Chitosan produces potent neuroprotection and physiological recovery following traumatic spinal cord injury

SUMMARY Chitosan, a non-toxic biodegradable polycationic polymer with low immunogenicity, has been extensively investigated in various biomedical applications. In this work, chitosan has been demonstrated to seal compromised nerve cell membranes thus serving as a potent neuroprotector following acute spinal cord trauma. Topical application of chitosan after complete transection or compression of the guinea pig spinal cord facilitated sealing of neuronal membranes in ex vivo tests, and restored the conduction of nerve impulses through the length of spinal cords in vivo, using somatosensory evoked potential recordings. Moreover, chitosan preferentially targeted damaged tissues, served as a suppressor of reactive oxygen species (free radical) generation, and the resultant lipid peroxidation of membranes, as shown in ex vivo spinal cord samples. These findings suggest a novel medical approach to reduce the catastrophic loss of behavior after acute spinal cord and brain injury.

[1]  K. Barbee,et al.  Mechanisms of cell death and neuroprotection by poloxamer 188 after mechanical trauma , 2006, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[2]  Lisbeth Illum,et al.  Chitosan as a Novel Nasal Delivery System for Peptide Drugs , 1994, Pharmaceutical Research.

[3]  J. Paul Robinson,et al.  Acrolein-induced cell death in PC12 cells: Role of mitochondria-mediated oxidative stress , 2005, Neurochemistry International.

[4]  D. Petersen,et al.  Protein adduct-trapping by hydrazinophthalazine drugs: mechanisms of cytoprotection against acrolein-mediated toxicity. , 2004, Molecular pharmacology.

[5]  Raphael C. Lee,et al.  Direct observation of poloxamer 188 insertion into lipid monolayers. , 2002, Biophysical journal.

[6]  C. Babbs,et al.  Intravenous polyethylene glycol inhibits the loss of cerebral cells after brain injury. , 2005, Journal of neurotrauma.

[7]  R. Shi,et al.  Acrolein induces oxidative stress in brain mitochondria , 2005, Neurochemistry International.

[8]  Z. A. Trapeznikova On the Interaction of , 1959 .

[9]  J. Brent Current Management of Ethylene Glycol Poisoning , 2012, Drugs.

[10]  Helen A. McNally,et al.  Three-dimensional imaging of living and dying neurons with atomic force microscopy , 2004, Journal of neurocytology.

[11]  R B Borgens,et al.  Acute repair of crushed guinea pig spinal cord by polyethylene glycol. , 1999, Journal of neurophysiology.

[12]  T. Fujinaga,et al.  Accelerating effects of chitosan for healing at early phase of experimental open wound in dogs. , 1999, Biomaterials.

[13]  M. Amiji,et al.  Synthesis of a fluorescent chitosan derivative and its application for the study of chitosan-mucin interactions , 1999 .

[14]  K. Janes,et al.  Chitosan nanoparticles as delivery systems for doxorubicin. , 2001, Journal of controlled release : official journal of the Controlled Release Society.

[15]  A. Woolf,et al.  Ethylene Glycol Exposure: an Evidence-Based Consensus Guideline for Out-of-Hospital Management , 2005, Clinical toxicology.

[16]  R. Shi,et al.  Behavioral recovery from spinal cord injury following delayed application of polyethylene glycol. , 2002, The Journal of experimental biology.

[17]  Xiaosong Gu,et al.  The interaction of Schwann cells with chitosan membranes and fibers in vitro. , 2004, Biomaterials.

[18]  U. Kang,et al.  Neuroprotective effect of the surfactant poloxamer 188 in a model of intracranial hemorrhage in rats. , 2007, Journal of neurosurgery.

[19]  G. Breur,et al.  A preliminary study of intravenous surfactants in paraplegic dogs: polymer therapy in canine clinical SCI. , 2004, Journal of neurotrauma.

[20]  R. Borgens Cellular Engineering: Molecular Repair of Membranes to Rescue Cells of the Damaged Nervous System , 2001, Neurosurgery.

[21]  Sudha Kumari,et al.  ARF1 is directly involved in dynamin-independent endocytosis , 2008, Nature Cell Biology.

[22]  R. Shi,et al.  Hydralazine rescues PC12 cells from acrolein‐mediated death , 2006, Journal of neuroscience research.

[23]  Borgens Rb,et al.  Voltage gradients and ionic currents in injured and regenerating axons. , 1988 .

[24]  K. Leong,et al.  Interactions of phospholipid bilayer with chitosan: effect of molecular weight and pH. , 2001, Biomacromolecules.

[25]  R. Shi,et al.  Repairing the damaged spinal cord and brain with nanomedicine. , 2008, Small.

[26]  D. Santos,et al.  Interaction of chitosan with cell membrane models at the air-water interface. , 2007, Biomacromolecules.

[27]  S. Madihally,et al.  Porous chitosan scaffolds for tissue engineering. , 1999, Biomaterials.

[28]  J. Trojanowski,et al.  Impact Acceleration Injury in the Rat: Evidence for Focal Axolemmal Change and Related Neurofilament Sidearm Alteration , 1997, Journal of neuropathology and experimental neurology.

[29]  R. Shi,et al.  Acrolein induces axolemmal disruption, oxidative stress, and mitochondrial impairment in spinal cord tissue , 2004, Neurochemistry International.

[30]  R. Shi,et al.  Immediate recovery from spinal cord injury through molecular repair of nerve membranes with polyethylene glycol , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  R. Bodmeier,et al.  A Novel Approach to the Oral Delivery of Micro- or Nanoparticles , 1989, Pharmaceutical Research.

[32]  Raphael C. Lee,et al.  Subcutaneous tri‐block copolymer produces recovery from spinal cord injury , 2004, Journal of neuroscience research.

[33]  S. Pyke,et al.  Hydralazine Inhibits Rapid Acrolein-Induced Protein Oligomerization: Role of Aldehyde Scavenging and Adduct Trapping in Cross-Link Blocking and Cytoprotection , 2006, Molecular Pharmacology.

[34]  R. Shi,et al.  Neuroprotection from secondary injury by polyethylene glycol requires its internalization , 2007, Journal of Experimental Biology.

[35]  R. Shi,et al.  Polyethylene glycol improves function and reduces oxidative stress in synaptosomal preparations following spinal cord injury. , 2004, Journal of neurotrauma.

[36]  R. Lee,et al.  Surfactant-induced sealing of electropermeabilized skeletal muscle membranes in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[37]  Tao Wang,et al.  Chitosan nanoparticle as protein delivery carrier--systematic examination of fabrication conditions for efficient loading and release. , 2007, Colloids and surfaces. B, Biointerfaces.

[38]  R. Shi,et al.  Acrolein inflicts axonal membrane disruption and conduction loss in isolated guinea-pig spinal cord , 2002, Neuroscience.

[39]  R. Borgens Restoring Function to the Injured Human Spinal Cord , 2003, Advances in Anatomy Embryology and Cell Biology.

[40]  R B Borgens,et al.  Voltage gradients and ionic currents in injured and regenerating axons. , 1988, Advances in neurology.

[41]  A. Shafiei,et al.  Chitosan Enhances the In Vitro Surface Activity of Dilute Lung Surfactant Preparations and Resists Albumin-Induced Inactivation , 2006, Pediatric Research.

[42]  Raphael C. Lee,et al.  The surfactant poloxamer-188 protects against glutamate toxicity in the rat brain , 2004, Neuroreport.

[43]  Krishnendu Roy,et al.  Oral gene delivery with chitosan–DNA nanoparticles generates immunologic protection in a murine model of peanut allergy , 1999, Nature Medicine.

[44]  M. Toner,et al.  Poloxamer 188 enhances functional recovery of lethally heat-shocked fibroblasts. , 1998, The Journal of surgical research.

[45]  J. Thiran,et al.  Localization of electrodes in the subthalamic nucleus on magnetic resonance imaging. , 2007, Journal of neurosurgery.

[46]  V. Chan,et al.  Chitosan-induced restructuration of a mica-supported phospholipid bilayer: an atomic force microscopy study. , 2003, Biomacromolecules.

[47]  R. Borgens,et al.  Polyethylene glycol treatment after traumatic brain injury reduces β‐amyloid precursor protein accumulation in degenerating axons , 2006, Journal of neuroscience research.

[48]  Riyi Shi,et al.  Polyethylene glycol immediately repairs neuronal membranes and inhibits free radical production after acute spinal cord injury , 2002, Journal of neurochemistry.

[49]  K. Mislick,et al.  Evidence for the role of proteoglycans in cation-mediated gene transfer. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[50]  Chiing-Chang Chen,et al.  Relationship between antibacterial activity of chitosan and surface characteristics of cell wall. , 2004, Acta pharmacologica Sinica.