The purpose of this study was to investigate the effects of combination therapy with methylprednisolone (MP) and Nogo-66 antagonistic peptide (NEP1-40) on morphological and functional recovery in adult rats subjected to thoracic compression spinal cord injury (SCI). Animals were randomized into four groups: a trauma control group, an MP group, an NEP1-40 group, and a combined treatment group. The inflammatory reaction, neuronal and oligodendrocyte survival, and ultrastructure were assessed at the injury site. Functional analysis was also performed using Basso, Beattie and Bresnahan (BBB) scoring. Rat behaviour was evaluated regularly up to week 4. NEP1-40 did not alter the beneficial effect of MP on haematogenous inflammatory cell infiltration, while combined treatment resulted in greater neuronal and oligodendrocyte survival compared with monotherapy or control. Combination therapy resulted in better locomotor scores. These results in a clinically-relevant SCI model showed that significant neuroprotection can be obtained by combining an initial acute IV injection of MP with continuously infused NEP1-40.
HuangHFanSJiX: Recombinant human erythropoietin protects against experimental spinal cord trauma injury by regulating expression of the proteins MKP-1 and p-ERK. J Int Med Res2009; 37: 511–519.
2.
BaptisteDCFehlingsMG: Pharmacological approaches to repair the injured spinal cord. J Neurotrauma2006; 23: 318–334.
3.
HallED: The neuroprotective pharmacology of methylprednisolone. J Neurosurg1992; 76: 13–22.
4.
KwonBKTetzlaffWGrauerJN: Pathophysiology and pharmacologic treatment of acute spinal cord injury. Spine J2004; 4: 451–464.
5.
BrackenMB: Methylprednisolone and acute spinal cord injury: An update of the randomized evidence. Spine (Phila PA 1976)2001; 26 (24 suppl): S47–S54.
6.
HurlbertRJ: Methylprednisolone for acute spinal cord injury: An inappropriate standard of care. J Neurosurg2000; 93 (1 suppl): 1–7.
7.
NadeauSRivestS: Glucocorticoids play a fundamental role in protecting the brain during innate immune response. J Neurosci2003; 23: 5536–5544.
8.
YanPXuJLiQ: Glucocorticoid receptor expression in the spinal cord after traumatic injury in adult rats. J Neurosci1999; 19: 9355–9363.
9.
YuPHuangLZouJ: Immunization with recombinant Nogo-66 receptor (NgR) promotes axonal regeneration and recovery of function after spinal cord injury in rats. Neurobiol Dis2008; 32: 535–542.
10.
WangFLiangZHouQ: Nogo-A is involved in secondary axonal degeneration of thalamus in hypertensive rats with focal cortical infarction. Neurosci Lett2007; 417: 255–260.
11.
Wannier-MorinoPSchmidlinEFreundP: Fate of rubrospinal neurons after unilateral section of the cervical spinal cord in adult macaque monkeys: Effects of an antibody treatment neutralizing Nogo-A. Brain Res2008; 1217: 96–109.
12.
StewardOSharpKYeeKM: A reassessment of the effects of a Nogo-66 receptor antagonist on regenerative growth of axons and locomotor recovery after spinal cord injury in mice. Exp Neurol2008; 209: 446–468.
13.
MingoranceASoleMMunetonV: Regeneration of lesioned entorhino-hippocampal axons in vitro by combined degradation of inhibitory proteoglycans and blockade of Nogo-66/NgR signaling. FASEB J2006; 20: 491–493.
14.
AtalayBBavbekMOzenO: Nogo-A inhibitory peptide (NEP1–40) increases pan-cadherin expression following mild cortical contusion injury in rats. Turk Neurosurg2008; 18: 356–365.
15.
JiBLiMBudelS: Effect of combined treatment with methylprednisolone and soluble Nogo-66 receptor after rat spinal cord injury. Eur J Neurosci2005; 22: 587–594.
16.
BayneK: Revised Guide for the Care and Use of Laboratory Animals available. American Physiological Society. Physiologist1996; 39: 199, 208–211.
17.
SchrageKKoopmansGJoostenEA: Macrophages and neurons are targets of retinoic acid signaling after spinal cord contusion injury. Eur J Neurosci2006; 23: 285–295.
18.
GokBSciubbaDMOkutanO: Immunomodulation of acute experimental spinal cord injury with human immunoglobulin G. J Clin Neurosci2009; 16: 549–553.
19.
BassoDMBeattieMSBresnahanJC: Graded histological and locomotor outcomes after spinal cord contusion using the NYU weight-drop device versus transection. Exp Neurol1996; 139: 244–256.
20.
Garcia-LopezPPerez-UrizarJIbarraA: Comparison between Sprague-Dawley and Wistar rats as an experimental model of pharmacokinetic alterations induced by spinal cord injury. Arch Med Res1996; 27: 453–457.
21.
HuangWLKingVRCurranOE: A combination of intravenous and dietary docosahexaenoic acid significantly improves outcome after spinal cord injury. Brain2007; 130 (pt 11): 3004–3019.
22.
FitchMTDollerCCombsCK: Cellular and molecular mechanisms of glial scarring and progressive cavitation: In vivo and in vitro analysis of inflammation-induced secondary injury after CNS trauma. J Neurosci1999; 19: 8182–8198.
23.
SchwartzMLazarov-SpieglerORapalinoO: Potential repair of rat spinal cord injuries using stimulated homologous macrophages. Neurosurgery1999; 44: 1041–1045; discussion 1045–1046.
24.
RapalinoOLazarov-SpieglerOAgranovE: Implantation of stimulated homologous macrophages results in partial recovery of paraplegic rats. Nat Med1998; 4: 814–821.
25.
PopovichPGJonesTB: Manipulating neuroinflammatory reactions in the injured spinal cord: Back to basics. Trends Pharmacol Sci2003; 24: 13–17.
26.
XuJQuZXHoganEL: Protective effect of methylprednisolone on vascular injury in rat spinal cord injury. J Neurotrauma1992; 9: 245–253.
27.
YangYGJiangDMQuanZX: Insulin with chondroitinase ABC treats the rat model of acute spinal cord injury. J Int Med Res2009; 37: 1097–1107.
28.
CaoYShumskyJSSabolMA: Nogo-66 receptor antagonist peptide (NEP1–40) administration promotes functional recovery and axonal growth after lateral funiculus injury in the adult rat. Neurorehabil Neural Repair2008; 22: 262–278.
29.
McGeeAWStrittmatterSM: The Nogo-66 receptor: Focusing myelin inhibition of axon regeneration. Trends Neurosci2003; 26: 193–198.
