Articles

The Effects of Cyclosporin-A on Functional Outcome and Axonal Regrowth Following Spinal Cord Injury in Adult Rats

Abstract

It has been shown that the immunophilin ligands have the special advantage in spinal cord repair. In this study, the effects of cyclosporine A (CsA) on functional recovery and histological outcome were evaluated following spinal cord injury in rats. After spinal cord hemisection in thirty six adult female Sprague-Dawley rats (200- 250 g), treatment groups received CsA (2.5 mg/kg i.p.) at 15min and 24h after lesion (CsA 15min group and CsA 24h group) daily, for 8 weeks. Control and sham groups received normal saline and in sham operated animals the spinal cord was exposed in the same manner as treatment groups, but was not hemisected. Hindlimb motor function was assessed in 1, 3, 5 and 7 weeks after lesion, using locomotive rating scale developed by Basso, Bresnahan and Beattie (BBB). Motor neurons were counted within the lamina IX of ventral horn and lesion size was measured in 5 mm of spinal lumbar segment with the epicenter of the lesion site. The mean number of motor neurons and the mean BBB scale in 3, 5 and 7 weeks in CsA 15min groups significantly increased compared to the control group. Although, the lesion size reduced in rats with CsA treatment compared to the control group, no significant difference was observed. Thus, it can be concluded that CsA can improve locomotor function and histological outcome in the partial spinal cord injury.

Liu F, You SW, Yao LP, Liu HL, Jiao XY, Shi M, Zhao QB, Ju G. Secondary degeneration reduced by inosine after spinal cord injury in rats. Spinal Cord 2006;44(7):421-6.

Gonzalez R, Glaser J, Liu MT, Lane TE, Keirstead HS. Reducing inflammation decreases secondary degeneration and functional deficit after spinal cord injury. Exp Neurol 2003;184(1):456-63.

Seggio AM, Narayanaswamy A, Roysam B, Thompson DM. Self-aligned Schwann cell monolayers demonstrate an inherent ability to direct neurite outgrowth. J Neural Eng 2010;7(4):046001.

Madduri S, Papaloïzos M, Gander B. Trophically and topographically functionalized silk fibroin nerve conduits for guided peripheral nerve regeneration. Biomaterials 2010;31(8):2323-34.

Ibarra A, Hernández E, Lomeli J, Pineda D, Buenrostro M, Martiñón S, Garcia E, Flores N, Guizar-Sahagun G, Correa D, Madrazo I. Cyclosporin-A enhances non-functional axonal growing after complete spinal cord transection. Brain Res 2007;1149:200-9.

Popovich PG, Wei P, Stokes BT. Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats. J Comp Neurol 1997;377(3):443-64.

Thuret S, Moon LD, Gage FH. Therapeutic interventions after spinal cord injury. Nat Rev Neurosci 2006;7(8):628-43.

Büki A, Okonkwo DO, Povlishock JT. Postinjury cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury. J Neurotrauma 1999;16(6):511-21.

Mbye LH, Singh IN, Carrico KM, Saatman KE, Hall ED. Comparative neuroprotective effects of cyclosporin A and NIM811, a nonimmunosuppressive cyclosporin A analog, following traumatic brain injury. J Cereb Blood Flow Metab 2009;29(1):87-97.

Colley BS, Phillips LL, Reeves TM. The effects of cyclosporin-A on axonal conduction deficits following traumatic brain injury in adult rats. Exp Neurol 2010;224(1):241-51.

Etzkorn FA, Chang ZY, Stolz LA, Walsh CT. Cyclophilin residues that affect noncompetitive inhibition of the protein serine phosphatase activity of calcineurin by the cyclophilin.cyclosporin A complex. Biochemistry 1994;33(9):2380-8.

Mahalati K, Belitsky P, Sketris I, West K, Panek R. Neoral monitoring by simplified sparse sampling area under the concentration-time curve: its relationship to acute rejection and cyclosporine nephrotoxicity early after kidney transplantation. Transplantation 1999;68(1):55-62.

Bavetta S, Hamlyn PJ, Burnstock G, Lieberman AR, Anderson PN. The effects of FK506 on dorsal column axons following spinal cord injury in adult rats: neuroprotection and local regeneration. Exp Neurol1999;158(2):382-93.

Yu Y, Chen XQ, Cui YY, Hu GY. Calcineurinindependent inhibition of the delayed rectifier K+ current by the immunosuppressant FK506 in rat hippocampal neurons. Brain Res 2007;1148:62-8.

Taskinen HS, Röyttä M. The dynamics of macrophage recruitment after nerve transection. Acta Neuropathol 1997;93(3):252-9.

Houle JD, Jin Y. Chronically injured supraspinal neurons exhibit only modest axonal dieback in response to a cervical hemisection lesion. Exp Neurol 2001;169(1):208-17.

Basso DM, Beattie MS, Bresnahan JC. A sensitive and reliable locomotor rating scale for open field testing in rats. J Neurotrauma 1995;12(1):1-21.

Rexed B. A cytoarchitectonic atlas of the spinal cord in the cat. J Comp Neurol 1954;100(2):297-379.

McMahon SS, Albermann S, Rooney GE, Moran C, Hynes J, Garcia Y, Dockery P, O'Brien T, Windebank AJ, Barry FP. Effect of cyclosporin A on functional recovery in the spinal cord following contusion injury. J Anat 2009;215(3):267-79.

Colley BS, Phillips LL, Reeves TM. The effects of cyclosporin-A on axonal conduction deficits following traumatic brain injury in adult rats. Exp Neurol 2010;224(1):241-51.

Sullivan PG, Rabchevsky AG, Hicks RR, Gibson TR, Fletcher-Turner A, Scheff SW. Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats. Neuroscience 2000;101(2):289-95.

Uchino H, Elmér E, Uchino K, Lindvall O, Siesjö BK. Cyclosporin A dramatically ameliorates CA1 hippocampal damage following transient forebrain ischaemia in the rat. Acta Physiol Scand 1995;155(4):469-71.

Rabchevsky AG, Fugaccia I, Sullivan PG, Scheff SW. Cyclosporin A treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing. J Neurotrauma 2001;18(5):513-22.

Stichel CC, Lausberg F, Hermanns S, Müller HW. Scarmodulation in subacute and chronic CNS lesions: Effects on axonal regeneration. Restor Neurol Neurosci 1999;15(1):1-15.

Rice T, Larsen J, Rivest S, Yong VW. Characterization of the early neuroinflammation after spinal cord injury in mice. J Neuropathol Exp Neurol 2007;66(3):184-95.

Yang L, Jones NR, Blumbergs PC, Van Den Heuvel C, Moore EJ, Manavis J, Sarvestani GT, Ghabriel MN. Severity-dependent expression of pro-inflammatory cytokines in traumatic spinal cord injury in the rat. J Clin Neurosci 2005;12(3):276-84.

Bethea JR. Spinal cord injury-induced inflammation: a dual-edged sword. Prog Brain Res 2000;128:33-42.

Hunt J, Morshead C. Cyclosporin enhances cell survival in neural precursor populations in the adult central nervous system. Mol Cell Pharmacol 2010;2(3):81-8.

Takahashi N, Hayano T, Suzuki M. Peptidyl-prolyl cistrans isomerase is the cyclosporin A-binding protein cyclophilin. Nature 1989;337(6206):473-5.

Beck KD, Nguyen HX, Galvan MD, Salazar DL, Woodruff TM, Anderson AJ. Quantitative analysis of cellular inflammation after traumatic spinal cord injury: evidence for a multiphasic inflammatory response in the acute to chronic environment. Brain 2010;133(Pt 2):433-47.

Hailer NP. Immunosuppression after traumatic or ischemic CNS damage: it is neuroprotective and illuminates the role of microglial cells. Prog Neurobiol 2008;84(3):211-33

Yin Y, Henzl MT, Lorber B, Nakazawa T, Thomas TT, Jiang F, Langer R, Benowitz LI. Oncomodulin is a macrophage-derived signal for axon regeneration in retinal ganglion cells. Nat Neurosci 2006;9(6):843-52.

Palladini G, Caronti B, Pozzessere G, Teichner A, Buttarelli FR, Morselli E, Valle E, Venturini G, Fortuna A,Pontieri FE. Treatment with cyclosporine A promotes axonal regeneration in rats submitted to transverse section of the spinal cord--II--Recovery of function. J Hirnforsch 1996;37(1):145-53.

Ibarra A, Correa D, Willms K, Merchant MT, Guizar- Sahagún G, Grijalva I, Madrazo I. Effects of cyclosporin- A on immune response, tissue protection and motor function of rats subjected to spinal cord injury. Brain Res 2003;979(1-2):165-78.

Rabchevsky AG, Fugaccia I, Sullivan PG, Scheff SW. Cyclosporin A treatment following spinal cord injury to the rat: behavioral effects and stereological assessment of tissue sparing. J Neurotrauma 2001;18(5):513-22.

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IssueVol 50, No 4 (2012) QRcode
SectionArticles
Keywords
Cyclosporin A Recovery of function Motor neurons Spinal cord

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How to Cite
1.
Roozbehi A, Joghataie MT, Mehdizadeh M, Mirzaei A, Delaviz H. The Effects of Cyclosporin-A on Functional Outcome and Axonal Regrowth Following Spinal Cord Injury in Adult Rats. Acta Med Iran. 1;50(4):226-232.