FK506 and a nonimmunosuppressant derivative reduce axonal and myelin damage in experimental autoimmune encephalomyelitis: Neuroimmunophilin ligand‐mediated neuroprotection in a model of multiple sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) in which demyelination and axonal loss result in permanent neurologic disability. We examined the neuroprotective property of the immunosuppressant FK506 (tacrolimus), FK1706 (a nonimmunosuppressant FK506 derivative) and cyclosporin A (CsA) in a chronic relapsing experimental autoimmune encephalomyelitis (EAE) model of MS. Female SJL/J mice were immunized by subcutaneous (s.c.) injection with proteolipid protein 139-151 peptide in complete Freund's adjuvant. At the onset of paralysis, 12-14 days after immunization, mice received daily s.c. injections of FK506 (0.2, 1, and 5 mg/kg), FK1706 (5 mg/kg), CsA (2, 10, and 50 mg/kg), saline or vehicle (30% dimethylsulfoxide) for 30 days. FK506 (at a dose of 5 mg/kg) reduced the severity of the initial disease and suppressed relapses. FK1706 did not significantly alter the clinical course and CsA (at a dose of 50 mg/kg) lessened the severity of the initial episode of EAE but did not alter relapses. In the thoracic spinal cord, FK506 (5 mg/kg), FK1706 (5 mg/kg), and CsA (50 mg/kg) significantly (P < 0.001) reduced the extent of damage in the dorsal, lateral, and ventral white matter by a mean of up to 95, 68, and 30%, respectively. A nonimmunosuppressant dose of FK506 (0.2 mg/kg) also significantly (P < 0.001) reduced the extent of damage in the spinal cord by a mean of up to 45%. Other dosages of these compounds were ineffective. FK506 markedly protects against demyelination and axonal loss in this MS model through immunosuppression and neuroprotection.

Cyclophilin D inactivation protects axons in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis

“…Taken together, our findings suggest that inhibitors of CyPD and the PTP may represent important new therapeutic targets for the prevention of axonal degeneration in MS. CyPD, as one molecular target in the PTP, can be inhibited by CsA. Indeed, CsA has been shown to reduce tissue injury in EAE, although differentiating its neuroprotective effects from its immunosuppressive effects was not possible (42,43). However, the toxicity associated with long-term CsA use has prevented its use as a treatment for MS (44).…”

“…Mice were perfused with 4% paraformaldehyde and 1-to 2-mm lengths of spinal cord were processed for sectioning as previously described (43,47). For phosphorylated NF staining, spinal cord sections were blocked and stained with anti-phosphorylated NF, SMI312 (Sternberger Monoclonals, Lutherville, MD).…”

A destructive feedback loop mediated by CXCL10 in central nervous system inflammatory disease

“…It is possible that FK506 may similarly act upon APCs in the brain. Inhibition of the EAE animal model of MS has been observed with FK506 treatment 35, 36. It would be interesting to determine whether treatment of EAE or MS patients with FK506 decreases CXCL10 levels in a fashion similar to that shown in our PND patients.…”

Astrocytes in the tempest of multiple sclerosis

“…Rapamycin (sirolimus) has recently been shown to modulate EAE [117] and to inhibit reactive astrogliosis in a model of spinal cord injury in rats [118]. Tacrolimus (FK506, fujimycin) is efficient in relapsing-remitting EAE in mice [119], and is currently under investigation in a clinical trial in MS patients in Canada (ClinicalTrials.gov Identifier: NCT00298662). This drug was reported to inhibit IL-1b and TNF synthesis in rat astrocytes [120].…”