Melatonin Attenuates Spinal Cord Injury in Mice by Activating the Nrf2/ARE Signaling Pathway to Inhibit the NLRP3 Inflammasome

Abstract

Spinal cord injury (SCI) is a central nervous system (CNS) trauma involving inflammation and oxidative stress, which play important roles in this trauma’s pathogenesis. Therefore, controlling inflammation is an effective strategy for SCI treatment. As a hormone, melatonin is capable of producing antioxidation and anti-inflammation effects. In the meantime, it also causes a neuroprotective effect in various neurological diseases. Nrf2/ARE/NLRP3 is a well-known pathway in anti-inflammation and antioxidation, and Nrf2 can be positively regulated by melatonin. However, how melatonin regulates inflammation during SCI is poorly explored. Therefore, it was investigated in this study whether melatonin can inhibit the NLRP3 inflammasome through the Nrf2/ARE signaling pathway in a mouse SCI model. Methods: A model of SCI was established in C57BL/6 mice and PC12 cells. The motor function of mice was detected by performing an open field test, and Nissl staining and terminal deoxynucleotidyl transferase dUTP nick end labeling were carried out to evaluate the survival of neurons. Mitochondrial dysfunction was detected by transmission electron microscopy (TEM) and by assessing the mitochondrial membrane potential. In addition, the expression of NLRP3 inflammasome and oxidative-stress-related proteins were detected through Western blot and immunofluorescence double staining. Results: By inhibiting neuroinflammation and reducing neuronal death, melatonin promotes the recovery of neuromotor function. Besides this, melatonin is able to reduce the damage that causes neuronal mitochondrial dysfunction, reduce the level of reactive oxygen species (ROS) and malondialdehyde, and enhance the activity of superoxide dismutase and the production of glutathione peroxidase. Mechanically, melatonin inhibits the activation of NLRP3 inflammasomes and reduces the secretion of pro-inflammatory factors through the Nrf2/ARE signaling. Conclusions: In conclusion, melatonin inhibits the NLRP3 inflammasome through stimulation of the Nrf2/ARE pathway, thereby suppressing neuroinflammation, reducing mitochondrial dysfunction, and improving the recovery of nerve function after SCI.

Alpinetin inhibits neuroinflammation and neuronal apoptosis via targeting the JAK2/STAT3 signaling pathway in spinal cord injury

“…BBB scores varied from 0 (total paralysis) to 21 (normal exercise). BBB scores were performed at 1,3,7,14,21,28,35,42,49, and 56 days after SCI to assess the extent of recovery of the hind limbs of the rats after injury. Footprint testing was performed 28 and 56 days after surgery for each group of rats.…”

“…In animal models of SCI, antineuroinflammatory drugs show some effect in improving motor function. 21,22 Over recent years, monomers derived from Chinese herbal medicines have received widespread attention in the treatment of SCI because of their low toxicity and reduced side effects. 23,24 Alpinetin is a natural flavonoid and the main active ingredient of Alpinia katsumadai Hayata, a traditional medicinal plant.…”

An emerging role of inflammasomes in spinal cord injury and spinal cord tumor

“…Minocycline inhibited microglia activation, thus reducing NLRP3-related inflammation and promoting functional recovery after SCI ( 53 ). More recently, an increasing number of chemicals and molecules, such as trehalose ( 54 ), cannabinoid receptor-2 ( 55 ), zinc ( 56 ), melatonin ( 57 ), and dopamine ( 58 ), have been found to improve functional recovery after SCI by targeting NLRP3 inflammasome directly or indirectly.…”

Role of NLRP3 Inflammasome in Post-Spinal-Cord-Injury Anxiety and Depression: Molecular Mechanisms and Therapeutic Implications

“…These factors contribute to further functional deterioration . Furthermore, the secondary damage is orchestrated by various pathophysiological mechanisms, including oxidative stress, immune responses, and mitochondrial dysfunction . Inflammatory responses following the injury involve the stimulation of resident immune cells, such as microglia and astrocytes, as well as the recruitment of immune cells like macrophages and neutrophils .…”