Tetramethylpyrazine, a natural alkaloid, attenuates pro-inflammatory mediators induced by amyloid β and interferon-γ in rat brain microglia

Neuroinflammation has been consistently reported as a pathological hallmark of Alzheimer's disease and other neurodegenerative diseases. Microglial cells are activated by diverse pathological stimuli and play key roles in development of neuroinflammation. Amyloid beta peptide (A beta), the major constituent of amyloid plaques in Alzheimer's brain, is known to activate cultured microglial cells to produce increased amounts of proinflammatory and neurotoxic factors. Tetramethylpyrazine (TMP) is the main bioactive alkaloid isolated from Ligusticum chuanxiong. IMP has multiple pharmacological activities, including anti-oxidant, anti-inflammatory, and anti-cancer effects. Neuroprotective potential of TMP has been demonstrated in animal models of neuropathologies. However, the efficacy of this compound for controlling A beta-related neuropathology has not been explored yet. We examined the efficacy of IMP in the repression of inflammatory response in cultured microglial cells stimulated with A beta(25-35) in the presence of interferon (IFN)-gamma. TMP significantly inhibited the A beta(25-35) and IFN-gamma-stimulated productions of nitric oxide, tumor necrosis factor (TNF)-alpha, interleukin (lL)-1 beta, monocyte chemoattractant protein-1, and intracellular reactive oxygen species from primary microglial cells. TMP also effectively reduced A beta(25-35) and IFN-gamma-elicited NF-kappa B activation. In organotypic hippocampal slice cultures (OHSCs), TMP significantly blocked A beta(25-35)-induced reactive oxygen species generation and phosphorylation of Akt. Furthermore, TMP also inhibited A beta(1-42)-induced TNF-alpha and 1L-1 beta production in primary microglial cells and neuronal death in OHSCs. These results suggest that TMP provide a possible therapeutic approach for alleviating the inflammatory progression of Alzheimer's disease. (C) 2014 Elsevier By. All rights reserved.