Fn Polymerization Regulates Blood-Spinal Cord Barrier Permeability and Inflammatory Response in Painful Neuropathy

Project: National Science and Technology CouncilNational Science and Technology Council Academic Grants

Project Details

Abstract

Alteration of the microenvironment in the spinal cord is responsible for the central sensitization of the neuropathic pain after the peripheral nerve injury. Except for neurons, glial cells and inflammatory cells extravasated from circulation through the compromised blood‐spinal cord barrier (BSCB) take parts in the central sensitization in the spinal cord. Glial cells in the spinal cord are activated in response to the peripheral nerve injury and upregulate their production of proinflammatory cytokines, which in turn disrupt the BSCB and exacerbate the hypersensitization of the neurons. In addition to the increased proinflammatory cytokines, fibronectin (FN), a principle component of extracellular matrix (ECM), has recently been shown an important role in the pain mechanism. Generally, the expression of FN in the spinal cord is limited to little amount in the subendothelial matrix of the microvessels. FN matrix deposition is significantly increased in the spinal cord microvessels and parenchyma in animals suffering neuropathic pain. Via binding to its cell surface receptor, integrin, FN is known to promote glial cell activation and dissociate endothelial cell‐cell adhesion complex leading to a leaky endothelial barrier. Therefore, we hypothesize that the robust expression of FN in the spinal cord after peripheral nerve injury may contribute to initiate the neuropathic pain in animals. In this proposal, we will test the hypothesis that inhibiting FN matrix assembly decouples the interaction of FN and integrin thus blocks the integrin‐induced signaling in glial and endothelial cells. In addition, inhibiting FN polymerization also attenuates the neuropathic pain in animals following peripheral nerve injury. The aims are: 1) to ascertain whether inhibiting FN polymerization restores the TNF‐‐induced endothelial barrier dysfunction by blocking integrin activation and the subsequent intracellular signaling; 2) to determine whether inhibition of FN polymerization decreases the integrin‐induced intracellular signaling and cytokine/chemokine production in FN‐activated spinal microglia and astrocyte; 3) to determine whether inhibition of FN polymerization by administrating FN polymerization inhibitor into animals subjected to the peripheral nerve injury decreases neuropathic pain. These results will provide us an insight to understand the mechanism in which FN regulate neuropathic pain and lead to the development of a treatment strategy for neuropathic pain in the future.

Project IDs

Project ID:PC10108-0907
External Project ID:NSC101-2320-B182-004
StatusFinished
Effective start/end date01/08/1231/07/13

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