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. 2013 Jul 28;29(4):460–466. doi: 10.1007/s12264-013-1364-5

Polyethylene glycol repairs membrane damage and enhances functional recovery: a tissue engineering approach to spinal cord injury

Riyi Shi 1,✉
PMCID: PMC5561946  PMID: 23893430

Abstract

The integrity of the neuronal membrane is crucial for its function and cellular survival; thus, ineffective repair of damaged membranes may be one of the key elements underlying the neuronal degeneration and overall functional loss that occurs after spinal cord injury (SCI). it has been shown that polyethylene glycol (PEG) can reseal axonal membranes following various injuries in multiple in vitro and in vivo injury models. in addition, PEG may also directly prevent the effects of mitochondria-derived oxidative stress on intracellular components. Thus, PEG repairs mechanically injured cells by at least two distinct pathways: resealing of the disrupted plasma membrane and direct protection of mitochondria. Besides repairing primary membrane damage, PEG treatment also results in significant attenuation of oxidative stress, likely due to its capacity to reseal the membrane, thereby breaking the cycle of cellular damage and free-radical production. Based on this, in addition to the practicality of its application, we expect that PEG may be established as an effective treatment for SCI where membrane disruption and mitochondrial damage are implicated.

Keywords: axolemmal, reseal, fusogen, cutaneous trunci muscle, somatosensory evoked potential, neuroprotection

References

  • [1].McNeil PL, Kirchhausen T. An emergency response team for membrane repair. Nat Rev Mol Cell Biol. 2005;6:499–505. doi: 10.1038/nrm1665. [DOI] [PubMed] [Google Scholar]
  • [2].Bansal D, Miyake K, Vogel SS, Groh S, Chen CC, Williamson R, et al. Defective membrane repair in dysferlin-deficient muscular dystrophy. Nature. 2003;423:168–172. doi: 10.1038/nature01573. [DOI] [PubMed] [Google Scholar]
  • [3].McNeil PL, Steinhardt RA. Plasma membrane disruption: repair, prevention, adaptation. Annu Rev Cell Dev Biol. 2003;19:697–731. doi: 10.1146/annurev.cellbio.19.111301.140101. [DOI] [PubMed] [Google Scholar]
  • [4].Nehrt A, Hamann K, Ouyang H, Shi R. Polyethylene glycol enhances axolemmal resealing following transection in cultured cells and in ex vivo spinal cord. J Neurotrauma. 2010;27:15–61. doi: 10.1089/neu.2009.0993. [DOI] [PubMed] [Google Scholar]
  • [5].Schlaepfer WW. Calcium-induced degeneration of axoplasm in isolated segments of rat peripheral nerve. Brain Res. 1974;69:203–215. doi: 10.1016/0006-8993(74)90002-X. [DOI] [PubMed] [Google Scholar]
  • [6].Fiskum G. Mitochondrial participation in ischemic and traumatic neural cell death. J Neurotrauma. 2000;17:843–855. doi: 10.1089/neu.2000.17.843. [DOI] [PubMed] [Google Scholar]
  • [7].Lewen A, Matz P, Chan PH. Free radical pathways in CNS injury. J Neurotrauma. 2000;17:871–890. doi: 10.1089/neu.2000.17.871. [DOI] [PubMed] [Google Scholar]
  • [8].Wieloch T. Mitochondrial involvement in acute neurodegeneration. iUBMB Life. 2001;52:247–254. doi: 10.1080/15216540152846064. [DOI] [PubMed] [Google Scholar]
  • [9].Ray SK, Hogan EL, Banik NL. Calpain in the pathophysiology of spinal cord injury: neuroprotection with calpain inhibitors. Brain Res Brain Res Rev. 2003;42:169–185. doi: 10.1016/S0165-0173(03)00152-8. [DOI] [PubMed] [Google Scholar]
  • [10].Wingrave JM, Schaecher KE, Sribnick EA, Wilford GG, Ray SK, Hazen-Martin DJ, et al. Early induction of secondary injury factors causing activation of calpain and mitochondriamediated neuronal apoptosis following spinal cord injury in rats. J Neurosci Res. 2003;73:95–104. doi: 10.1002/jnr.10607. [DOI] [PubMed] [Google Scholar]
  • [11].Borgens RB, Jaffe LF, Cohen MJ. Large and persistent electrical currents enter the transected lamprey spinal cord. Proc Natl Acad Sci U S A. 1980;77:1209–1213. doi: 10.1073/pnas.77.2.1209. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [12].Howard AC, McNeil AK, McNeil PL. Promotion of plasma membrane repair by vitamin E. Nat Commun. 2011;2:597. doi: 10.1038/ncomms1594. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [13].Xie X, Barrett JN. Membrane resealing in cultured rat septal neurons after neurite transection: evidence for enhancement by Ca2+-triggered protease activity and cytoskeletal disassembly. J Neurosci. 1991;11:3257–3267. doi: 10.1523/JNEUROSCI.11-10-03257.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [14].Spira ME, Benbassat D, Dormann A. Resealing of the proximal and distal cut ends of transected axons: electrophysiological and ultrastructural analysis. J Neurobiol. 1993;24:300–316. doi: 10.1002/neu.480240304. [DOI] [PubMed] [Google Scholar]
  • [15].Krause TL, Fishman HM, Ballinger ML, Bittner GD. Extent and mechanism of sealing in transected giant axons of squid and earthworms. J Neurosci. 1994;14:6638–6651. doi: 10.1523/JNEUROSCI.14-11-06638.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [16].Eddleman CS, Ballinger ML, Smyers ME, Godell CM, Fishman HM, Bittner GD. Repair of plasmalemmal lesions by vesicles. Proc Natl Acad Sci U S A. 1997;94:4745–4750. doi: 10.1073/pnas.94.9.4745. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [17].Shi R, Asano T, Vining NC, Blight AR. Control of membrane sealing in injured mammalian spinal cord axons. J Neurophysiol. 2000;84:1763–1769. doi: 10.1152/jn.2000.84.4.1763. [DOI] [PubMed] [Google Scholar]
  • [18].Shi R, Borgens RB. Anatomical repair of nerve membranes in crushed mammalian spinal cord with polyethylene glycol. J Neurocytol. 2000;29:633–643. doi: 10.1023/A:1010879219775. [DOI] [PubMed] [Google Scholar]
  • [19].Shi R, Pryor JD. Temperature dependence of membrane sealing following transection in mammalian spinal cord axons. Neuroscince. 2000;98:157–166. doi: 10.1016/S0306-4522(00)00096-8. [DOI] [PubMed] [Google Scholar]
  • [20].Pettus EH, Christman CW, Giebel ML, Povlishock JT. Traumatically induced altered membrane permeability: its relationship to traumatically induced reactive axonal change. J Neurotrauma. 1994;11:507–522. doi: 10.1089/neu.1994.11.507. [DOI] [PubMed] [Google Scholar]
  • [21].Pettus EH, Povlishock JT. Characterization of a distinct set of intra-axonal ultrastructural changes associated with traumatically induced alteration in axolemmal permeability. Brain Res. 1996;722:1–11. doi: 10.1016/0006-8993(96)00113-8. [DOI] [PubMed] [Google Scholar]
  • [22].Yawo H, Kuno M. How a nerve fiber repairs its cut end: involvement of phospholipase A2. Science. 1983;222:1351–1352. doi: 10.1126/science.6658457. [DOI] [PubMed] [Google Scholar]
  • [23].Smith DH, Wolf JA, Lusardi TA, Lee VM, Meaney DF. High tolerance and delayed elastic response of cultured axons to dynamic stretch injury. J Neurosci. 1999;19:4263–4269. doi: 10.1523/JNEUROSCI.19-11-04263.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [24].Geddes DM, Cargill RS, 2nd, LaPlaca MC. Mechanical stretch to neurons results in a strain rate and magnitude-dependent increase in plasma membrane permeability. J Neurotrauma. 2003;20:1039–1049. doi: 10.1089/089771503770195885. [DOI] [PubMed] [Google Scholar]
  • [25].Shi R, Borgens RB. Acute repair of crushed guinea pig spinal cord by polyethylene glycol. J Neurophysiol. 1999;81:2406–2414. doi: 10.1152/jn.1999.81.5.2406. [DOI] [PubMed] [Google Scholar]
  • [26].Shi R, Borgens RB, Blight AR. Functional reconnection of severed mammalian spinal cord axons with polyethylene glycol. J Neurotrauma. 1999;16:727–738. doi: 10.1089/neu.1999.16.727. [DOI] [PubMed] [Google Scholar]
  • [27].Shi R, Qiao X, Emerson N, Malcom A. Dimethylsulfoxide enhances CNS neuronal plasma membrane resealing after injury in low temperature or low calcium. J Neurocytol. 2001;30:829–839. doi: 10.1023/A:1019645505848. [DOI] [PubMed] [Google Scholar]
  • [28].Shi R. The dynamics of axolemmal disruption in guinea pig spinal cord following compression. J Neurocytol. 2004;33:203–211. doi: 10.1023/B:NEUR.0000030695.76840.19. [DOI] [PubMed] [Google Scholar]
  • [29].Young W, Yen V, Blight A. Extracellular calcium ionic activity in experimental spinal cord contusion. Brain Res. 1982;253:105–113. doi: 10.1016/0006-8993(82)90677-1. [DOI] [PubMed] [Google Scholar]
  • [30].Stokes BT, Fox P, Hollinden G. Extracellular calcium activity in the injured spinal cord. Exp Neurol. 1983;80:561–572. doi: 10.1016/0014-4886(83)90307-2. [DOI] [PubMed] [Google Scholar]
  • [31].Lucas JH, Gross GW, Emery DG, Gardner CR. Neuronal survival or death after dendrite transection close to the perikaryon: correlation with electrophysiologic, morphologic, and ultrastructural changes. Cent Nerv Syst Trauma. 1985;2:231–255. doi: 10.1089/cns.1985.2.231. [DOI] [PubMed] [Google Scholar]
  • [32].Lucas JH, Gross GW. Cellular and molecular recovery responses. J Neurotrauma. 1988;5:223–225. doi: 10.1089/neu.1988.5.223. [DOI] [PubMed] [Google Scholar]
  • [33].Davidson RL, O’Malley KA, Wheeler TB. Induction of mammalian somatic cell hybridization by polyethylene glycol. Somat. Cell Genet. 1976;2:271–280. doi: 10.1007/BF01538965. [DOI] [PubMed] [Google Scholar]
  • [34].O’Lague PH, Huttner SL. Physiological and morphological studies of rat pheochromocytoma cells (PC12) chemically fused and grown in culture. Proc Nat Acad Sci U S A. 1980;77:1701–1705. doi: 10.1073/pnas.77.3.1701. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [35].Krause TL, Bittner GD. Rapid morphological fusion of severed myelinated axons by polyethylene glycol. Proc Natl Acad Sci U S A. 1990;87:1471–1475. doi: 10.1073/pnas.87.4.1471. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [36].Lee J, Lentz BR. Evolution of lipidic structures during model membrane fusion and the relation of this process to cell membrane fusion. Biochemistry. 1997;36:6251–6259. doi: 10.1021/bi970404c. [DOI] [PubMed] [Google Scholar]
  • [37].Lentz BR. Polymer-induced membrane fusion: potential mechanism and relation to cell fusion events. Chem Phys Lipids. 1994;73:91–106. doi: 10.1016/0009-3084(94)90176-7. [DOI] [PubMed] [Google Scholar]
  • [38].Lentz BR, Lee JK. Poly(ethylene glycol) (PEG)-mediated fusion between pure lipid bilayers: a mechanism in common with viral fusion and secretory vesicle release? Mol Membr Biol. 2000;16:279–296. doi: 10.1080/096876899294508. [DOI] [PubMed] [Google Scholar]
  • [39].Shi R, Blight AR. Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience. 1997;77:553–562. doi: 10.1016/S0306-4522(96)00477-0. [DOI] [PubMed] [Google Scholar]
  • [40].Shi R, Borgens RB, Blight AR. Functional reconnection of severed mammalian spinal cord axons with polyethylene glycol. J Neurotrauma. 1999;16:727–738. doi: 10.1089/neu.1999.16.727. [DOI] [PubMed] [Google Scholar]
  • [41].Shi R, Borgens RB. Acute repair of crushed guinea pig spinal cord by polyethylene glycol. J Neurophysiol. 1999;81:2406–2414. doi: 10.1152/jn.1999.81.5.2406. [DOI] [PubMed] [Google Scholar]
  • [42].Luo J, Borgens RB, Shi R. Polyethylene glycol immediately repairs neuronal membranes and inhibits free radical production after acute spinal cord injury. J Neurochem. 2002;83:471–480. doi: 10.1046/j.1471-4159.2002.01160.x. [DOI] [PubMed] [Google Scholar]
  • [43].Luo J, Borgens R, Shi R. Polyethylene glycol improves function and reduces oxidative stress in synaptosomal preparations following spinal cord injury. J Neurotrauma. 2004;21:994–1007. doi: 10.1089/0897715041651097. [DOI] [PubMed] [Google Scholar]
  • [44].Luo J, Shi R. Diffusive oxidative stress following acute spinal cord injury in guinea pigs and its inhibition by polyethylene glycol. Neurosci Lett. 2004;359:167–170. doi: 10.1016/j.neulet.2004.02.027. [DOI] [PubMed] [Google Scholar]
  • [45].Hall ED. Free radicals and CNS injury. Crit Care Clin. 1989;5:793–805. [PubMed] [Google Scholar]
  • [46].Hall ED, Yonkers PA, Andrus PK, Cox JW, Anderson DK. Biochemistry and pharmacology of lipid antioxidants in acute brain and spinal cord injury. J Neurotrauma. 1992;9:S425–442. doi: 10.1089/neu.1992.9.173. [DOI] [PubMed] [Google Scholar]
  • [47].Hall ED. Inhibition of lipid peroxidation in central nervous system trauma and ischemia. J the Neurol Sci. 1995;134:79–83. doi: 10.1016/0022-510X(95)00211-J. [DOI] [PubMed] [Google Scholar]
  • [48].Hamann K, Shi R. Acrolein scavenging: a potential novel mechanism of attenuating oxidative stress following spinal cord injury. J Neurochem. 2009;111:1348–1356. doi: 10.1111/j.1471-4159.2009.06395.x. [DOI] [PubMed] [Google Scholar]
  • [49].Young W. Role of calcium in central nervous system injuries. J Neurotrauma. 1992;9:S9–S25. [PubMed] [Google Scholar]
  • [50].Borgens RB, Shi R. Immediate recovery from spinal cord injury through molecular repair of nerve membranes with polyethylene glycol. FASEB J. 2000;14:27–35. doi: 10.1096/fasebj.14.1.27. [DOI] [PubMed] [Google Scholar]
  • [51].Borgens RB, Shi R, Bohnert D. Behavioral recovery from spinal cord injury following delayed application of polyethylene glycol. J Exp Biol. 2002;205:1–12. doi: 10.1242/jeb.205.1.1. [DOI] [PubMed] [Google Scholar]
  • [52].Borgens RB, Bohnert D. Rapid recovery from spinal cord injury following subcutaneously administered polyethylene glycol. J Neurosci Res. 2001;66:1179–1186. doi: 10.1002/jnr.1254. [DOI] [PubMed] [Google Scholar]
  • [53].Duerstock BS, Borgens RB. Three-dimentional morphometry of spinal cord injury follow polyethylene glycol treatment. J Exp Biol. 2002;205:13–24. doi: 10.1242/jeb.205.1.13. [DOI] [PubMed] [Google Scholar]
  • [54].Detloff MR, Lavik E, Fisher LC, Langer R, Basso DM. Polyethylene glycol administration after moderate spinal cord injury decreases lesionsize and improves locomotor recovery. J Neurotrauma. 2005;22:1219. [Google Scholar]
  • [55].Baptiste DC, Austin JW, Zhao W, Nahirny A, Sugita S, Fehlings MG. Systemic polyethylene glycol promotes neurological recovery and tissue sparing in rats after cervical spinal cord injury. J Neuropathol Exp Neurol. 2009;68:661–676. doi: 10.1097/NEN.0b013e3181a72605. [DOI] [PubMed] [Google Scholar]
  • [56].Ditor DS, John SM, Roy J, Marx JC, Kittmer C, Weaver LC. Effects of polyethylene glycol and magnesium sulfate administration on clinically relevant neurological outcomes after spinal cord injury in the rat. J Neurosci Res. 2007;85:1458–1467. doi: 10.1002/jnr.21283. [DOI] [PubMed] [Google Scholar]
  • [57].Luo J, Shi R. Polyethylene glycol inhibits apoptotic cell death following traumatic spinal cord injury. Brain Res. 2007;1155:10–16. doi: 10.1016/j.brainres.2007.03.091. [DOI] [PubMed] [Google Scholar]
  • [58].Beattie MS, Farooqui AA, Bresnahan JC. Review of current evidence for apoptosis after spinal cord injury. J Neurotrauma. 2000;17:915–925. doi: 10.1089/neu.2000.17.915. [DOI] [PubMed] [Google Scholar]
  • [59].Crowe MJ, Bresnahan JC, Shuman SL, Masters JN, Beattie MS. Apoptosis and delayed degeneration after spinal cord injury in rats and monkeys. Nat Med. 1997;3:73–76. doi: 10.1038/nm0197-73. [DOI] [PubMed] [Google Scholar]
  • [60].Li QM, Tep C, Yune TY, Zhou XZ, Uchida T, Lu KP, et al. Opposite regulation of oligodendrocyte apoptosis by JNK3 and Pin1 after spinal cord injury. J Neurosci. 2007;27:8395–8404. doi: 10.1523/JNEUROSCI.2478-07.2007. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [61].Laverty PH, Leskovar A, Breur GJ, Coates JR, Bergman RL, Widmer WR, et al. A preliminary study of intravenous surfactants in paraplegic dogs: polymer therapy in canine clinical SCi. J Neurotrauma. 2004;21:1767–1777. doi: 10.1089/neu.2004.21.1767. [DOI] [PubMed] [Google Scholar]
  • [62].Donaldson J, Shi R, Borgens R. Polyethylene glycol rapidly restores physiological functions in damaged sciatic nerves of guinea pigs. Neurosurgery. 2002;50:147–156. doi: 10.1097/00006123-200201000-00023. [DOI] [PubMed] [Google Scholar]
  • [63].Koob A, Duerstock BS, Babbs CF, Sun Y, Borgens RB. Intravenous polyethylene glycol inhibits the loss of cerebral cells after brain injury. J Neurotrauma. 2005;22:1092–1111. doi: 10.1089/neu.2005.22.1092. [DOI] [PubMed] [Google Scholar]
  • [64].Chen H, Shi R. Polyethylene glycol improves function of isolated brain mitochondria: implication in central nervous system trauma. J. Neurotrauma. 2004;21:1303. [Google Scholar]
  • [65].Chen H, Quick E, Leung G, Hamann K, Fu Y, Cheng JX, et al. Polyethylene glycol protects injured neuronal mitochondria. Pathobiology. 2009;76:117–128. doi: 10.1159/000209389. [DOI] [PubMed] [Google Scholar]

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