Leflunomide abrogates neuroinflammatory changes in a rat model of Alzheimer's disease: the role of TNF-α/NF-κB/IL-1β axis inhibition.

Alzheimer's disease (AD) is one of the most common neurodegenerative diseases and is associated with disrupted cognition and behavior. Neuroinflammatory pathogenesis is the main component that contributes to AD initiation and progression through microglial activation and neuronal damage. Thus, targeting inflammatory pathways may help manage AD. In this study, for the first time, the potential prophylactic and therapeutic effects of leflunomide were investigated either alone or in combination with rivastigmine in aluminum chloride (AlCl 3 )-induced AD-like rats using behavioral, biochemical, and histological approaches. Thirty-six adult male albino rats were divided into two protocols: the treatment protocol, subdivided into five groups (n = 6)-(1) control group, (2) AlCl 3 (50, 70, 100 mg/kg/I.P) group, (3) reference group (rivastigmine 2 mg/kg/P.O.), (4) experimental group (leflunomide 10 mg/kg/P.O.), and (5) combination group (rivastigmine + leflunomide); and the prophylactic protocol (leflunomide 10 mg/kg/P.O.), which started 2 weeks before AlCl 3 induction. The results showed that AlCl 3 disrupted learning and memory parameters in rats and increased amyloid-β plaque deposition and neurofibrillary tangle aggregation. Moreover, AlCl 3 administration markedly elevated acetylcholinesterase activity, nuclear factor-kappa β, tumor necrosis factor-α, and interleukin-1 beta, and marked degenerative changes in the pyramidal neurons. However, administration of leflunomide alone or with rivastigmine in AlCl 3 -induced AD rats restored most of the behavioral, biochemical, and histological parameters triggered by AlCl 3 in rats. Our findings suggest that leflunomide can potentially restore most of the neuronal damage in the hippocampal tissues of AlCl 3 -induced AD rats. However, these preclinical findings still need to be confirmed in clinical trials.