Functional recovery in spinal cord injured rats using polypyrrole/iodine implants and treadmill training
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Abstract
Currently, there is no universally accepted treatment for traumatic spinal cord injury (TSCI), a pathology that can cause paraplegia or quadriplegia. Due to the complexity of TSCI, more than one therapeutic strategy may be necessary to regain lost functions. Therefore, the present study proposes the use of implants of mesoparticles (MPs) of polypyrrole/iodine (PPy/I) synthesized by plasma for neuroprotection promotion and functional recovery in combination with treadmill training (TT) for neuroplasticity promotion and maintenance of muscle tone. PPy/I films were synthesized by plasma and pulverized to obtain MPs. Rats with a TSCI produced by the NYU impactor were divided into four groups: Vehicle (saline solution); MPs (PPy/I implant); Vehicle-TT (saline solution + TT); and MPs-TT (PPy/I implant + TT). The vehicle or MPs (30 μL) were injected into the lesion site 48 h after a TSCI. Four days later, TT was carried out 5 days a week for 2 months. Functional recovery was evaluated weekly using the BBB motor scale for 9 weeks and tissue protection using histological and morphometric analysis thereafter. Although the MPs of PPy/I increased nerve tissue preservation (P = 0.03) and promoted functional recovery (P = 0.015), combination with TT did not produce better neuroprotection, but significantly improved functional results (P = 0.000) when comparing with the vehicle group. So, use these therapeutic strategies by separately could stimulate specific mechanisms of neuroprotection and neuroregeneration, but when using together they could mainly potentiate different mechanisms of neuronal plasticity in the preserved spinal cord tissue after a TSCI and produce a significant functional recovery.
Graphical Abstract
Keywords
Spinal Cord Functional Recovery Injured Spinal Cord Spinal Cord Tissue Training TreadmillNotes
Acknowledgments
The work was supported by Instituto Mexicanos del Seguro Social (IMSS), Grant No. FIS/IMSS/PROT/G11/943 and by Consejo Nacional de Ciencia y Tecnología (CONACyT), Grant No. 47467. Laura Alvarez received a scholarship from CONACyT (No. 172211). The authors thank María del Carmen Baltazar for her invaluable technical assistance.
Compliance with Ethical Standards
Conflict of interest
No potential conflict of interest relevant to this article is reported.
References
- 1.Sekhon LH, Fehlings MG. Epidemiology, demographics, and pathophysiology of acute spinal cord injury. Spine. 2001;26(24 Suppl.):S2–12.CrossRefGoogle Scholar
- 2.Raineteau O. Plastic responses to spinal cord injury. Behav Brain Res. 2008;192:114–23.CrossRefGoogle Scholar
- 3.Cafferty WB, Gardiner NJ, Das P, Qiu J, McMahon SB, Thompson SW. Conditioning injury-induced spinal axon regeneration fails in interleukin-6 knock-out mice. J Neurosci. 2004;24(18):4432–43.CrossRefGoogle Scholar
- 4.Oudega M, Xu XM. Schwann cell transplantation for repair of the adult spinal cord. J Neurotrauma. 2006;23:453–67.CrossRefGoogle Scholar
- 5.Levi AD, Dancausse H, Li X, Duncan S, Horkey L, Oliviera M. Peripheral nerve grafts promoting central nervous system regeneration after spinal cord injury in the primate. J Neurosurg. 2002;96(2 Suppl):197–205.Google Scholar
- 6.Coumans JV, Lin TT, Dai HN, MacArthur L, McAtee M, Nash C, Bregman BS. Axonal regeneration and functional recovery after complete spinal cord transection in rats by delayed treatment with transplants and neurotrophins. J Neurosci. 2001;21:9334–44.Google Scholar
- 7.Nakajima H, Uchida K, Guerrero AR, Watanabe S, Sugita D, Takeura N, Yoshida A, et al. Transplantation of mesenchymal stem cells promotes an alternative pathway of macrophage activation and functional recovery after spinal cord injury. J Neurotrauma. 2012;29:1614–25.CrossRefGoogle Scholar
- 8.Straley KS, Foo CW, Heilshorn SC. Biomaterial design strategies for the treatment of spinal cord injuries. J Neurotrauma. 2010;27(1):1–19.CrossRefGoogle Scholar
- 9.Wang M, Zhaid P, Chen X, Schreyer DJ, Sun X, Cui F. Bioengineered scaffolds for spinal cord repair. Tissue Eng Part B Rev. 2011;17:177–94.CrossRefGoogle Scholar
- 10.Josten EA. Biodegradable biomatrices and bridging the injured spinal cord: the corticospinal tract as a proof of principle. Cell Tissue Res. 2012;349:375–95.CrossRefGoogle Scholar
- 11.Ahn HS, Hwang JY, Kim MS, Lee JY, Kim JW, Kim HS, Shin US, et al. Carbon-nanotube-interfaced glass fiber scaffold for regeneration of transected sciatic nerve. Acta Biomater. 2015;13:324–34.CrossRefGoogle Scholar
- 12.Kataoka K, Suzuki Y, Kitada M, Hashimoto T, Chou H, Bai H, Ohta M, Wu S, Suzuki K, et al. Alginate enhances elongation of early regenerating axons in spinal cord of young rats. Tissue Eng. 2004;10:493–504.CrossRefGoogle Scholar
- 13.Stokols S, Tuszynski MH. Freeze-dried agarose scaffolds with uniaxial channels stimulate and guide linear axonal growth following spinal cord injury. Biomaterials. 2006;27:443–51.CrossRefGoogle Scholar
- 14.Chen J, Zhang Z, Liu J, Zhou R, Zheng X, Chen T, Wang L, et al. Acellular spinal cord scaffold seeded with bone marrow stromal cells protects tissue and promotes functional recovery in spinal cord-injured rats. J Neurosci Res. 2014;92(3):307–17.CrossRefGoogle Scholar
- 15.Bakshi A, Fisher O, Dagci T, Himes BT, Fischer I, Lowman A. Mechanically engineered hydrogel scaffolds for axonal growth and angiogenesis after transplantation in spinal cord injury. J Neurosurg Spine. 2004;1:322–9.CrossRefGoogle Scholar
- 16.Hejcl A, Urdzikova L, Sedy J, Lesny P, Pradny M, Michalek J, Burian M, et al. Acute and delayed implantation of positively charged 2-hydroxyethyl methacrylate scaffolds in spinal cord injury in the rat. J Neurosurg Spine. 2008;8:67–73.CrossRefGoogle Scholar
- 17.Woerly S, Doan VD, Sosa N, de Vellis J, Espinosa-Jeffrey A. Prevention of gliotic scar formation by NeuroGel allows partial endogenous repair of transected cat spinal cord. J Neurosci Res. 2004;75:262–72.CrossRefGoogle Scholar
- 18.Olayo R, Rios C, Salgado-Ceballos H, Cruz GJ, Morales J, Olayo MG, Alcaraz-Zubeldia M, et al. Tissue spinal cord response in rats after implants of polypyrrole and polyethylene glycol obtained by plasma. J Mater Sci Mater Med. 2008;19:817–26.CrossRefGoogle Scholar
- 19.Cruz GJ, Mondragón-Lozano R, Diaz-Ruiz A, Manjarrez J, Olayo R, Salgado-Ceballos H, Olayo MG, et al. Plasma polypyrrole implants recover motor function in rats after spinal cord transection. J Mater Sci Mater Med. 2012;23:2583–92.CrossRefGoogle Scholar
- 20.Zamani F, Amani-Tehran M, Latifi M, Shokrgozar MA, Zaminy A. Promotion of spinal cord axon regeneration by 3D nanofibrous core-sheath scaffolds. J Biomed Mater Res A. 2014;102(2):506–13.CrossRefGoogle Scholar
- 21.Ghasemi-Mobarakeh L, Prabhakaran MP, Morshed M, Nasr-Esfahani MH, Baharvand H, Kiani S, Al-Deyab SS, et al. Application of conductive polymers, scaffolds and electrical stimulation for nerve tissue engineering. J Tissue Eng Regen Med. 2011;5(4):e17–35.CrossRefGoogle Scholar
- 22.Gomez N, Schmidt CE. Nerve growth factor-immobilized polypyrrole: bioactive electrically conducting polymer for enhanced neurite extension. J Biomed Mater Res A. 2007;81:135–49.CrossRefGoogle Scholar
- 23.Cruz GJ, Olayo MG, López OG, Gomez LM, Morales J, Olayo R. Nanospherical particles of polypyrrole synthesized and doped by plasma. Polymer. 2010;51:4314–8.CrossRefGoogle Scholar
- 24.Vaynman S, Gomez-Pinilla F. License to run: exercise impacts functional plasticity in the intact and injured central nervous system by using neurotrophins. Neurorehabil Neural Repair. 2005;19:283–95.CrossRefGoogle Scholar
- 25.Cotman CW, Berchtold NC, Christie LA. Exercise builds brain health: key roles of growth factor cascades and inflammation. Trends Neurosci. 2007;30:464–72.CrossRefGoogle Scholar
- 26.Lynskey JV, Belanger A, Jung R. Activity-dependent plasticity in spinal cord injury. J Rehabil Res Dev. 2008;45:229–40.CrossRefGoogle Scholar
- 27.Nessler JA, De Leon RD, Sharp K, Kwak E, Minakata K, Reinkensmeyer DJ. Robotic gait analysis of bipedal treadmill stepping by spinal contused rats: characterization of intrinsic recovery and comparison with BBB. J Neurotrauma. 2006;23:882–96.CrossRefGoogle Scholar
- 28.Knikou M. Plasticity of corticospinal neural control after locomotor training in human spinal cord injury. Neural Plast. 2012. doi: 10.1155/2012/254948.Google Scholar
- 29.Martinez M, Delivet-Mongrain H, Rossignol S. Treadmill training promotes spinal changes leading to locomotor recovery after partial spinal cord injury in cats. J Neurophysiol. 2013;109:2909–22.CrossRefGoogle Scholar
- 30.Ley General de Salud de la República Mexicana. 6th ed. México D.F.: Porrúa; 1995.Google Scholar
- 31.Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma. 1995;12:1–21.CrossRefGoogle Scholar
- 32.Morales J, Olayo MG, Cruz GJ, Olayo R. Synthesis by plasma and characterization of bi-layer aniline-pyrrole thin films doped with iodine. J Polym Sci Part B. 2002;40:1850–6.CrossRefGoogle Scholar
- 33.Krishna V, Konakondla S, Nicholas J, Varma A, Kindy M, Wen X. Biomaterial-based interventions for neuronal regeneration and functional recovery in rodent model of spinal cord injury: a systematic review. J Spinal Cord Med. 2013;36(3):174–90.CrossRefGoogle Scholar
- 34.Piantino J, Burdick JA, Goldberg D, Langer R, Benowitz LI. An injectable, biodegradable hydrogel for trophic factor delivery enhances axonal rewiring and improves performance after spinal cord injury. Exp Neurol. 2006;201:359–67.CrossRefGoogle Scholar
- 35.King VR, Alovskaya A, Wei DY, Brown RA, Priestley JV. The use of injectable forms of fibrin and fibronectin to support axonal ingrowth after spinal cord injury. Biomaterials. 2010;31:4447–56.CrossRefGoogle Scholar
- 36.Cigognini D, Satta A, Colleoni B, Silva D, Donegà M, Antonini S, Gelain F. Evaluation of early and late effects into the acute spinal cord injury of an injectable functionalized self-assembling scaffold. PLoS ONE. 2011;6:e19782.CrossRefGoogle Scholar
- 37.Tsai EC, Dalton PD, Shoichet MS, Tator CH. Matrix inclusion within synthetic hydrogel guidance channels improves specific supraspinal and local axonal regeneration after complete spinal cord transection. Biomaterials. 2006;27:519–33.CrossRefGoogle Scholar
- 38.Fine EG, Valentini RF, Bellamkonda R, Aebischer P. Improved nerve regeneration through piezoelectric vinylidene fluoride-trivfluoroethylene copolymer guidance channels. Biomaterials. 1991;12:775–80.CrossRefGoogle Scholar
- 39.Kotwal A, Schmidt CE. Electrical stimulation alters protein adsorption and nerve cell interactions with electrically conducting biomaterials. Biomaterials. 2001;22:1055–64.CrossRefGoogle Scholar
- 40.Zhang Z, Rouabhia M, Wang Z, Roberge C, Shi G, Roche P, Li J, et al. Electrically conductive biodegradable polymer composite for nerve regeneration: electricity-stimulated neurite outgrowth and axon regeneration. Artif Organs. 2007;31:13–22.CrossRefGoogle Scholar
- 41.HajjHassan M, Chodavarapu V, Musallam S. Neuro MEMS: neural probe microtechnologies. Sensors. 2008;8:6704–26.CrossRefGoogle Scholar
- 42.Smith RR, Brown EH, Shum-Siu A, Whelan A, Burke DA, Benton RL, Magnuson DSK. Swim training initiated acutely after spinal cord injury is ineffective and induces extravasation in and around the epicenter. J Neurotrauma. 2009;26:1017–27.CrossRefGoogle Scholar
- 43.Nothias JM, Mitsui T, Shumsky JS, Fischer I, Antonacci MD, Murray M. Combined effects of neurotrophin secreting transplants, exercise, and serotonergic drug challenge improve function in spinal rats. Neurorehabil Neural Repair. 2005;19:296–312.CrossRefGoogle Scholar
- 44.Reese NB, Skinner RD, Mitchell D, Yates C, Barnes CN, Kiser TS, Garcia-Rill E. Restoration of frequency-dependent depression of the H-reflex by passive exercise in spinal rats. Spinal Cord. 2006;44:28–34.CrossRefGoogle Scholar
- 45.Engesser-Cesar C, Ichiyama RM, Nefas AL, Hill MA, Edgerton VR, Cotman CW, Anderson AJ. Wheel running following spinal cord injury improves locomotor recovery and stimulates serotonergic fiber growth. Eur J Neurosci. 2007;25:1931–9.CrossRefGoogle Scholar
- 46.Grasso R, Ivanenko YP, Zago M, Molinari M, Scivoletto G, Castellano V, Macellari V, et al. Distributed plasticity of locomotor pattern generators in spinal cord injured patients. Brain. 2004;127:1019–34.CrossRefGoogle Scholar
- 47.Edgerton VR, Courtine G, Gerasimenko YP, Lavrov I, Ichiyama RM, Fong AJ, Cai LL, et al. Training locomotor networks. Brain Res Rev. 2008;57:241–54.CrossRefGoogle Scholar
- 48.Moshonkina T, Avelev V, Gerasimenko Y, Mathur R, Bijlani RL. Treadmill training accelerates restoration of locomotion after complete spinal cord transection in the rat. Indian J Physiol Pharmacol. 2002;46:499–503.Google Scholar
- 49.Oh MJ, Seo TB, Kwon KB, Yoon SJ, Elzi DJ, Kim BG, Namgung U. Axonal outgrowth and Erk1/2 activation by training after spinal cord injury in rats. J Neurotrauma. 2009;26:2071–82.CrossRefGoogle Scholar
- 50.Foret A, Quertainmont R, Botman O, Bouhy D, Amabili P, Brook G, Schoenen J, et al. Stem cells in the adult rat spinal cord: plasticity after injury and treadmill training exercise. J Neurochem. 2010;112:762–72.CrossRefGoogle Scholar
- 51.Sun T, Ye C, Wu J, Zhang Z, Cai Y, Yue F. Treadmill step training promotes spinal cord neural plasticity after incomplete spinal cord injury. Neural Regen Res. 2013;8:2540–7.Google Scholar
