Microglia signaling as a target of donepezil.

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Hwang J, Hwang H, Lee HW, Suk K

Microglia signaling as a target of donepezil.

Neuropharmacology. 2010 Jun;58(7):1122-9. doi: 10.1016/j.neuropharm.2010.02.003. Epub 2010 Feb 11.

PubMed ID

20153342 [ View in PubMed

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Abstract

Donepezil is a reversible and noncompetitive cholinesterase inhibitor. The drug is considered as a first-line treatment in patients with mild to moderate Alzheimer's disease. Recently, anti-inflammatory and neuroprotective effects of the drug have been reported. "Cholinergic anti-inflammation pathway" has major implications in these effects. Here, we present evidence that donepezil at 5-20 microM directly acts on microglial cells to inhibit their inflammatory activation. Our conclusion is based on the measurement of nitric oxide and proinflammatory mediators using purified microglia cultures and microglia cell lines: donepezil attenuated microglial production of nitric oxide and tumor necrosis factor (TNF)-alpha, and suppressed the gene expression of inducible nitric oxide synthase, interleukin-1 beta, and TNF-alpha. Subsequent studies showed that donepezil inhibited a canonical inflammatory NF-kappaB signaling. Microglia/neuroblastoma coculture and animal experiments supported the anti-inflammatory effects of donepezil. Based on the studies using nicotinic acetylcholine receptor antagonists, the donepezil inhibition of microglial activation was independent of acetylcholine and its receptor. Thus, inflammatory activation signaling of microglia may be one of the direct targets of donepezil in the central nervous system. It should be noted, however, that there is a large gap between the therapeutic dose of the drug used clinically and the concentration of the drug that exerts the direct action on microglial cells.

DrugBank Data that Cites this Article

Drugs

Donepezil

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Donepezil	Interleukin-1 beta	Protein	Humans	Unknown	Inhibitor Inducer	Details
Donepezil	Nitric oxide synthase, brain	Protein	Humans	Unknown	Inhibitor Inducer	Details
Donepezil	Tumor necrosis factor-inducible gene 6 protein	Protein	Humans	Unknown	Inhibitor	Details