Enhanced neuroinflammation and pain hypersensitivity after peripheral nerve injury in rats expressing mutated superoxide dismutase 1

Abstract

BackgroundNeuroinflammation and nitroxidative stress are implicated in the pathophysiology of neuropathic pain. In view of both processes, microglial and astroglial activation in the spinal dorsal horn play a predominant role. The present study investigated the severity of neuropathic pain and the degree of glial activation in an inflammatory- and nitroxidative-prone animal model.MethodsTransgenic rats expressing mutated superoxide dismutase 1 (hSOD1G93A) are classically used as a model for amyotrophic lateral sclerosis (ALS). Because of the associated inflammatory- and nitroxidative-prone properties, this model was used to study thermal and mechanical hypersensitivity following partial sciatic nerve ligation (PSNL). Next to pain hypersensitivity assessment, microglial and astroglial activation states were moreover characterized, as well as inflammatory marker gene expression and the glutamate clearance system.ResultsPSNL induced thermal and mechanical hypersensitivity in both wild-type (WT) and transgenic rats. However, the degree of thermal hypersensitivity was found to be exacerbated in transgenic rats while mechanical hypersensitivity was only slightly and not significantly increased. Microglial Iba1 expression was found to be increased in the ipsilateral dorsal horn of the lumbar spinal cord after PSNL but such Iba1 up-regulation was enhanced in transgenic rats as compared WT rats, both at 3 days and at 21 days after injury. Moreover, mRNA levels of Nox2, a key enzyme in microglial activation, but also of pro-inflammatory markers (IL-1β and TLR4) were not modified in WT ligated rats at 21 days after PSNL as compared to WT sham group while transgenic ligated rats showed up-regulated gene expression of these 3 targets. On the other hand, the PSNL-induced increase in GFAP immunoreactivity spreading that was evidenced in WT rats was unexpectedly found to be attenuated in transgenic ligated rats. Finally, GLT-1 gene expression and uptake activity were shown to be similar between WT sham and WT ligated rats at 21 days after injury, while both parameters were significantly increased in the ipsilateral dorsal region of the lumbar spinal cord of hSOD1G93A rats.ConclusionsTaken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

Regulation of Postnatal Forebrain Amoeboid Microglial Cell Proliferation and Development by the Transcription Factor Runx1

“…10S,T ). Microglia aggregates with similar characteristics have been previously observed in the injured or diseased spinal cord and shown to contain microglia with morphological and immunological hallmarks of activation (Sanagi et al, 2010;Berger et al, 2011;David and Kroner, 2011). Interestingly, Runx1 expression was detected in only a subpopulation of microglia in these aggregates, possibly because not all cells in these clusters were equally activated.…”

Opposite regulation of metabotropic glutamate receptor 3 and metabotropic glutamate receptor 5 by inflammatory stimuli in cultured microglia and astrocytes

“…Regarding microglia, LPS triggered the gene up-regulation of CD11b in both genotypes. These changes were, however, clearly enhanced in hSOD1 G93A microglia, validating the inflammatory-prone properties of the ALS model, as suggested in vitro (Xiao et al, 2007) and in vivo (Berger et al, 2011). Down-regulation of mGluR5 was already evidenced in differentiated astrocytes treated with IL-1␤ (Aronica et al, 2005) or thrombin (Miller et al, 1996), and in naive astrocytes incubated with conditioned media from LPS-activated microglia (Tilleux et al, 2007), both at the mRNA and protein levels.…”

New Insights onNOXEnzymes in the Central Nervous System

“…In mouse models, NOX2 expression in the lumbar spinal cord can also be used as a marker of neuroinflammation and microgliosis (15,20). Indeed, when comparing microglia purified from SOD1 G93A mice at different stages of disease, Liao et al (108) observed that microglia at an early stage presented a neuroprotective activity while it became neurotoxic for primary motoneurons at an end stage.…”