Document Type : Original Article


1 Department of Clinical Science, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran

2 Department of Pathobiology, Faculty of Specialized Veterinary Science, Science and Research Branch, Islamic Azad University, Tehran, Iran


Some pharmacological agents can be effective for peripheral nerve injuries treatments. Present study aimed to apply different agents and compare the nerve regenerative effects following crushed sciatic nerve injuries. Twenty four (n=24) adult male mice were conducted in this study. Standard unilateral left side sciatic nerve crush was performed with 2 mm width mosquito hemostat forceps. The mice were randomly divided into 4 groups with the same numbers in each group which received subcutaneously, estrogen (group I), tacrolimus (group II), the combination of estrogen and tacrolimus (group III), and saline 0.9%. Functional recovery, histopathology, and Immunohistochemistry (IHC), were assessed on days 14th and 28th. Walking track analysis on day 14th showed no significant difference between experimental groups (P>0.05) but they showed significant difference compared to the control group (P<0.05). At the same time, experimental groups showed similar results of inflammatory cell infiltration, axonal edema, and count with significant differences between the control (P<0.05). At the end of the study, group I and III showed a significant difference in functional recovery between group II and control (P<0.05). After fourth week significant histopathological difference of axonal count was observed in group III (P<0.05). On day 28th, only IHC assessment in group III increased more Glial fibrillary acidic protein (GFAP) expression compared with the same group on day 14th. This study revealed subcutaneous administration of combined estrogen and tacrolimus can be effective with acceptable results in nerve regeneration.


  1. Kouyoumdjian JA. Peripheral nerve injuries: a retrospective survey of 456 cases. Muscle Nerve 2006; 34(6): 785- 788.
  2. Denny HR, Butterworth SJ. A guide to canine and feline orthopedic surgery. 4th Oxford, UK: Wiley-Blackwell 2000; 24-30.
  3. Platt SR, de Costa RC. Cervical Spine. In: Tobias KM, Johnston SA (Eds.). Veterinary surgery small animal. 1st Maryland, USA: Elsevier Saunders 2012; 410- 448.
  4. Alvites R, Caseiro AR, Pedrosa SS, et al. Peripheral nerve injury and axonotmesis: State of the art and recent advance. Cogent Med 2018; 5(1): 1466404, doi:10.1080/2331205X.2018.146640.
  5. Dewey CW, Coates JR. Miscellaneous spinal condition and peripheral nerve injuries. In: Slatter D (Ed). Textbook of small animal surgery. 3rd Philadelphia, USA: Elsevier Science 2003; 1209-1226.
  6. Letaif OB, Cristante AF, Barros Filho TE, et al. Effects of estrogen on functional and neurological recovery after spinal cord injury: An experimental study with rats. Clinics (Sao Paulo) 2015; 70(10): 700-705.
  7. Nobakhti_Afshar A, Najafpour A, Mohammadi R, et al. Assessment of neuroprotective effects of local administration of 17-Beta-estradiol on peripheral nerve regeneration in ovariectomized female rats. Bull Emerg Trauma 2016; 4(3): 141-149.
  8. Grand AG, Myckatyn TM, Mackinnon SE, et al. Axonal regeneration after cold preservation of nerve allografts and immunosuppression with tacrolimus in mice. J Neurosurg 2002; 96(5): 944-932.
  9. Shabeed D, Najafi M, Keshavarz M, et al Recent finding in repair of peripheral nerve lesion using pharmacological agents: Common methods for evaluating the repair process. Cent Nerv Syst Agents Med Chem 2018; 18(3): 161-172.
  10. Mekaj AY, Morina AA, Bytyqi CI, et al. Application of topical pharmacological agents at the site of peripheral nerve injury and methods used for evaluating the success of the regenerative process. J Orthop Surg Res 2014; 9: (94): doi: 10.1186/s13018-014-0094-3.
  11. Suchyta MA, Sabbagh MD, Morsy M, et al. Advances in peripheral nerve regeneration as it relates to VCA. Vascularized Composite Allotransplantation 2017; 3(1, 2): 75-88.
  12. Ahmed Y, Lin DL, Ferguson C, et al. Effect of estrogen on urethral function and nerve regeneration following pudendal nerve crush in the female rat. J Urol 2006; 175(5): 1948-1952.
  13. Schumacher M, Akwa Y, Guennoun R, et al. Steroid synthesis and metabolism in nervous system: trophic and protective effects. J Neurocytol 2000; 29 (5-6): 307-326.
  14. Islamov RR, Hendricks WA, Jones RJ, et al. 17Beta-estradiol stimulates regeneration of sciatic nerve in female mice. Brain Res 2002; 943(2): 283- 286.
  15. Yang RK, Lowe JB 3rd, Sobol JB, et al. Dose-dependent effects of Fk506 on neuroregeneration in a rat model. Plast Reconstr Surg 2001; 112(7): 1832-1840.
  16. Wang MS, Zeleny-Pooley M, Gold BG. Comparative dose-dependence study of FK506 and cyclosporine A on the rate of axonal regeneration in the rat sciatic nerve. J Pharmacol Exp Ther 1997; 282(2): 1084-1093.
  17. Sun W, Sun C, Lin H, et al. The effect of collagen-binding NGF-beta on the promotion of sciatic nerve regeneration in a rat sciatic nerve crush injury model. Biomaterials 2009; 30(27): 4649-4656.
  18. Danzi MC, Motti D, Avison DL, et al. Treatment with analgesics after mouse sciatic nerve injury does not alter expression of wound healing-associated genes. Neural Regen Res 2016; 11(1): 144-149.
  19. Garcia-Segura LM, Azcoitia I, DonCarlos LL. Neuroprotection by estradiol. Prog Neurobiol 2001; 63(1): 29-60.
  20. Kane DD, Kerns JM, Lin DL, et al. Early structural effects of estrogen on pudendal nerve regeneration in the rat. BJU Int 2004; 93(6): 870-878.
  21. Islamov RR, Hendricks WA, Katwa LC, et al. Effect of 17beta–estradiol on gene expression in lumbar spinal cord following sciatic nerve crush injury in ovariectomized mice. Brain Res 2003; 966(1): 65-75.
  22. Jones KJ, Coers S, Storer PD, et al. Androgenic regulation of the central glia response following nerve damage. J Neurobiol 1999; 40(4), 560-573.
  23. Jordan CL, Price RH Jr, Handa RJ. Androgen receptor messenger RNA and protein in adult rat sciatic nerve: implication for site of androgen action. J Neurosci Res 2002; 69(4): 509-518.
  24. de Mesquita Coutinho PR, Cristante AF, de Barros Filho TE, et al. Effects of tacrolimus and erythropoietin in experimental spinal cord lesion in rats: functional and histological evaluation. Spinal Cord 2016; 54(6): 439-444.
  25. Devesa P, Gelabert M, Gonźez-Mosquera T, et al. Growth hormone treatment enhances the functional recovery of sciatic nerves after transection and repair. Muscle Nerve 2012; 45(3): 385-392.
  26. Tehranipour M, Kabiri M. The effect of exogenous testosterone administration on peripheral nerves regeneration after sciatic nerve compression in rat. J Biol Sci 2009; 9(7): 692-696.
  27. Fargo KN, Foecking EM, Jones KJ, et al. Neuroprotective action of androgen on motoneurons. Front Neuro-endocrinol 2009; 30(2): 130-141.