Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia.

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Citation

Haraguchi Y, Mizoguchi Y, Ohgidani M, Imamura Y, Murakawa-Hirachi T, Nabeta H, Tateishi H, Kato TA, Monji A

Donepezil suppresses intracellular Ca(2+) mobilization through the PI3K pathway in rodent microglia.

J Neuroinflammation. 2017 Dec 22;14(1):258. doi: 10.1186/s12974-017-1033-0.

PubMed ID
29273047 [ View in PubMed
]
Abstract

BACKGROUND: Microglia are resident innate immune cells which release many factors including proinflammatory cytokines or nitric oxide (NO) when they are activated in response to immunological stimuli. Pathophysiology of Alzheimer's disease (AD) is related to the inflammatory responses mediated by microglia. Intracellular Ca(2+) signaling is important for microglial functions such as release of NO and cytokines. In addition, alteration of intracellular Ca(2+) signaling underlies the pathophysiology of AD, while it remains unclear how donepezil, an acetylcholinesterase inhibitor, affects intracellular Ca(2+) mobilization in microglial cells. METHODS: We examined whether pretreatment with donepezil affects the intracellular Ca(2+) mobilization using fura-2 imaging and tested the effects of donepezil on phagocytic activity by phagocytosis assay in rodent microglial cells. RESULTS: In this study, we observed that pretreatment with donepezil suppressed the TNFalpha-induced sustained intracellular Ca(2+) elevation in both rat HAPI and mouse primary microglial cells. On the other hand, pretreatment with donepezil did not suppress the mRNA expression of both TNFR1 and TNFR2 in rodent microglia we used. Pretreatment with acetylcholine but not donepezil suppressed the TNFalpha-induced intracellular Ca(2+) elevation through the nicotinic alpha7 receptors. In addition, sigma 1 receptors were not involved in the donepezil-induced suppression of the TNFalpha-mediated intracellular Ca(2+) elevation. Pretreatment with donepezil suppressed the TNFalpha-induced intracellular Ca(2+) elevation through the PI3K pathway in rodent microglial cells. Using DAF-2 imaging, we also found that pretreatment with donepezil suppressed the production of NO induced by TNFalpha treatment and the PI3K pathway could be important for the donepezil-induced suppression of NO production in rodent microglial cells. Finally, phagocytosis assay showed that pretreatment with donepezil promoted phagocytic activity of rodent microglial cells through the PI3K but not MAPK/ERK pathway. CONCLUSIONS: These suggest that donepezil could directly modulate the microglial function through the PI3K pathway in the rodent brain, which might be important to understand the effect of donepezil in the brain.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
DonepezilNitric oxide synthase, brainProteinHumans
Unknown
Inhibitor
Inducer
Details