Resveratrol suppresses glial activation and alleviates trigeminal neuralgia via activation of AMPK.
BACKGROUND
Glial activation and neuroinflammation in the spinal trigeminal nucleus (STN) play a pivotal role in the genesis and maintenance of trigeminal neuralgia (TN). Resveratrol, a natural compound from grape and red wine, has a potential anti-inflammatory effect. We hypothesized that resveratrol could significantly suppress neuroinflammation in the STN mediated by glial activation and further relieve TN. In this study, we evaluated whether resveratrol could alleviate trigeminal allodynia and explore the mechanism underlying the antinociceptive effect of resveratrol.


METHODS
Animals were orally injected with resveratrol after chronic constriction injury (CCI) of the infraorbital nerve. Mechanical thresholds of the affected whisker pad were measured to assess nociceptive behaviors. The STN was harvested to quantify the changing levels of p-NR1, p-PKC, TNF-α, and IL1-β by western blotting and detect the expression of calcitonin gene-related peptide (CGRP) and c-Fos by immunofluorescence. Glial activation was observed by immunofluorescence and western blotting. Mitogen-activated protein kinase (MAPK) phosphorylation in vivo and in vitro was examined by western blotting.


RESULTS
We found that resveratrol significantly attenuated trigeminal allodynia dose-dependently and decreased the increased expression of CGRP and c-Fos in the STN. Additionally, resveratrol showed an inhibitory effect on CCI-evoked astrocyte and microglia activation and reduced production of pro-inflammatory cytokines in the STN. Furthermore, the antinociceptive effect of resveratrol was partially mediated by reduced phosphorylation of MAP kinases via adenosine monophosphate-activated protein kinase (AMPK) activation.


CONCLUSIONS
AMPK activation in the STN glia via resveratrol has utility in the treatment of CCI-induced neuroinflammation and further implicates AMPK as a novel target for the attenuation of trigeminal neuralgia.
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China. yangyanjing@njmu.edu.cn.
Yan-jing
YJ
Yang
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China.
Liang
L
Hu
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China.
Ye-peng
YP
Xia
Jiangsu Key Laboratory of Neurodegeneration, Department of Pharmacology, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China.
Chun-yi
CY
Jiang
Department of Pathology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
Chen
C
Miao
Department of Pathology, First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
Chun-qing
CQ
Yang
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China.
Miao
M
Yuan
Jiangsu Key Laboratory of Oral Disease, Nanjing Medical University, 140 Hanzhong Road, Nanjing, Jiangsu, 210029, People's Republic of China. lw603@njmu.edu.cn.
Lin
L
Wang
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D015153:Blotting, Western; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D005455:Fluorescent Antibody Technique; D006930:Hyperalgesia / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D009457:Neuroglia / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D014277:Trigeminal Neuralgia / Q000378:metabolism / Q000503:physiopathology*
D000893:Anti-Inflammatory Agents; D013267:Stilbenes; D055372:AMP-Activated Protein Kinases; D000077185:Resveratrol
AMPK; Cytokines; Glia activation; MAPK; Resveratrol; TN