| 17093087 |
Franciosi S, Ryu JK, Choi HB, Radov L, Kim SU, McLarnon JG: Broad-spectrum effects of 4-aminopyridine to modulate amyloid beta1-42-induced cell signaling and functional responses in human microglia. J Neurosci. 2006 Nov 8;26(45):11652-64.
We investigated the modulating actions of the nonselective K (+) channel blocker 4-aminopyridine (4-AP) on amyloid beta (Abeta (1-42))-induced human microglial signaling pathways and functional processes. Whole-cell patch-clamp studies showed acute application of Abeta (1-42) (5 mum) to human microglia led to rapid expression of a 4-AP-sensitive, non-inactivating outwardly rectifying K (+) current (I (K)). Intracellular application of the nonhydrolyzable analog of GTP, GTPgammaS, induced an outward K (+) current with similar properties to the Abeta (1-42)-induced I (K) including sensitivity to 4-AP (IC (50) = 5 mm). Reverse transcriptase-PCR showed a rapid expression of a delayed rectifier Kv3.1 channel in Abeta (1-42)-treated microglia. Abeta (1-42) peptide also caused a slow, progressive increase in levels of [Ca (2+)](i) (intracellular calcium) that was partially blocked by 4-AP. Chronic exposure of human microglia to Abeta (1-42) led to enhanced p38 mitogen-activated protein kinase and nuclear factor kappaB expression with factors inhibited by 4-AP. Abeta (1-42) also induced the expression and production of the pro-inflammatory cytokines interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha, the chemokine IL-8, and the enzyme cyclooxygenase-2; 4-AP was effective in reducing all of these pro-inflammatory mediators. Additionally, toxicity of supernatant from Abeta (1-42)-treated microglia on cultured rat hippocampal neurons was reduced if 4-AP was included with peptide. In vivo, injection of Abeta (1-42) into rat hippocampus induced neuronal damage and increased microglial activation. Daily administration of 1 mg/kg 4-AP was found to suppress microglial activation and exhibited neuroprotection. The overall results suggest that 4-AP modulation of an Abeta (1-42)-induced I (K) (candidate channel Kv3.1) and intracellular signaling pathways in human microglia could serve as a therapeutic strategy for neuroprotection in Alzheimer's disease pathology. |
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