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Tumor necrosis factor-α (TNF-α) and nitric oxide (NO), both of which are produced by activated microglial cells, are involved in the neuropathogenesis of many diseases affecting the central nervous system (CNS). There is a need to develop drugs that inhibit neurotoxic processes in neurodegenerative diseases. The aim of this study was to evaluate the effect of two neuroleptics, flupentixol and trifluperidol, on the release of pro-apoptotic TNF-α and NO by LPS-activated rat microglial cells. Flupentixol and trifluperidol reduced the TNF-α and NO release by cultured microglia exposed to LPS for 6 and 24 h. The results suggest that flupentixol and trifluperidol, which are well-known antipsychotic drugs, may be used in the treatment of CNS diseases associated with excessive TNF-α and NO release.