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

Berger JV, Deumens R, Goursaud S, Schäfer S, Lavand'homme P, Joosten EA, Hermans E - J Neuroinflammation (2011)

Bottom Line: 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.Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.

ABSTRACT

Background: Neuroinflammation 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.

Methods: Transgenic rats expressing mutated superoxide dismutase 1 (hSOD1 G93A) 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.

Results: PSNL 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 hSOD1 G93A rats.

Conclusions: Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

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hSOD1G93A rats show higher mRNA levels of the glutamate transporters GLAST and GLT-1 after PSNL. (A) mRNA expression of the glutamate transporter GLAST (normalized for GAPDH mRNA expression) is slightly increased in the ipsilateral dorsal horn of transgenic rats when compared to WT animals at 21 days after PSNL (#p< 0.05). (B) mRNA levels of the glutamate transporter GLT-1 after GAPDH normalization are higher in the ipsilateral dorsal horn of transgenic rats at 21 days after PSNL when compared to the sham control rats or to WT ligated rats ($$$ p< 0.001, # p< 0.05). Each group included 5 animals, ANOVA and Tukey post-hoc test for statistical analyses.
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Figure 5: hSOD1G93A rats show higher mRNA levels of the glutamate transporters GLAST and GLT-1 after PSNL. (A) mRNA expression of the glutamate transporter GLAST (normalized for GAPDH mRNA expression) is slightly increased in the ipsilateral dorsal horn of transgenic rats when compared to WT animals at 21 days after PSNL (#p< 0.05). (B) mRNA levels of the glutamate transporter GLT-1 after GAPDH normalization are higher in the ipsilateral dorsal horn of transgenic rats at 21 days after PSNL when compared to the sham control rats or to WT ligated rats ($$$ p< 0.001, # p< 0.05). Each group included 5 animals, ANOVA and Tukey post-hoc test for statistical analyses.

Mentions: Changes in glial glutamate handling likely contribute to altered pain transmission in the spinal cord of animals with peripheral nerve injuries. Therefore, the expression and activity of the two key glial glutamate transporters were compared in samples from WT and transgenic animals after PSNL. Quantitative PCR revealed that no significant changes in GLAST and GLT-1 mRNA levels were detected at 21 days after lesion in the ipsilateral dorsal quadrant of the lumbar spinal cord of WT rats. In contrast, a discrete but significant increase in GLAST expression was observed when comparing the groups of ligated animals (Figure 5A). Such difference was even more pronounced for GLT-1, as statistical analysis revealed increased expression associated with PSNL in transgenic rats when compared either to transgenic sham littermates or to WT ligated rats (Figure 5B).


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

Berger JV, Deumens R, Goursaud S, Schäfer S, Lavand'homme P, Joosten EA, Hermans E - J Neuroinflammation (2011)

hSOD1G93A rats show higher mRNA levels of the glutamate transporters GLAST and GLT-1 after PSNL. (A) mRNA expression of the glutamate transporter GLAST (normalized for GAPDH mRNA expression) is slightly increased in the ipsilateral dorsal horn of transgenic rats when compared to WT animals at 21 days after PSNL (#p< 0.05). (B) mRNA levels of the glutamate transporter GLT-1 after GAPDH normalization are higher in the ipsilateral dorsal horn of transgenic rats at 21 days after PSNL when compared to the sham control rats or to WT ligated rats ($$$ p< 0.001, # p< 0.05). Each group included 5 animals, ANOVA and Tukey post-hoc test for statistical analyses.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3090736&req=5

Figure 5: hSOD1G93A rats show higher mRNA levels of the glutamate transporters GLAST and GLT-1 after PSNL. (A) mRNA expression of the glutamate transporter GLAST (normalized for GAPDH mRNA expression) is slightly increased in the ipsilateral dorsal horn of transgenic rats when compared to WT animals at 21 days after PSNL (#p< 0.05). (B) mRNA levels of the glutamate transporter GLT-1 after GAPDH normalization are higher in the ipsilateral dorsal horn of transgenic rats at 21 days after PSNL when compared to the sham control rats or to WT ligated rats ($$$ p< 0.001, # p< 0.05). Each group included 5 animals, ANOVA and Tukey post-hoc test for statistical analyses.
Mentions: Changes in glial glutamate handling likely contribute to altered pain transmission in the spinal cord of animals with peripheral nerve injuries. Therefore, the expression and activity of the two key glial glutamate transporters were compared in samples from WT and transgenic animals after PSNL. Quantitative PCR revealed that no significant changes in GLAST and GLT-1 mRNA levels were detected at 21 days after lesion in the ipsilateral dorsal quadrant of the lumbar spinal cord of WT rats. In contrast, a discrete but significant increase in GLAST expression was observed when comparing the groups of ligated animals (Figure 5A). Such difference was even more pronounced for GLT-1, as statistical analysis revealed increased expression associated with PSNL in transgenic rats when compared either to transgenic sham littermates or to WT ligated rats (Figure 5B).

Bottom Line: 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.Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

View Article: PubMed Central - HTML - PubMed

Affiliation: Group of Neuropharmacology, Institute of Neuroscience, Université catholique de Louvain, Brussels, Belgium.

ABSTRACT

Background: Neuroinflammation 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.

Methods: Transgenic rats expressing mutated superoxide dismutase 1 (hSOD1 G93A) 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.

Results: PSNL 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 hSOD1 G93A rats.

Conclusions: Taken together, our findings show that exacerbated microglial activation and subsequent inflammatory and nitroxidative processes are associated with the severity of neuropathic pain symptoms.

Show MeSH
Related in: MedlinePlus