Abstract
We studied the effects of fasudil, a selective Rho-kinase inhibitor, on experimental
autoimmune neuritis (EAN). Continuous parenteral administration of fasudil prevented
the development of EAN induced by P0 peptide 180–199 in Lewis rats while it also reduced
EAN severity when administered after disease onset. Immunohistochemical examination
disclosed a marked decrease in the amount of inflammatory cell infiltration and attenuation
of demyelination and axonal degeneration. Specific proliferation of lymphocytes from
fasudil-treated rats in response to P0 peptide was significantly reduced as compared
with those from phosphate-buffered saline (PBS)-treated rats. Fasudil treatment was
associated with a significant reduction in secretion of IFN-γ; by contrast, secretion
of IL-4 was almost the same in the fasudil- and PBS-treated groups. As a result, the
IFN-γ/IL-4 ratio in the supernatant was significantly deceased in fasudil-treated
rats compared with PBS-treated ones. Therefore, our results indicate a beneficial
effect of selective blockade of Rho-kinase in animals with autoimmune inflammation
of the peripheral nerves, and may provide a rationale for the selective blockade of
Rho-kinase as a new therapy for Guillain-Barré syndrome.
Keywords
To read this article in full you will need to make a payment
Purchase one-time access:
Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online accessOne-time access price info
- For academic or personal research use, select 'Academic and Personal'
- For corporate R&D use, select 'Corporate R&D Professionals'
Subscribe:
Subscribe to Journal of the Neurological SciencesAlready a print subscriber? Claim online access
Already an online subscriber? Sign in
Register: Create an account
Institutional Access: Sign in to ScienceDirect
References
- Identification of the neuritogen for experimental allergic neuritis.Nature. 1979; 277: 140-141
- P0 myelin protein produces experimental allergic neuritis in Lewis rats.J Neurol Sci. 1987; 79: 275-285
- New minimum length requirement for a T cell epitope for experimental allergic neuritis.J Neuroimmunol. 1990; 27: 187-190
- Toyka KV. Immunopathogenesis and treatment of the Guillain – Barre syndrome: Part I.Muscle Nerve. 1995; 18: 137-153
- Th1-like cell responses to peripheral nerve myelin components over the course of experimental allergic neuritis in Lewis rats.Acta Neurol Scand. 1994; 90: 19-25
- Autoimmune response in peripheral nerve.Springer Semin Immunopathol. 1996; 18: 97-123
- Cytokine production and the pathogenesis of experimental autoimmune neuritis and Guillain – Barre syndrome.J Neuroimmunol. 1998; 84: 40-52
- Pathogenesis of Guillain–Barre syndrome.J Neuroimmunol. 1999; 100: 74-97
- T cell responses to myelin in Guillain-Barré syndrome.J Neurol Sci. 1992; 111: 200-203
- Treatment of relapsing paralysis in experimental encephalomyelitis by targeting Th1 cells through atorvastatin.J Exp Med. 2003; 197: 725-733
- Lovastatin inhibits brain endothelial cell Rho-mediated lymphocyte migration and attenuates experimental autoimmune encephalomyelitis.FASEB J. 2003; 17: 905-907
- Potential targets of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor for multiple sclerosis therapy.J Immunol. 2004; 172: 1273-1286
- Amelioration of experimental allergic encephalomyelitis in Lewis rats by lovastatin.Neurosci Lett. 1999; 269: 71-74
- The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease.Nature. 2002; 420: 78-84
- Are statins a treatment option for multiple sclerosis?.Lancet Neurol. 2004; 3: 369-371
- Regulation and functions of Rho-associated kinase.Exp Cell Res. 2000; 261: 44-51
- Rho-Rho-kinase pathway in smooth muscle contraction and cytoskeletal reorganization of non-muscle cells.Trends Pharmacol Sci. 2001; 22: 32-39
- Rho-kinase is an important therapeutic target in cardiovascular medicine.Arterioscler Thromb Vasc Biol. 2005; 25: 1767-1775
- Inhibition of Rho GTPases with protein prenyltransferase inhibitors prevents leukocyte recruitment to the central nervous system and attenuates clinical signs of disease in an animal model of multiple sclerosis.J Immunol. 2002; 168: 4087-4094
- Flavonoids influence monocytic GTPase activity and are protective in experimental allergic encephalitis.J Exp Med. 2004; 200: 1667-1672
- The selective Rho-kinase inhibitor Fasudil is protective and therapeutic in experimental autoimmune encephalomyelitis.J Neuroimmunol. 2006; 180: 126-134
- Expression of RhoA by inflammatory macrophages and T cells in rat experimental autoimmune neuritis.J Cell Mol Med. 2007; 11: 111-119
- Differences between T-cell reactivities to major myelin protein-derived peptides in opticospinal and conventional forms of multiple sclerosis and healthy controls.Tissue Antigens. 2001; 57: 447-456
- Intrathecal activation of the IL-17/IL-8 axis in opticospinal multiple sclerosis.Brain. 2005; 128: 988-1002
- Long-term inhibition of Rho-kinase suppresses angiotensin II-induced cardiovascular hypertrophy in rats in vivo: effect on endothelial NAD(P)H oxidase system.Circ Res. 2003; 93: 767-775
- Neurofilament phosphoforms: surrogate markers for axonal injury, degeneration and loss.J Neurol Sci. 2005; 233: 183-198
- Immunosuppressive effect of FK506 on experimental allergic neuritis in Lewis rats: change of T cell subsets.Intern Med. 1992; 31: 6-10
- Experimental allergic neuritis in the SJL/J mouse: induction of severe and reproducible disease with bovine peripheral nerve myelin and pertussis toxin with or without interleukin-12.J Neuroimmunol. 2000; 107: 1-7
- Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site.Nat Med. 2001; 7: 687-692
- Comparison of effects of Y-27632 and Isoproterenol on release of cytokines from human peripheral T cells.Int Immunopharmacol. 2003; 3: 1619-1625
- The distal pole complex: a novel membrane domain distal to the immunological synapse.Immunol Rev. 2002; 189: 111-122
- ERM-dependent movement of CD43 defines a novel protein complex distal to the immunological synapse.Immunity. 2001; 15: 739-750
- Synergistic effect of IFN-γ and TNF-α on expression of immune molecules and antigen presentation by Schwann cell.Cell Immunol. 1995; 165: 65-70
- Effects of fasudil on early atherosclerotic plaque formation and established lesion progression in apolipoprotein E-knockout mice.Atherosclerosis. 2009; 207: 68-73
- Fasudil attenuates myocardial fibrosis in assocation with inhibition of monocyte/macrophage infiltration in the heart of DOCA/salt hypertensive rats.J Cardiovasc Pharmacol. 2007; 50: 187-194
- Rho kinase, a promising drug target for neurological disorders.Nat Rev Drug Discov. 2005; 4: 387-398
- Regulation of SNAREs by tomosyn and ROCK: implication in extension and retraction of neurites.J Cell Biol. 2004; 166: 17-25
- Intra-arterial infusion of fasudil hydrochloride for treating vasospasm following subarachnoid haemorrhage.Acta Neurochir Wien. 1999; 141: 13-19
Article info
Publication history
Published online: April 19, 2011
Accepted:
March 18,
2011
Received in revised form:
February 14,
2011
Received:
June 11,
2010
Identification
Copyright
© 2011 Elsevier B.V. Published by Elsevier Inc. All rights reserved.
