Nitric oxide-producing microglia mediate thrombin-induced degeneration of dopaminergic neurons in rat midbrain slice culture

Journal of Neurochemistry
Hiroshi KatsukiAkinori Akaike

Abstract

Activated microglia are considered to play important roles in degenerative processes of midbrain dopaminergic neurons. Here we examined mechanisms of neurotoxicity of thrombin, a protease known to trigger microglial activation, in organotypic midbrain slice cultures. Thrombin induced a progressive decline in the number of dopaminergic neurons, an increase in nitric oxide (NO) production, and whole tissue injury indicated by lactate dehydrogenase release and propidium iodide uptake. Microglia expressed inducible NO synthase (iNOS) in response to thrombin, and inhibition of iNOS rescued dopaminergic neurons without affecting whole tissue injury. Inhibitors of mitogen-activated protein kinases (MAPKs) such as extracellular signal-regulated kinase (ERK), p38 MAPK and c-Jun N-terminal kinase (JNK) attenuated thrombin-induced iNOS induction and dopaminergic cell death. Whole tissue injury was also attenuated by inhibition of ERK and p38 MAPK. Moreover, depletion of resident microglia from midbrain slices abrogated thrombin-induced NO production and dopaminergic cell death, but did not inhibit tissue injury. Finally, antioxidative drugs prevented thrombin-induced dopaminergic cell death without affecting whole tissue injury. Hence, NO...Continue Reading

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Citations

Jan 14, 2016·International Journal of Molecular Sciences·Harald KrenzlinBeat Alessandri
Dec 7, 2006·Biochemical Pharmacology·Mitsugi OkawaraAkinori Akaike
May 24, 2017·Cellular and Molecular Neurobiology·John Alimamy KabbaTao Pang
Feb 11, 2020·The Journal of Pharmacy and Pharmacology·Masatoshi OhnishiAtsuko Inoue
May 1, 2021·Biomolecules·Nathan A ShlobinChaim G Pick

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