Ningning Wang, Weizhen Li, Tuo Yang, Baolong Li, Chuikai Meng, Xiongyao Zhou, Jialu Sun, Kaiming Yu, Shusen Cui, Rangjuan Cao
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引用次数: 0
Abstract
Background: Ion homeostasis is disrupted following nerve injury, and elevated Ca2+ levels have been reported to induce Schwann cell (SC) death. Notably, clinical interventions such as electrical stimulation enhance Ca2+ influx and facilitate nerve regeneration. These findings highlight the need to clarify the precise role of Ca2+ signaling in nerve regeneration. Methods: We assessed extracellular Ca2+ concentrations in both human and murine peripheral nerve tissues after injury. Transcriptomic profiling identified CB1R as a key Ca2+-related gene and in vitro validation was performed with primary cultured SC and nerve explants. A sciatic nerve crush model was established in SC-specific CB1R knockout mice. Mitophagy, cellular metabolic homeostasis, and axonal regeneration were systematically assessed using proteomics, calcium imaging, and in vivo analyses. Additionally, the CB1R antagonist JD5037 was administered in both sciatic and optic nerve injury models to evaluate its translational potential. Results: Peripheral nerve injury (PNI) leads to elevated extracellular Ca2+ levels at the injury site, where a moderate increase (~1.5-fold) favors SC survival. PNI also induces upregulation of CB1R, genetic ablation of CB1R enhances Ca2+ influx, promotes SC survival, and maintains metabolic homeostasis. Mechanistically, CB1R interference upregulates adenine nucleotide translocase 2 (ANT2) expression, promotes mitochondrial permeability transition pore (mPTP) opening and mitochondrial membrane depolarization, thereby activating PINK1/Parkin-mediated mitophagy. This process improves mitochondrial quality and enhances energy metabolic efficiency, ultimately promoting axonal regeneration and functional recovery. Furthermore, systemic administration of the CB1R antagonist JD5037 similarly enhances regeneration of both peripheral and optic nerves in vivo. Conclusion: Moderate extracellular Ca2+ elevation establishes a pro-regenerative microenvironment after nerve injury. Targeting CB1R facilitates Ca2+ influx, enhances mitophagy via the PINK1/Parkin pathway, and promotes nerve regeneration. These findings identify CB1R as a viable therapeutic target and support the translational potential of JD5037 for nerve injury treatment.
期刊介绍:
Theranostics serves as a pivotal platform for the exchange of clinical and scientific insights within the diagnostic and therapeutic molecular and nanomedicine community, along with allied professions engaged in integrating molecular imaging and therapy. As a multidisciplinary journal, Theranostics showcases innovative research articles spanning fields such as in vitro diagnostics and prognostics, in vivo molecular imaging, molecular therapeutics, image-guided therapy, biosensor technology, nanobiosensors, bioelectronics, system biology, translational medicine, point-of-care applications, and personalized medicine. Encouraging a broad spectrum of biomedical research with potential theranostic applications, the journal rigorously peer-reviews primary research, alongside publishing reviews, news, and commentary that aim to bridge the gap between the laboratory, clinic, and biotechnology industries.