Cyclophilin inhibitor NIM811 ameliorates experimental allergic encephalomyelitis

- The non-immunosuppressive, non-selective cyclophilin inhibitor NIM811 reduces clinical disease severity in EAE.
- A cyclophilin D-dependent mechanism does not entirely explain effect of NIM811 in EAE.
- A cyclophilin A-dependent mechanism is suggested by reduction in CNS infiltrating leucocytes in NIM811-treated mice.

Cyclophilins have diverse functions that may affect the course of central nervous system (CNS) inflammatory disorders. Anti-inflammatory and neuroprotective mechanisms may be targeted by inhibition of cyclophilin A-dependent and cyclophilin D-dependent functions, respectively. We tested the effect of cyclophilin inhibition on CNS inflammation by administering N-methyl-4-isoleucine-cyclosporin (NIM811) to mice undergoing experimental allergic encephalomyelitis (EAE). Treatment with NIM811 resulted in significant reduction of EAE clinical severity. Analysis of mitochondrial calcium retention capacity and the course of EAE in cyclophilin D knockout mice indicated that the effect of NIM811 on EAE was not entirely cyclophilin D-dependent. NIM811-treated EAE animals showed reduction in interleukin-2 expression and reduction in CNS inflammatory infiltrates. These results indicate that anti-inflammatory rather than neuroprotective mechanisms associated with cyclophilins are likely involved in the mechanism of NIM811 in EAE.