DJ-1-Binding Compound Improves Peripheral Nerve Injury in the Spinal Dorsal Horn by Restraining STAT3-Mediated Neurotoxic Reactive Astrocytes.

Astrocytes are significantly activated after peripheral nerve injury (PNI) and affect the nerve repair by mediating neuroinflammation. DJ-1 is highly expressed in astrocytes, and its binding compounds exert significant neuroprotective effects by regulating antioxidant and anti-inflammatory responses. This study is designed to investigate the therapeutic effects of DJ-1-binding compound P-DJ-1A in a rat PNI model induced by spared nerve injury (SNI) surgery. The results revealed that SNI surgery induced the aggregation of activated astrocytes and the phosphorylated form of STAT3 in the ipsilateral dorsal spinal horn (DSH), which was concentrated mainly in the projection area of the injured nerve. Moreover, SNI surgery led to the extensive induction of proinflammatory and neurotoxic mediators, including IL-1β, TNF-α, IL-6, IL-18, and C3, while reducing the expression of TGF-β, IL-10, and S100A10. Treatment with P-DJ-1A or AG490 alleviated mechanical hyperalgesia and thermal hyperalgesia induced by SNI surgery, reduced "A1" astrocyte activation, and inhibited the expression of proinflammatory cytokines but increased the levels of TGF-β, IL-10, and S100A10. Mechanistically, P-DJ-1A or AG490 inhibited STAT3 activation and the NF-κB/NLRP3/IL-18 pathway. Collectively, the DJ-1-binding compound P-DJ-1A can alleviate SNI-induced injury by modulating neurotoxic astrocyte activation and inhibiting neuroinflammation, highlighting its potential as a novel therapeutic strategy.