Effects of Cyclosporin A on Neurological Outcome and Serum Biomarkers in the Same Setting of Spinal Cord Ischemia Model

Spinal cord ischemic injury is one of the feared complications during aortic cross-clamping. The aim of this study was to investigate whether cyclosporin A (CsA) has a protective effect on spinal cord during ischemia in a rabbit model. A total of 22 New Zealand white rabbits were studied in three groups. One of the groups served as a sham group (n = 7), in which only laparatomy was performed and closed. One group served as a control group (n = 7), in which rabbits had their abdominal aortas cross-clamped for 40 min following median laparatomy. The last group was the CsA group (n = 8), in which rabbits underwent the same procedure as the control group as well as CsA infusion at 20 mg/(kg · hr) over 60 min starting with aortic cross-clamping and continuing in the first 20 min of reperfusion. Neurological outcome of rabbits was evaluated according to Johnson’s scale at postoperative hours 24 and 48 in all groups, and then they were killed. Their spinal cords were harvested, and segments corresponding to L4-L6 were prepared for pathological examination. Serum neuron-specific enolase (NSE) and nitric oxide (NO) levels were measured prior to and following aortic occlusion, and comparisons were made. Physiological data were similar in all groups. Rabbits in the sham group did not have any neurological deficit. However, all rabbits in the control group showed severe neurological deficits, including total paraplegia in five. According to Johnson’s scale, neurological status of the rabbits at postoperative hour 48 was better in the CsA group compared to controls (p < 0.01). Pathological examination of spinal cord specimens revealed a higher viability index in the CsA group compared to controls (p < 0.01). Serum NSE and NO levels were lower in CsA-treated animals compared to controls. Our results demonstrate that CsA, when administered during ischemia and in the early period of reperfusion, may reduce neuronal damage in the spinal cord in a rabbit model of transient spinal cord ischemia.

[1]  H. Hårdemark,et al.  S-100 protein and neuron-specific enolase in cerebrospinal fluid and serum: markers of cell damage in human central nervous system. , 1987, Stroke.

[2]  P. Morris.  Cyclosporine, FK-506 and other drugs in organ transplantation. , 1991, Current opinion in immunology.

[3]  S. Mckinstry,et al.  Serum neurone specific enolase (NSE) levels as an indicator of neuronal damage in patients with cerebral infarction , 1991, European journal of clinical investigation.

[4]  D. Lyster,et al.  Pharmacologic interventions for prevention of spinal cord injury caused by aortic crossclamping. , 1992, The Journal of thoracic and cardiovascular surgery.

[5]  G. Graeber,et al.  Effects of Flunarizine on Neurological Recovery and Spinal Cord Blood Flow in Experimental Sinal Cord Ischemia in Rabbits , 1993, Stroke.

[6]  J. Coselli,et al.  Experience with 1509 patients undergoing thoracoabdominal aortic operations. , 1993, Journal of vascular surgery.

[7]  F. Gharagozloo,et al.  Spinal cord protection during surgical procedures on the descending thoracic and thoracoabdominal aorta: review of current techniques. , 1996, Chest.

[8]  J. Arenas,et al.  Semiautomated measurement of nitrate in biological fluids. , 1998, Clinical chemistry.

[9]  A. Menkis,et al.  Cyclosporine heart transplantation. , 1998, Transplantation proceedings.

[10]  W. Schaper,et al.  Hypoxia induces permeability in brain microvessel endothelial cells via VEGF and NO. , 1999, American journal of physiology. Cell physiology.

[11]  Alexander Sasha Rabchevsky,et al.  Dose-response curve and optimal dosing regimen of cyclosporin A after traumatic brain injury in rats , 2000, Neuroscience.

[12]  M. Underwood,et al.  Prevention of spinal cord ischaemia during descending thoracic and thoracoabdominal aortic surgery. , 2001, European journal of cardio-thoracic surgery : official journal of the European Association for Cardio-thoracic Surgery.

[13]  Á. Almeida,et al.  Oxygen and glucose deprivation induces mitochondrial dysfunction and oxidative stress in neurones but not in astrocytes in primary culture , 2002, Journal of neurochemistry.

[14]  Eun-Jin Lee,et al.  Regulation and localization of neuronal nitric oxide synthase in the ischemic rabbit spinal cord. , 2003, Molecules and cells.

[15]  T. Horinouchi,et al.  Cyclosporin A reduces delayed motor neuron death after spinal cord ischemia in rabbits. , 2003, The Annals of thoracic surgery.

[16]  P. Sarzi-Puttini,et al.  Successful treatment of pure red cell aplasia in systemic lupus erythematosus with cyclosporin A. , 2003, Clinical and experimental rheumatology.

[17]  S. Agrawal,et al.  Role of calcineurin in calcium-mediated hypoxic injury to white matter. , 2003, The spine journal : official journal of the North American Spine Society.

[18]  M. Cavaglià,et al.  Peripheral markers of brain damage and blood-brain barrier dysfunction. , 2003, Restorative neurology and neuroscience.

[19]  T. Wieloch,et al.  Powerful cyclosporin inhibition of calcium-induced permeability transition in brain mitochondria , 2003, Brain Research.

[20]  M. Zawadzka,et al.  Molecular mechanisms of neuroprotective action of immunosuppressants ‐ facts and hypotheses , 2004, Journal of cellular and molecular medicine.

[21]  C. Ríos,et al.  Cyclosporin-A Inhibits Constitutive Nitric Oxide Synthase Activity and Neuronal and Endothelial Nitric Oxide Synthase Expressions after Spinal Cord Injury in Rats , 2005, Neurochemical Research.

[22]  D. Loy,et al.  Serum Biomarkers for Experimental Acute Spinal Cord Injury: Rapid Elevation of Neuron-specific Enolase and S-100β , 2005, Neurosurgery.

[23]  K. Yasuda,et al.  Immunophilin ligands FK506 and cyclosporine A improve neurologic and histopathologic outcome after transient spinal cord ischemia in rabbits. , 2005, The Journal of thoracic and cardiovascular surgery.