Physiopathological and molecular characterization of a transgenic mouse overexpressing tnf-alpha in schwann cells reveals a model for chronic peripheral neuropathy
- Autores: Belén García
- Directores de la Tesis: Assumpció Bosc Merino (dir. tes.)
- Lectura: En la Universitat Autònoma de Barcelona ( España ) en 2017
- Idioma: español
- Tribunal Calificador de la Tesis: Enric Verdú (presid.), Esther Udina Bonet (secret.), Jordi Casanova Molla (voc.)
- Programa de doctorado: Programa de Doctorado en Bioquímica, Biología Molecular y Biomedicina por la Universidad Autónoma de Barcelona
- Materias:
- Enlaces
- Tesis en acceso abierto en: TDX
- Resumen
Tumor Necrosis Factor alpha (TNF-α) has been implicated in the pathogenesis of diabetic peripheral neuropathy (DPN), among other inflammatory demyelinating diseases and neuropathic pain. TNF-α is a pro-inflammatory cytokine that can act at several steps in the demyelination process. It is produced by Schwann cells in the peripheral nervous system (PNS) after nerve injury and released into the local environment to attract and activate macrophages at the site of injury, contributing to Wallerian degeneration and demyelination.
An important observation in different peripheral neuropathies is the increased levels of TNF-α in plasma, being implicated in the onset and/or malignant progression of peripheral nerve diseases. In vivo studies demonstrated a local inflammation in the sciatic nerve of rats after injection of TNF-α, followed by demyelination and axonal degeneration. Furthermore, the administration of TNF-α resulted in acute mechanical hyperalgesia, a main characteristic of neuropathic pain and therefore TNF-α is postulated as a biomarker for painful alterations after nerve injury.
Nowadays, there is not an effective therapy to stop and reverse the axonal degeneration and pain that characterize peripheral neuropathies. Unfortunately, the preclinical data using animal models demonstrated the lack of optimum models and outcome measures to underlay the pathogenesis of the disease. An appropriate animal model is critical for replicating the essential features of peripheral neuropathies, understanding DPN pathophysiology and to develop effective strategies.
Although the increasing worldwide prevalence of diabetes has fueled the development of several mouse models, the main discrepancies related to the proper generation of a mouse model for the study of peripheral neuropathies, and complications of DM, like diabetic peripheral neuropathy, are a consequence of the anatomical differences and the incomparable life expectancies between humans and rodents.
With the aim to characterize TNF-α effects in the development of peripheral neuropathy and chronic neuropathic pain, a transgenic mouse model overexpressing TNF-α in Schwann cells, under the peripheral myelin protein P0 promoter, was generated.
Here we characterized the overexpression of TNF-α in myelinated Schwann cells at different steps of myelination (postnatal days 5, 21 and 65) showing that high levels of TNF-α in sciatic nerve leads to the downregulation of the major PNS myelin proteins (P0, MBP, PMP22, MAG) compared to wild type mice, correlating with the loss of structured myelin and an increase in p75NTR in the sciatic nerve, a marker for immature and non-myelinated Schwann cells. Local inflammation was also demonstrated by high levels of macrophage infiltration in both sciatic nerve and spinal cord, compared with wild type animals.
Furthermore, stress conditions were induced by sciatic nerve crush after which recovery and subsequent remyelination were delayed in the transgenic mice, as evaluated by the Sciatic Functional Index and electrophysological tests. On the other hand, algesimetrical tests revealed unaltered mechanical nociception, with or without injury, although transgenic animals showed thermal hypersensivity, higher after peripheral injury, correlating with the microglial and astrocyte activation in the spinal cord. Moreover, high expression of BDNF and CCL2, as well as overexpression of Nav1.7 and Nav1.8 channels, all related to the maintenance of chronic inflammatory pain, were detected in DRGs of TNF-α transgenic mice.
A morphometrical study of tibialis nerves showed no differences in the total nerve surface between genotypes and injury. However, transgenic mice exhibited a slight reduction in the axonal diameter and a significant thinner myelin sheath than wild type animals.
This model could be helpful in the characterization of the role TNF-α in pain development, injury and DPN as well as in developing efficient therapeutic strategies to modulate such pathological conditions.
