Pharmacological Inhibition of Cyclophilin Ameliorates Experimental Allergic Encephalomyelitis

• Main Author: Huang, Zi L
• Format: Others
• Published: VCU Scholars Compass 2016
• Subjects: Multiple Sclerosis; Experimental Allergic Encephalomyelitis; Cyclophilin D; Mitochondrial Permeability Transition Pore; Cyclophilin A; Neurology
• Online Access: http://scholarscompass.vcu.edu/etd/4294; http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=5295&context=etd

A subset of cyclophilins have been implicated in mechanisms of neuroinflammation and neurodegeneration that contributes to the pathogenesis of Multiple Sclerosis. Mitochondrial dysfunction leading to mitochondrial permeability transition plays a pivotal role in axonal damage and disease progression in Multiple Sclerosis. Cyclophilin D (CypD) is a crucial regulatory component of the mitochondrial permeability transition pore and it was demonstrated that the cyclophilin D knockout animals showed reduced experimental allergic encephalomyelitis (EAE) clinical disease severity and axonal injury. We investigated the effect of N-methyl-4-isoleucine-cyclosporin (NIM811), a non-immunosuppressive and non-selective cyclophilin inhibitor, on the course and severity of EAE. EAE mice treated with NIM811 showed a significant reduction in clinical disease severity compared to vehicle treated mice. FACS analysis performed with the dissociated thoracolumbar spine showed that NIM811 treatment was associated with a reduction in CNS macrophages but does not alter T-helper lineage frequencies. In addition, we demonstrated NIM811’s effect on crude mitochondrial fraction obtained from brain and liver homogenates of both wild type and CypD knockout mice in order to determine drug specificity. Benefits observed from the pharmacological inhibition of cyclophilin may lead to a novel MS therapy but NIM811’s exact mechanism of action has yet to be elucidated.