Hirudin promotes peripheral nerve repair and alleviates pain by regulating the EGFR-PI3K/AKT/mTOR pathway

Peripheral nerve injury (PNI) often results in severe neuropathic pain and impaired nerve regeneration. Hirudin, derived from the traditional Chinese medicinal leech, has not yet been investigated for its therapeutic potential in the treatment of PNI.

A total of 144 male Sprague-Dawley rats were subjected to a sciatic nerve crush injury model. Rats were grouped into 5 cohorts: sham, control, PNI + Hirudin (10 mg/kg), PNI + Hirudin (15 mg/kg), and PNI + Hirudin (15 mg/kg) + NSC228155. There were various assessments conducted, including histological staining, immunofluorescence, transmission electron microscopy (TEM), behavioral tests, and Western blot analyses.

Our experiments demonstrated that Hirudin significantly improved the structural integrity of regenerating nerves, enhanced orderly axonal regeneration and remyelination. It also alleviated neuropathic pain, as evidenced by reduced autotomy scores and decreased expression of pain-related markers (Iba-1, C-Fos, and substance P). Mechanistic studies revealed that Hirudin downregulated the activation of the EGFR-dependent PI3K/AKT/mTOR signaling pathway, which contributed to its therapeutic effects.

Hirudin can effectively enhance peripheral nerve regeneration and alleviate neuropathic pain following PNI. These findings suggest that Hirudin holds promise as a therapeutic agent for the treatment of PNI-induced neuropathic pain and impaired nerve regeneration.