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Published on: August 11, 2021
AMPK activation attenuates central sensitization in a recurrent nitroglycerin-induced chronic migraine mouse model by
Guangshuang Lu1,2,3, Shaobo Xiao1,2, Fanchao Meng1,2
1Medical School of Chinese PLA, Beijing, 100853, China.
Background:
Energy metabolism disorders and neurogenic inflammation play important roles in the central sensitization to chronic migraine (CM). AMP-activated protein kinase (AMPK) is an intracellular energy sensor, and its activation regulates inflammation and reduces neuropathic pain. However, studies on the involvement of AMPK in the regulation of CM are currently lacking. Therefore, this study aimed to explore the mechanism underlying the involvement of AMPK in the central sensitization to CM.
Methods:
Mice with recurrent nitroglycerin (NTG)-induced CM were used to detect the expression of AMPK protein in the trigeminal nucleus caudalis (TNC). Following intraperitoneal injection of the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C, the mechanical pain threshold, activity level, and pain-like behaviors in the mice were measured. The expression of calcitonin gene-related peptide (CGRP) and cytokines, M1/M2 microglia, and NF-κB pathway activation were detected after the intervention.
Results:
Repeated NTG injections resulted in a gradual decrease in AMPK protein expression, and the negative regulation of AMPK by increased ubiquitin-like plant homeodomain and RING finger domain 1 (UHRF1) expression may counteract AMPK activation by increasing ADP/ATP. AICAR can reduce the hyperalgesia and pain-like behaviors of CM mice, improve the activity of mice, reduce the expression of CGRP, IL-1β, IL-6, and TNF-α in the TNC region, and increase the expression of IL-4 and IL-10. Moreover, AMPK in TNC was mainly located in microglia. AICAR could reduce the expression of inducible NO synthase (iNOS) in M1 microglia and increase the expression of Arginase 1 (Arg1) in M2 microglia by inhibiting the activation of NF-κB pathway.
Conclusions:
AMPK was involved in the central sensitization of CM, and the activation of AMPK reduced neuroinflammation in NTG-induced CM mice. AMPK may provide new insights into interventions for energy metabolism disorders and neurogenic inflammation in migraine.
Insights
AMP-activated protein kinase (AMPK) activation reduces central sensitization in chronic migraine (CM) by decreasing neuroinflammation. This study shows AMPK activation alleviates pain and improves activity in CM mouse models, offering new therapeutic insights.
Area of Science:
- Neuroscience
- Molecular Biology
- Pain Research
Background:
- Energy metabolism disorders and neurogenic inflammation are key factors in chronic migraine (CM) central sensitization.
- AMP-activated protein kinase (AMPK), an energy sensor, regulates inflammation and neuropathic pain.
- The role of AMPK in CM regulation is not yet understood.
Purpose of the Study:
- To investigate the mechanism of AMPK's involvement in central sensitization in CM.
- To explore the therapeutic potential of AMPK activation for CM.
Main Methods:
- Utilized a mouse model of recurrent nitroglycerin (NTG)-induced CM to assess AMPK protein expression in the trigeminal nucleus caudalis (TNC).
- Administered the AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) and inhibitor compound C to evaluate effects on pain, activity, and related molecular markers.
- Measured expression of calcitonin gene-related peptide (CGRP), cytokines (IL-1β, IL-6, TNF-α, IL-4, IL-10), microglial phenotypes (M1/M2), and NF-κB pathway activation.
Main Results:
- NTG induction decreased AMPK expression, potentially counteracted by increased UHRF1.
- AICAR treatment reduced hyperalgesia, pain-like behaviors, and TNC expression of CGRP, IL-1β, IL-6, and TNF-α, while increasing IL-4 and IL-10.
- AICAR modulated microglial M1/M2 balance and inhibited NF-κB activation, reducing iNOS and increasing Arg1 expression.
Conclusions:
- AMPK activation plays a significant role in mitigating central sensitization in a mouse model of CM.
- AMPK activation effectively reduces neuroinflammation and associated pain behaviors in NTG-induced CM.
- Targeting AMPK may offer novel therapeutic strategies for managing energy metabolism disorders and neuroinflammation in migraine.
