Leflunomide Exerts Neuroprotective Effects in an MPTP-Treated Mouse Model of Parkinsonism

Abstract

Neuroinflammation and the immune response are recognized as significant mechanisms contributing to the progression and pathophysiology of Parkinson's disease (PD). Consequently, extensive research is being conducted on drugs targeting inflammation and immune response. Leflunomide, known for its anti-inflammatory and immunomodulatory properties, is currently used as a disease-modifying agent for the treatment of rheumatoid arthritis. The objective of this study was to investigate the effect of leflunomide on PD. The PD model was established by administering 18 mg/kg of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intraperitoneally for 5 consecutive days. Leflunomide was administered intraperitoneally at doses of 1, 5, and 10 mg/kg for 14 days. Motor and behavioral deficits were assessed using the rotarod test, locomotor activity assessment, hanging wire test, and pole test. MPTP administration impaired motor function and locomotor activity, and caused muscle weakness and bradykinesia. Leflunomide at a dose of 10 mg/kg mitigated the severity of motor deficits and muscle weakness. Furthermore, leflunomide at a dose of 10 mg/kg suppressed the MPTP-induced elevation of interleukin-2, interleukin-6, and tumor necrosis factor-alpha levels in the brain tissue. Similarly, leflunomide attenuated the increased expression of nuclear factor kappa B and inducible nitric oxide synthase caused by MPTP treatment. Moreover, leflunomide at a dose of 10 mg/kg preserved neuronal integrity and prevented the loss of tyrosine hydroxylase expression induced by MPTP administration. Based on our findings, leflunomide exhibited a beneficial effect on the MPTP-induced PD