Cyclosporine-A as a neuroprotective agent against stroke: Its translation from laboratory research to clinical application

Neuropeptides

Volumn 45, Issue 6, 2011, Pages 359-368

  Osman, Mohamed M ^a   Lulic, Dzenan ^a   Glover, Loren ^a   Stahl, Christine E ^b   Lau, Tsz ^a   van Loveren, Harry ^a   Borlongan, Cesar V ^a  

^a UNIVERSITY OF SOUTH FLORIDA   (United States)

^b MacDill Air Force Base   (United States)

Author keywords

Cerebral ischemia; Immunosuppressant; Mitochondria; Neurological disorders; Neuroprotection

Indexed keywords

CYCLOSPORIN A; MITOCHONDRIAL PERMEABILITY TRANSITION PORE;

AMINOTRANSFERASE BLOOD LEVEL; BILIRUBIN BLOOD LEVEL; CAUSE OF DEATH; CLINICAL PRACTICE; DISABILITY; DRUG ACTIVITY; DRUG EFFICACY; DRUG RESEARCH; DRUG SAFETY; HIRSUTISM; HUMAN; HYPERTENSION; IMMUNOMODULATION; IMMUNOSUPPRESSIVE TREATMENT; MENTAL HEALTH; NEPHROTOXICITY; NERVE CELL NECROSIS; NEUROPROTECTION; NEUROTOXICITY; NONHUMAN; POSTERIOR REVERSIBLE ENCEPHALOPATHY SYNDROME; PRIORITY JOURNAL; REVIEW; SEIZURE; SIDE EFFECT; STROKE; VISUAL DISORDER;

ANIMALS; BRAIN INJURIES; CELL DEATH; CLINICAL TRIALS AS TOPIC; CYCLOSPORINE; HUMANS; IMMUNOSUPPRESSIVE AGENTS; MITOCHONDRIA; MITOCHONDRIAL MEMBRANE TRANSPORT PROTEINS; MOLECULAR STRUCTURE; NEUROPROTECTIVE AGENTS; STROKE; TREATMENT OUTCOME;

EID: 83355166870     PISSN: 01434179     EISSN: 15322785     Source Type: Journal    
DOI: 10.1016/j.npep.2011.04.002     Document Type: Review

References (97)

1. Actis G.C., Aimo G., Priolo G., Moscato D., Rizzetto M., Pagni R. Efficacy and efficiency of oral microemulsion cyclosporine versus intravenous and soft gelatin capsule cyclosporine in the treatment of severe steroid-refractory ulcerative colitis: an open-label retrospective trial. Inflamm. Bowel Dis. 1998, 4:276-279.
2. Adams H.P., del Zoppo G., Alberts M.J., Bhatt D.L., Brass L., Furlan A., Grubb R.L., Higashida R.T., Jauch E.C., Kidwell C., Lyden P.D., Morgenstern L.B., Qureshi A.I., Rosenwasser R.H., Scott P.A., Wijdicks E.F. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke 2007, 38:1655-1711.
3. Akl K., Samara O. Posterior reversible encephalopathy syndrome. Saudi J. Kidney Dis. Transpl. 2010, 21:957-958.
4. Astrup J., Siesjo B.K., Symon L. Thresholds in cerebral ischemia - the ischemic penumbra. Stroke 1981, 12:723-725.
5. Baiza-Duran L., Medrano-Palafox J., Hernandez-Quintela E., Lozano-Alcazar J., Alaniz-de la O.J. A comparative clinical trial of the efficacy of two different aqueous solutions of cyclosporine for the treatment of moderate-to-severe dry eye syndrome. Br. J. Ophthalmol. 2010, 94:1312-1315.
6. Bartus R.T., Elliott P.J., Dean R.L., Hayward N.J., Nagle T.L., Huff M.R., Snodgrass P.A., Blunt D.G. Controlled modulation of BBB permeability using the bradykinin agonist, RMP-7. Exp. Neurol. 1996, 142:14-28.
7. Berth-Jones J. The use of ciclosporin in psoriasis. J. Dermatolog. Treat. 2005, 16:258-277.
8. Boddie D.E., Currie D.G., Eremin O., Heys S.D. Immune suppression and isolated severe head injury: a significant clinical problem. Br. J. Neurosurg. 2003, 17:405-417.
9. Borel J.F., Feurer C., Gubler H.U., Stahelin H. Biological effects of Cyclosporin A: a new antilymphocytic agent. Agents Actions 1976, 6:468-475.
10. Borel J.F., Baumann G., Chapman I., Donatsch P., Fahr A., Mueller E.A., Vigouret J.M. In vivo pharmacological effects of ciclosporin and some analogues. Adv. Pharmacol. 1996, 35:115-246.
11. Borlongan C.V., Fujisaki T., Watanabe S. Chronic Cyclosporine-A injection in rats with damaged blood-brain barrier does not impair retention of passive avoidance. Neurosci. Res. 1998, 32:195-200.
12. Borlongan, C.V., Isacson, O., Sanberg, P.R. (Eds.), 2002a. Humana Press, Totowa, New Jersey, vol. 1, pp. 141-157.
13. Borlongan C.V., Emerich D.F., Hoffer B.J., Bartus R.T. Bradykinin receptor agonist facilitates low-dose Cyclosporine-A protection against 6-hydroxydopamine neurotoxicity. Brain Res. 2002, 956:211-220.
14. Borlongan C.V., Emerich D.F. Facilitation of drug entry into the CNS via transient permeation of blood brain barrier: laboratory and preliminary clinical evidence from bradykinin receptor agonist, Cereport. Brain Res. Bull. 2003, 60:297-306.
15. Borlongan C.V., Stahl C.E., Fujisaki T., Sanberg P.R., Watanabe S. Cyclosporine A-induced hyperactivity in rats: Is it mediated by immunosuppression, neurotrophism, or both? Cell Transplant. 1999, 8:153-159.
16. Borlongan C.V., Stahl C.E., Keep M.F., Elmér E., Watanabe S. Cyclosporine-A enhances choline acetyltransferase immunoreactivity in the septal region of adult rats. Neurosci. Lett. 2000, 279:73-76.
17. Borlongan C.V., Yu G., Matsukawa N., Xu L., Hess D.C., Sanberg P.R., Wang Y. Acute functional effects of Cyclosporine-A and methylprednisolone treatment in adult rats exposed to transient ischemic stroke. Life Sci. 2005, 76:1503-1512.
18. Büki A., Okonkwo D.O., Povlishock J.T. Postinjury Cyclosporin A administration limits axonal damage and disconnection in traumatic brain injury. J. Neurotrauma 1999, 16:511-521.
19. Callen J.P. Immunosuppressive and cytotoxic drugs in the treatment of rheumatic skin disorders. Semin. Cutan. Med. Surg. 2001, 20:58-68.
20. Cholongitas E., Shusang V., Germani G., Tsochatzis E., Raimondo M.L., Marelli L., Senzolo M., Davidson B.R., Patch D., Rolles K., Burroughs A.K. Long-term follow-up of immunosuppressive monotherapy in liver transplantation: tacrolimus and microemulsified cyclosporin. Clin. Transplant. 2010, doi:10.1111/j.1399.0012.2010.01321.x [Epub ahead of print].
21. Costantini L.C., Chaturvedi P., Armistead D.M., McCaffrey P.G., Deacon T.W., Isacson O. A novel immunophilin ligand: distinct branching effects on dopaminergic neurons in culture and neurotrophic actions after oral administration in an animal model of Parkinson's disease. Neurobiol. Dis. 1998, 5:97-106.
22. Cousin M.A., Robinson P.J. The dephosphins: dephosphorylation by calcineurin triggers synaptic vesicle endocytosis. Trends Neurosci. 2001, 24:659-665.
23. Dawson T.M., Steiner J.P., Dawson V.L., Dinerman J.L., Uhl G.R., Snyder S.H. Immunosuppressant FK506 enhances phosphorylation of nitric oxide synthase and protects against glutamate neurotoxicity. Proc. Natl. Acad. Sci. USA 1993, 90:9808-9812.
24. Dawson V.L., Kizushi V.M., Huang P.L., Snyder S.H., Dawson T.M. Resistance to neurotoxicity in cortical cultures from neuronal nitric oxide synthase-deficient mice. J. Neurosci. 1996, 16:2479-2487.
25. Diaz-Ruiz A., Rios C., Duarte I., Correa D., Guizar-Sahagun G., Grijalva I., Ibarra A. Cyclosporin-A inhibits lipid peroxidation after spinal cord injury in rats. Neurosci. Lett. 1999, 266:61-64.
26. Domañska-Janik K., Buzañska L., Dluzniewska J., Kozlowska H., Sarnowska A., Zablocka B. Neuroprotection by Cyclosporin A following transient brain ischemia correlates with the inhibition of the early efflux of cytochrome c to cytoplasm. Mol. Brain Res. 2004, 121:50-59.
27. Donnan G.A., Fisher M., Macleod M., Davis S.M. Stroke. Lancet 2008, 371:1612-1623.
28. Empey P.E., McNamara P.J., Young B., Rosbolt M.B., Hatton J. Cyclosporin A disposition following acute traumatic brain injury. J. Neurotrauma 2006, 23:109-116.
29. Gabryel B., Bernacki J. Effect of FK506 and Cyclosporine A on the expression of BDNF, tyrosine kinase B and p75 neurotrophin receptors in astrocytes exposed to simulated ischemia in vitro. Cell Biol. Int. 2009, 33:739-748.
30. Gerloni V., Cimaz R., Gattinara M., Arnoldi C., Pontikaki I., Fantini F. Efficacy and safety profile of Cyclosporin A in the treatment of juvenile chronic (idiopathic) arthritis. Results of a 10-year prospective study. Rheumatology (Oxford) 2001, 40:907-913.
31. Gold B.G. Neuroimmunophilin ligands: evaluation of their therapeutic potential for the treatment of neurological disorders. Expert. Opin. Investig. Drugs 2000, 9:2331-2342.
32. Goldner F.M., Patrick J.W. Neuronal localization of the cyclophilin A protein in the adult rat brain. J. Comp. Neurol. 1996, 372:283-293.
33. Group M.S.S. Efficacy and toxicity of cyclosporine in chronic progressive multiple sclerosis: a randomized, double-blinded, placebo-controlled clinical trial. The Multiple Sclerosis Study Group. Ann. Neurol. 1990, 27:591-605.
34. Hanauer S.B. Medical therapy for ulcerative colitis 2004. Gastroenterology 2004, 126:1582-1592.
35. Hansson M.J., Mattiasson G., Mansson R., Karlsson J., Keep M.F., Waldmeier P., Ruegg U.T., Dumont J.M., Besseghir K., Elmer E. The nonimmunosuppressive cyclosporin analogs NIM811 and UNIL025 display nanomolar potencies on permeability transition in brain-derived mitochondria. J. Bioenerg. Biomembr. 2004, 36:407-413.
36. Hatton J., Rosbolt B., Empey P., Kryscio R., Young B. Dosing and safety of cyclosporine in patients with severe brain injury. J. Neurosurg. 2008, 109:699-707.
37. Hayashi T., Kaneko Y., Yu S., Bae E., Stahl C.E., Kawase T., van Loveren H., Sanberg P.R., Borlongan C.V. Quantitative analyses of matrix metalloproteinase activity after traumatic brain injury in adult rats. Brain Res. 2009, 1280:172-177.
38. Hayashi Y., Shumsky J.S., Connors T., Otsuka T., Fischer I., Tessler A., Murray M. Immunosuppression with either cyclosporine a or FK506 supports survival of transplanted fibroblasts and promotes growth of host axons into the transplant after spinal cord injury. J. Neurotrauma 2005, 22:1267-1281.
39. He L., Lemasters J.J. Regulated and unregulated mitochondrial permeability transition pores: a new paradigm of pore structure and function? FEBS Lett. 2002, 512:1-7.
40. Hui K.K., Liadis N., Robertson J., Kanungo A., Henderson J.T. Calcineurin inhibition enhances motor neuron survival following injury. J. Cell. Mol. Med. 2010, 14:671-686.
41. Hesselink D.A., Gregoor P.J.H.S., Weimar W. The use of cyclosporine in renal transplantation. Transplant. Proc. 2004, 36:S99-S106.
42. Ibarra A., Reyes J., Martinez S., Correa D., Guizar-Sahagun G., Grijalva I., Castaneda-Hernandez G., Flores-Murrieta F.J., Franco-Bourland R., Madrazo I. Use of Cyclosporin-A in experimental spinal cord injury: design of a dosing strategy to maintain therapeutic levels. J. Neurotrauma 1996, 13:569-572.
43. Iida K., Iwata E., Asanuma M., Asanuma S.N., Gomez-Vargas M., Miyazaki I., Nakanishi T., Ogawa N. Effects of repeated Cyclosporin A administration on iminodipropionitrile-induced dyskinesia and TRE-/CRE-binding activities in rat brain. Neurosci. Res. 1998, 30:185-193.
44. Inamura T., Black K.L. Bradykinin selectively opens blood-tumor barrier in experimental brain tumors. J. Cereb. Blood Flow Metab. 1994, 14:862-870.
45. Jauch, E., 2010. Acute stroke management: treatment & medication. In: e Medicine. eMedicine.com.
46. Kahan B.D. Optimization of cyclosporine therapy. Transplant. Proc. 1993, 25:5-9.
47. Kaminska B., Gaweda-Walerych K., Zawadzka M. Molecular mechanisms of neuroprotective action of immunosuppressants - facts and hypotheses. J. Cell. Mol. Med. 2004, 8:45-58.
48. Khan M. Immunopharmacology 2008, vol. 1. Science Media, LLC, Omaha, NE, pp. 87-103.
49. Leger P.L., De Paulis D., Branco S., Bonnin P., Couture-Lepetit E., Baud O., Renolleau S., Ovize M., Gharib A., Charriaut-Marlangue C. Evaluation of Cyclosporine A in a stroke model in the immature rat brain. Exp. Neurol. 2010.
50. Leung A.W.C., Halestrap A.P. Recent progress in elucidating the molecular mechanism of the mitochondrial permeability transition pore. Biochim. Biophys. Acta (BBA) - Bioenerg. 2008, 1777:946-952.
51. Leventhal L., Sortwell C.E., Hanbury R., Collier T.J., Kordower J.H., Palfi S. Cyclosporin A protects striatal neurons in vitro and in vivo from 3-nitropropionic acid toxicity. J. Comp. Neurol. 2000, 425:471-478.
52. Malouitre S., Dube H., Selwood D., Crompton M. Mitochondrial targeting of Cyclosporin A enables selective inhibition of cyclophilin-D and enhanced cytoprotection after glucose and oxygen deprivation. Biochem. J. 2010, 425:137-148.
53. Margaritis A., Chahal P.S. Development of a fructose based medium for biosynthesis of Cyclosporin-A. Biotechnol. Lett. 1989, 11:765-768.
54. Marler J. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N. Engl. J. Med. 1995, 333:1581-1587.
55. Marsh J.D., Keyrouz S.G. Stroke prevention and treatment. J. Am. Coll. Cardiol. 2010, 56:683-691.
56. Mattson, M.P., 2003. Immunosupressant analogs in neuroprotection. In: Immunosupressant Analogs in Neuroprotection.
57. Minones J., Yebra-Pimentel E., Conde O., Iribarnegaray E., Casas M., Vila Jato J.L., Seijo B. Interaction between cyclosporin and poly(isobutyl cyanoacrylate) nanoparticles in monolayers. Langmuir 1994, 10:1888-1893.
58. Mazzeo A.T., Kunene N.K., Gilman C.B., Hamm R.J., Hafez N., Bullock M.R. Severe human traumatic brain injury, but not cyclosporin a treatment, depresses activated T lymphocytes early after injury. J. Neurotrauma 2006, 23:962-975.
59. Mazzeo A.T., Brophy G.M., Gilman C.B., Alves O.L., Robles J.R., Hayes R.L., Povlishock J.T., Bullock M.R. Safety and tolerability of Cyclosporin A in severe traumatic brain injury patients: results from a prospective randomized trial. J. Neurotrauma 2009, 26:2195-2206.
60. Miyata K., Omori N., Uchino H., Yamaguchi T., Isshiki A., Shibasaki F. Involvement of the brain-derived neurotrophic factor/TrkB pathway in neuroprotecive effect of Cyclosporin A in forebrain ischemia. Neuroscience 2001, 105:571-578.
61. Muramatsu Y., Furuichi Y., Tojo N., Moriguchi A., Maemoto T., Nakada H., Hino M., Matsuoka N. Neuroprotective efficacy of FR901459, a novel derivative of Cyclosporin A, in vitro mitochondrial damage and in vivo transient cerebral ischemia models. Brain Res. 2007, 1149:181-190.
62. Murozono M., Matsumoto S., Matsumoto E., Isshiki A., Watanabe Y. Neuroprotective and neurotoxic effects of Cyclosporine A on transient focal ischemia in mdr1a knockout mice. Eur. J. Pharmacol. 2004, 498:115-118.
63. Nicolli A., Basso E., Petronilli V., Wenger R.M., Bernardi P. Interactions of cyclophilin with the mitochondrial inner membrane and regulation of the permeability transition pore, and Cyclosporin A-sensitive channel. J. Biol. Chem. 1996, 271:2185-2192.
64. Nomura T., Inamura T., Black K.L. Intracarotid infusion of bradykinin selectively increases blood-tumor permeability in 9L and C6 brain tumors. Brain Res. 1994, 659:62-66.
65. Oger J. Immunosuppression: promises and failures. J. Neurol. Sci. 2007, 259:74-78.
66. Ouary S., Bizat N., Altairac S., Menetrat H., Mittoux V., Conde F., Hantraye P., Brouillet E. Major strain differences in response to chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid in rats: implications for neuroprotection studies. Neuroscience 2000, 97:521-530.
67. Peterson J., Nishizawa S., Hackett J., Bun T., Teramura A., Zervas N. Cyclosporine A reduces cerebral vasospasm after subarachnoid hemorrhage in dogs. Stroke 1990, 21:133-137.
68. Ramos-Casals M., Tzioufas A.G., Stone J.H., Siso A., Bosch X. Treatment of primary Sjogren syndrome: a systematic review. JAMA 2010, 304:452-460.
69. Roman I.D., Monte M.J., Esteller A., Jiminez R.A. Cholestasis in the rat by means of intravenous administration of cyclosporine vehicle, Cremophor EL. Transplantation 1989, 48:554-558. PubMed.
70. Rosenwirth B., Billich A., Datema R., Donatsch P., Hammerschmid F., Harrison R., Hiestand P., Jaksche H., Mayer P., Peichl P., et al. Inhibition of human immunodeficiency virus type 1 replication by SDZ NIM 811, a nonimmunosuppressive cyclosporine analog. Antimicrob. Agents Chemother. 1994, 38:1763-1772.
71. Saeed, B., Abou-Zor, N., Amer, Z., Kanani, I., Hilal, M., 2008. Cyclosporin-A induced Posterior Reversible Encephalopathy Syndrome, vol. 19, pp. 439-442.
72. Santos J.B., Schauwecker P.E. Protection provided by Cyclosporin A against excitotoxic neuronal death is genotype dependent. Epilepsia 2003, 44:995-1002.
73. Schinkel A.H., Smit J.J., van Tellingen O., Beijnen J.H., Wagenaar E., van Deemter L., Mol C.A., van der Valk M.A., Robanus-Maandag E.C., te Riele H.P., et al. Disruption of the mouse mdr1a P-glycoprotein gene leads to a deficiency in the blood-brain barrier and to increased sensitivity to drugs. Cell 1994, 77:491-502.
74. Schinkel A.H., Wagenaar E., van Deemter L., Mol C.A., Borst P. Absence of the mdr1a P-Glycoprotein in mice affects tissue distribution and pharmacokinetics of dexamethasone, digoxin, and Cyclosporin A. J. Clin. Invest. 1995, 96:1698-1705.
75. Schinkel A.H., Wagenaar E., Mol C.A., van Deemter L. P-glycoprotein in the blood-brain barrier of mice influences the brain penetration and pharmacological activity of many drugs. J. Clin. Invest. 1996, 97:2517-2524.
76. Schinzel A.C., Takeuchi O., Huang Z., Fisher J.K., Zhou Z., Rubens J., Hetz C., Danial N.N., Moskowitz M.A., Korsmeyer S.J. Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia. Proc. Natl. Acad. Sci. USA 2005, 102:12005-12010.
77. Serkova N.J., Christians U., Benet L.Z. Biochemical mechanisms of cyclosporine neurotoxicity. Mol. Interv. 2004, 4:97-107.
78. Shou Y., Li L., Prabhakaran K., Borowitz J.L., Isom G.E. Calcineurin-mediated bad translocation regulates cyanide-induced neuronal apoptosis. Biochem. J. 2004, 379:805-813.
79. Sims N.R., Muyderman H. Mitochondria, oxidative metabolism and cell death in stroke. Biochim. Biophys. Acta 2010, 1802:80-91.
80. Snyder S.H., Sabatini D.M., Lai M.M., Steiner J.P., Hamilton G.S., Suzdak P.D. Neural actions of immunophilin ligands. Trends Pharmacol. Sci. 1998, 19:21-26.
81. Sheehan J., Eischeid A., Saunders R., Pouratian N. Potentiation of neurite outgrowth and reduction of apoptosis by immunosuppressive agents: implications for neuronal injury and transplantation. Neurosurg. Focus 2006, 20:E9.
82. Sokol P.P., Capodagli L.C., Dixon M., Holohan P.D., Ross C.R., Coulson R., Jones D.B. Cyclosporin A and vehicle toxicity in primary cultures of rabbit renal proximal tubule cells. Am. J. Physiol. 1990, 259:C897-C903.
83. Sullivan P.G., Thompson M., Scheff S.W. Continuous infusion of Cyclosporin A postinjury significantly ameliorates cortical damage following traumatic brain injury. Exp. Neurol. 2000, 161:631-637.
84. Sullivan P.G., Sebastian A.H., Hall E.D. Therapeutic window analysis of the neuroprotective effects of cyclosporine a after traumatic brain injury. J. Neurotrauma 2011, 28:311-318.
85. Thrift A.G., Dewey H.M., Macdonell R.A., McNeil J.J., Donnan G.A. Incidence of the major stroke subtypes: initial findings from the North East Melbourne stroke incidence study (NEMESIS). Stroke 2001, 32:1732-1738.
86. Tindall R.S., Rollins J.A., Phillips J.T., Greenlee R.G., Wells L., Belendiuk G. Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis. N. Engl. J. Med. 1987, 316:719-724.
87. Truwit C.L., Denaro C.P., Lake J.R., DeMarco T. MR imaging of reversible Cyclosporin A-induced neurotoxicity. Am. J. Neuroradiol. 1991, 12:651-659.
88. Uchino H., Minamikawa-Tachino R., Kristian T., Perkins G., Narazaki M., Siesjo B.K., Shibasaki F. Differential neuroprotection by Cyclosporin A and FK506 following ischemia corresponds with differing abilities to inhibit calcineurin and the mitochondrial permeability transition. Neurobiol. Dis. 2002, 10:219-233.
89. Wakita H., Tomimoto H., Akiguchi I., Kimura J. Protective effect of Cyclosporin A on white matter changes in the rat brain after chronic cerebral hypoperfusion. Stroke 1995, 26:1415-1422.
90. Waldmeier P.C., Zimmermann K., Qian T., Tintelnot-Blomley M., Lemasters J.J. Cyclophilin D as a drug target. Curr. Med. Chem. 2003, 10:1485-1506.
91. 2+-induced apoptosis through calcineurin dephosphorylation of BAD. Science 1999, 284:339-343.
92. Wang X., Carlsson Y., Basso E., Zhu C., Rousset C.I., Rasola A., Johansson B.R., Blomgren K., Mallard C., Bernardi P., Forte M.A., Hagberg H. Developmental shift of cyclophilin D contribution to hypoxic-ischemic brain injury. J. Neurosci. 2009, 29:2588-2596.
93. Wang X., Han W., Du X., Zhu C., Carlsson Y., Mallard C., Jacotot E., Hagberg H. Neuroprotective effect of bax-inhibiting peptide on neonatal brain injury. Stroke 2010, 41:2050-2055.
94. White D.J.G., Calne R.Y. The use of Cyclosporin A immunosuppression in organ grafting. Immunol. Rev. 1982, 65:115-131.
95. Windebank A.J., Blexrud M.D., de Groen P.C. Potential neurotoxicity of the solvent vehicle for cyclosporine. J. Pharmacol. Exp. Ther. 1994, 268:1051-1056.
96. Yoshimoto T., Siesjö B.K. Posttreatment with the immunosuppressant Cyclosporin A in transient focal ischemia. Brain Res. 1999, 839:283-291.
97. Yu G., Hess D.C., Borlongan C.V. Combined Cyclosporine-A and methylprednisolone treatment exerts partial and transient neuroprotection against ischemic stroke. Brain Res. 2004, 1018:32-37.