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Titolo: Activation of M3 muscarinic acetylcholine receptors protects against interferon-β-induced neuronal cell death. 44th Meeting of the Society for Neuroscience. 15-19 November 2014 Washington, U.S.A.
Data di pubblicazione: 2014
Abstract: The clinical use of type I interferons (IFNs), such as IFN-α and IFN-β, is known to be frequently associated with the occurrence of central nervous system (CNS) side effects, including anxiety, confusion, cognitive deficits, mania, psychosis, depression and suicidal behaviour. In addition, chronically elevated IFN-α production in the CNS is considered a pathogenic factor in Aicardi-Goutieres syndrome, a genetically determined encephalopathy. At the cellular level, long-term exposure to type I IFNs induces neuronal cell death through activation of apoptosis. In the present study we used the SH-SY5Y cell line as a human neuronal cell model to identify neurochemical mechanisms capable of preventing type I IFN neurotoxicity. We found that cell treatment with either carbachol (CCh), a cholinergic receptor agonist, or oxotremorine M, a selective muscarinic acetylcholine receptor (mAChR) agonist, markedly suppressed IFN-β-induced neuronal cell death. The neuroprotective effect of CCh was antagonized by 4-DAMP, a M3 mAChR preferring antagonist, but not methoctramine, a M2 mAChR preferring antagonist, or MT-7, a selective M1 mAChR antagonist. Concurrent cell treatment with CCh inhibited IFN-β-induced cytochrome c release from mitochondria, caspase activation and cleavage of poly-(ADP ribose) polymerase. CCh induced a long-lasting activation of either p38 or ERK 1 and 2 (ERK1/2) MAP kinases. Pharmacological inhibition of ERK1/2 but not p38 MAP kinase prevented the antiapoptotic effect of CCh. These data indicate that in SH-SY5Y neuronal cells activation of M3 mAChR counteracts IFN-β-induced neuronal apoptosis through activation of ERK1/2 pathway.
Tipologia:4.3 Poster

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