Objective To investigate the effect of SC79, an AKT activator, on axonal regeneration and functional recovery following sciatic nerve crush injury in mice. Methods Mouse models of sciatic nerve crush injury were established and randomly divided into a control group and an SC79 group (40 mg/kg, intraperitoneal injection). Dorsal root ganglion (DRG) explant axotomy models were also established, and SC79 (4 mg/ml) was added to the culture medium. Western blot was used to detect the activation of the AKT signaling pathway. Immunofluorescence was applied to evaluate axonal regeneration, Schwann cell proliferation, and myelin regeneration. Neural circuit reconstruction and functional recovery were assessed by cholera toxin subunit B (CTB) retrograde tracing, neuromuscular junction staining, gastrocnemius morphological analysis, and the sciatic functional index (SFI). Results At 3 days after sciatic nerve crush injury, the p-AKT/AKT ratio in the sciatic nerve and lumbosacral spinal cord was significantly higher in the SC79 group than in the control group (P<0.05). At 7 days post-injury, SC79 significantly increased the density of distal regenerated axons and the proportion of S-100β/Ki67 double-positive Schwann cells (P<0.001). At 30 days post-injury, SC79 markedly increased axonal cross-sectional area, myelin thickness, and the number of CTB-positive spinal anterior horn neurons (P<0.001). In vitro, SC79 significantly promoted DRG axonal regeneration (P<0.001) and partially reversed growth cone collapse. Functional assessments showed that SC79 significantly improved neuromuscular junction reinnervation, gastrocnemius wet weight ratio, and SFI (P<0.05). Conclusion SC79 promotes axonal regeneration, neural circuit reconstruction, and functional recovery after sciatic nerve crush injury in mice by activating the AKT pathway. Immediate administration yields the optimal effect, indicating that SC79 is a promising candidate for peripheral nerve injury repair.
Key words
AKT agonist; /
/
SC79; /
/
sciatic nerve crush injury; /
/
axonal regeneration
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
References
[1] Randall ZD, Navarro BJ, Brogan DM, et al. Insights Into the Epidemiology of Peripheral Nerve Injuries in the United States: Systematic Review[J]. Hand (N Y), 2026,21(2), 194-201. DOI: 10.1177/15589447241299050.
[2] Widodo W, Aprilya D, Satria O. Regenerative Medicine: A New Horizon in Peripheral Nerve Injury and Repair [J]. Orthop Rev (Pavia), 2025, 17: 133572. DOI: 10.52965/001c.133572.
[3] Grosu-Bularda A, Vancea CV, Hodea FV, et al. Optimizing peripheral nerve regeneration: surgical techniques, biomolecular and regenerative strategies-a narrative review[J]. Int J Mol Sci, 2025, 26(8): 3895. DOI: 10.3390/ijms26083895.
[4] Hausott B, Klimaschewski L. Promotion of peripheral nerve regeneration by stimulation of the extracellular signal-regulated kinase (ERK) pathway[J]. Anat Rec, 2019, 302(8): 1261-1267. DOI: 10.1002/ar.24126.
[5] Jo H, Mondal S, Tan D, et al. Small molecule-induced cytosolic activation of protein kinase Akt rescues ischemia-elicited neuronal death[J]. Proc Natl Acad Sci U S A, 2012, 109(26): 10581-10586. DOI: 10.1073/pnas.1202810109.
[6] Luan Q, Pan LX, He DY, et al. SC79, the AKT activator protects cerebral ischemia in a rat model of ischemia/reperfusion injury[J]. Med Sci Monit, 2018, 24: 5391-5397. DOI: 10.12659/MSM.910191.
[7] Jing ZT, Liu W, Xue CR, et al. AKT activator SC79 protects hepatocytes from TNF-α-mediated apoptosis and alleviates d-Gal/LPS-induced liver injury[J]. Am J Physiol Gastrointest Liver Physiol, 2019, 316(3): G387-G396. DOI: 10.1152/ajpgi.00350.2018.
[8] Liu X, Kiss GZ, Mellender SJ, et al. Activation of Akt by SC79 decreased cerebral infarct in early cerebral ischemia-reperfusion despite increased BBB disruption[J]. Neurosci Lett, 2018, 681: 78-82. DOI: 10.1016/j.neulet.2018.05.046.
[9] Zhou H, Yu Y, Zhang JN, et al. Protective effects of the Akt activator SC79 in hepatic ischemia-reperfusion injury[J]. Med Sci Monit, 2018, 24: 4346-4354. DOI: 10.12659/MSM.911178.
[10]Namini MS, Beheshtizadeh N, Ebrahimi-Barough S, et al. Human endometrial stem cell-derived small extracellular vesicles enhance neurite outgrowth and peripheral nerve regeneration through activating the PI3K/AKT signaling pathway[J]. J Transl Med, 2025, 23(1): 6. DOI: 10.1186/s12967-024-06048-z.
[11]Zheng K, Zhang Q, Lin G, et al. Activation of Akt by SC79 protects myocardiocytes from oxygen and glucose deprivation (OGD)/re-oxygenation[J]. Oncotarget, 2017, 8(9): 14978-14987. DOI:10.18632/oncotarget.14785.
[12]Wang H, Fang F, Jing X, et al. Augmentation of functional recovery via ROCK/PI3K/AKT pathway by Fasudil Hydrochloride in a rat sciatic nerve transection model[J]. J Orthop Translat, 2024, 47: 74-86. DOI: 10.1016/j.jot.2024.06.006.
[13]Dou S, Li ZJ, Zheng BY, et al. ROCK inhibition promotes axon and myelin regeneration via PI3K/Akt/GSK3β in a mouse sciatic nerve injury model[J]. Int J Mol Med, 2026, 57(1): 14. DOI: 10.3892/ijmm.2025.5685.
[14]Zhang DD, Zhang HS, Hao SY, et al. Akt specific activator SC79 protects against early brain injury following subarachnoid hemorrhage[J]. ACS Chem Neurosci, 2016, 7(6): 710-718. DOI: 10.1021/acschemneuro.5b00306.
[15]Zhang BY, Sajilafu, Liu CM, et al. Akt-independent GSK3 inactivation downstream of PI3K signaling regulates mammalian axon regeneration[J]. Biochem Biophys Res Commun, 2014, 443(2): 743-748. DOI: 10.1016/j.bbrc.2013.12.037.
[16]Sakuma M, Gorski G, Sheu SH, et al. Lack of motor recovery after prolonged denervation of the neuromuscular junction is not due to regenerative failure[J]. Eur J Neurosci, 2016, 43(3): 451-462. DOI: 10.1111/ejn.13059.
[17]Frison-Roche C, Demier CM, Cottin S, et al. MBNL deficiency in motor neurons disrupts neuromuscular junction maintenance and gait coordination[J]. Brain, 2025, 148(4): 1180-1193. DOI: 10.1093/brain/awae336.
[18]Sawai S, Sowa Y, Kishida T, et al. Micronized cellular adipose matrix promotes the therapeutic effect of an artificial nerve conduit in peripheral nerve gap injury[J]. Plast Reconstr Surg, 2023, 151(6): 959e-969e. DOI: 10.1097/PRS.0000000000010136.
[19]Nishimura Y, Chunthorng-Orn J, Lord S, et al. Ubiquitin E3 ligase Atrogin-1 protein is regulated via the rapamycin-sensitive mTOR-S6K1 signaling pathway in C2C12 muscle cells[J]. Am J Physiol Cell Physiol, 2022, 323(1): C215-C225. DOI: 10.1152/ajpcell.00384.2021.
[20]Sun R, Li B, Zhang M, et al. Combined delivery of glial cell line-derived neurotrophic factor and basic fibroblast growth factor for peripheral nerve regeneration[J]. J Tissue Eng Regen Med, 2022, 16(2): 161-171, DOI:10.1002/term.3264
PDF(4551 KB)
