytokine release by microglia in response to PAR-2 stimulation

Abstract

Activated microglia exerts both beneficial and deleterious effects on neurons, but the signaling mechanism controlling these distinct responses remain unclear. We demonstrated that treatment of microglial cultures with the PAR-2 agonist, 2-Furoyl-LIGRLO-NH2, evoked early transient release of BDNF, while sustained PAR-2 stimulation evoked the delayed release of inflammatory cytokines (IL-1β and TNF-α) and nitric oxide. Culture medium harvested during the early phase (at 1 h) of microglial activation induced by 2-Furoyl-LIGRLO-NH2 (microglial conditioned medium, MCM) had no deleterious effects on cultured neurons, while MCM harvested during the late phase (at 72 h) promoted DNA fragmentation and apoptosis as indicated by TUNEL and annexin/PI staining. Blockade of PAR-1 during the early phase of PAR-2 stimulation enhanced BDNF release (by 11%, small but significant) while a PAR-1 agonist added during the late phase (24 h after 2-Furoyl-LIGRLO-NH2 addition) suppressed the release of cytokines and NO. The neuroprotective and neurotoxic effects of activated microglial exhibit distinct temporal profiles that are regulated by PAR-1 and PAR-2 stimulation. It may be possible to facilitate neuronal recovery and repair by appropriately timed stimulation and inhibition of microglial PAR-1 and PAR-2 receptors.

Homeostatic effects of coagulation protease‐dependent signaling and protease activated receptors

“…In agreement with the above‐proposed concentration‐dependent effects of thrombin in the cardiovascular system and the lung, several studies revealed dichotomous effects of thrombin in neurons and astrocytes . Furthermore, a temporal regulation of PAR‐1/PAR‐2 expression and signaling has been shown in microglia cells in vitro . While short‐term PAR‐2 activation with 2‐Furoyl‐LIGRLO‐NH2 evoked the release of the neurotrophin BDNF, sustained PAR‐2 activation caused release of inflammatory cytokines (IL‐1β and TNF‐α) and NO.…”

Altered Prostasin (CAP1/Prss8) Expression Favors Inflammation and Tissue Remodeling in DSS-induced Colitis

“…Primers for IL-6, TNFa, TGFb1, PAR2, iNOS, and Gapdh were previously described. [29][30][31][32] The sequences of the primers used were the following: IL-1b_F: 5'-CCT TGT GCA AGT GTC TGA AGC-3', IL-…”

Effect of oxidative stress induced by intracranial iron overload on central pain after spinal cord injury

“…Previous studies have shown that intracranial iron overload plays an important role in the development and progression of some central nervous system diseases, such as Alzheimer’s disease, Parkinson’s disease, and cerebral hemorrhage [ 9 – 11 ]. It has also been suggested that oxidative stress injury of neurons is related to iron toxicity via the Fenton reaction; peroxidation may affect neuronal ATPase activity, inhibit calcium influx, mediate inflammation [ 12 , 13 ], and ultimately lead to neuronal injury or loss [ 14 , 15 ].…”