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Published on: March 30, 2018
Emodin Promotes Peripheral Nerve Repair by Modulating Inflammasome Activation Through Autophagy via the
Zhengyang Long1,2,3,4, Yixun Huang1,2,3,4, Tao Lin1,2,3,4
1Department of Orthopedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China.
Abstract:
To investigate the potential of emodin in promoting nerve regeneration following PNI by targeting macrophage polarization, NLRP3 inflammasome activation, autophagy, and the EGFR/PI3K/Akt/mTOR pathway. A cohort of 78 male Sprague-Dawley rats was used to develop models of sciatic nerve damage, with an additional 18 rats in the sham surgery group. The rats were randomly assigned to eight groups: Sham, Control, PNI + Emodin (20 mg/kg), PNI + Emodin (80 mg/kg), PNI + MCC950 (10 mg/kg), PNI + Rapamycin (2 mg/kg), PNI + Emodin (80 mg/kg) + 3-MA (15 mg/kg), and PNI + Emodin (80 mg/kg) + NSC 228155 (5 mg/kg). Emodin was administered intragastrical daily, while the inhibitors or agonist were administered via intraperitoneal injection, as per the respective dosages and schedules. The treatment period included assessments of nerve regeneration and functional recovery, such as histological staining, immunofluorescence for cellular markers, TEM for ultrastructural changes, SFI for functional recovery, and western blot analysis for autophagy and inflammatory proteins. IF and TEM images showed that emodin enhanced axonal and myelin regeneration. Histological analysis revealed emodin reduced muscular atrophy and collagen deposition. Emodin decreased pro-inflammatory macrophage markers (CD68) while increasing M2 markers (CD206), inhibited the NLRP3 inflammasome, and reduced IL-1β and caspase-1. It activated autophagy in Schwann cells, with increased LC3-II levels. Network pharmacology and molecular docking identified EGFR in the PI3K/AKT/mTOR pathway as a key target, with emodin inhibiting EGFR activation. This study reveals that emodin promotes early nerve recovery by enhancing functional outcomes, axonal remyelination, and reducing muscle atrophy. It boosts autophagy in Schwann cells, inhibits NLRP3 inflammasome activation, and promotes M2 macrophage polarization. These effects are closely related to the EGFR/PI3K/AKT/mTOR pathway.
Insights
Emodin promotes nerve regeneration after injury by enhancing autophagy, reducing inflammation, and activating the EGFR/PI3K/Akt/mTOR pathway. This natural compound aids functional recovery and reduces muscle atrophy, offering potential therapeutic benefits for peripheral nerve injury.
Area of Science:
- Neuroscience
- Pharmacology
- Regenerative Medicine
Background:
- Peripheral nerve injury (PNI) leads to significant functional deficits.
- Current treatments for PNI have limitations in promoting complete nerve regeneration.
- Understanding molecular mechanisms underlying nerve repair is crucial for developing effective therapies.
Purpose of the Study:
- To investigate emodin's potential to promote nerve regeneration following PNI.
- To elucidate the molecular targets of emodin, including macrophage polarization, NLRP3 inflammasome, autophagy, and the EGFR/PI3K/Akt/mTOR pathway.
Main Methods:
- Sciatic nerve injury model in Sprague-Dawley rats.
- Treatment groups included emodin, MCC950, rapamycin, 3-MA, and NSC 228155.
- Assessment of nerve regeneration and function via histology, immunofluorescence, TEM, SFI, and Western blot.
Main Results:
- Emodin enhanced axonal and myelin regeneration, reduced muscle atrophy and collagen deposition.
- Emodin modulated macrophage polarization towards M2 phenotype, inhibited NLRP3 inflammasome, and activated autophagy in Schwann cells.
- Network pharmacology identified EGFR as a key target, with emodin inhibiting its activation within the PI3K/AKT/mTOR pathway.
Conclusions:
- Emodin promotes early nerve recovery and functional improvement after PNI.
- Emodin's therapeutic effects involve boosting autophagy, inhibiting NLRP3 inflammasome, promoting M2 macrophage polarization, and modulating the EGFR/PI3K/AKT/mTOR pathway.
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