Abstract

Background: Peripheral nerve injuries (PNI) frequently result in incomplete functional recovery, creating a significant translational gap despite advances in surgical techniques. While <i>Hericium erinaceus</i> (<i>H. erinaceus</i>), lithium, and vitamin B12 have individually demonstrated promising neuromodulatory and neurotrophic properties —targeting axonal growth, myelination, and neuroprotection — no existing experimental model has investigated their combined synergistic potential. This lack of integrated approach represents a major barrier to developing effective multimodal therapies. Hypothesis: We propose a “triple neuromodulatory axis” hypothesis: that the combined administration of <i>H. erinaceus</i>, lithium, and vitamin B12 will exert a synergistic effect on peripheral nerve regeneration. This synergy is mechanistically driven by the agents’ convergence on three vital pathways: neurotrophic signaling (TrkA/ERK), glial modulation (GSK-3β/β-catenin), and metabolic/methylation support. The coordinated action of this axis is hypothesized to ensure simultaneous initiation of axonal growth, rapid Schwann cell proliferation, and sustained myelination. Translational rationale: The convergence of these mechanisms suggests that the triple axis, when tested in appropriate in vivo models of nerve injury, will yield superior functional outcomes (e.g., Sciatic Functional Index) and histological repair (e.g., myelin density and axon count) compared to standard treatments or mono-treatments. Conclusion: The triple neuromodulatory axis provides a testable translational framework for designing future multi-arm studies aimed at validating a novel, synergistic pharmacological strategy for enhancing neurorepair in diabetic and post-traumatic neuropathies.


Author Details

Authors

• Dražen Radanović¹,²
• Lukas Rasulić¹,²
• Andrija Savić¹,²
• Slađana Matić¹,⁴
• Dušan Micić¹,⁵
• Predrag Petrović⁶
• Nevena Divac¹,³

Departments

• ¹ Faculty of Medicine, University of Belgrade,
• ² Clinic of Neurosurgery, University Clinical Center of Serbia,
• ³ Department of Pharmacology, Clinical Pharmacology and Toxicology, University of Belgrade, Faculty of Medicine,
• ⁴ Orthopedic and Traumatology Clinic,
• ⁵ Emergency Center, University Clinical Center of Serbia, and
• ⁶ Innovation Center of the Faculty of Technology and Metallurgy, University of Belgrade, Belgrade, Serbia

Address

Nevena Divac, MD, PhD, Department of Pharmacology, Clinical Pharmacology and Toxicology, Faculty of Medicine, University of Belgrade, Dr Subotića 1, 11000 Belgrade, Serbia
Email: [email protected]

Citation