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- Title
Bioenergetic and excitotoxic determinants of cofilactin rod formation.
- Authors
Nguyen Mai; Long Wu; Uruk, Gökhan; Mocanu, Ebony; Swanson, Raymond A.
- Abstract
Cofilactin rods (CARs), which are 1:1 aggregates of cofilin-1 and actin, lead to neurite loss in ischemic stroke and other disorders. The biochemical pathways driving CAR formation are well-established, but how these pathways are engaged under ischemic conditions is less clear. Brain ischemia produces both ATP depletion and glutamate excitotoxicity, both of which have been shown to drive CAR formation in other settings. Here, we show that CARs are formed in cultured neurons exposed to ischemialike conditions: oxygen–glucose deprivation (OGD), glutamate, or oxidative stress. Of these conditions, only OGD produced significant ATP depletion, showing that ATP depletion is not required for CAR formation. Moreover, the OGD-induced CAR formation was blocked by the glutamate receptor antagonists MK-801 and kynurenic acid; the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase inhibitors GSK2795039 and apocynin; as well as an ROS scavenger. The findings identify a biochemical pathway leading from OGD to CAR formation in which the glutamate release induced by energy failure leads to activation of neuronal glutamate receptors, which in turn activates NADPH oxidase to generate oxidative stress and CARs.
- Subjects
GLUTAMATE receptors; NICOTINAMIDE adenine dinucleotide phosphate; EXCITATORY amino acid antagonists; NADPH oxidase; CEREBRAL ischemia; ISCHEMIC stroke; OXIDATIVE stress
- Publication
Journal of Neurochemistry, 2024, Vol 168, Issue 5, p899
- ISSN
0022-3042
- Publication type
Article
- DOI
10.1111/jnc.16065