Affiliation:
1. Department of Neurology University of California San Francisco California USA
2. Neurology Service, San Francisco Veterans Affairs Medical Center San Francisco California USA
Abstract
AbstractCofilactin 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 ischemia‐like 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.
Funder
U.S. Department of Veterans Affairs
National Institute of Neurological Disorders and Stroke
Subject
Cellular and Molecular Neuroscience,Biochemistry
Reference55 articles.
1. Diffuse axonal injury in head injury: Definition, diagnosis and grading;Adams J. H.;Histopathology,1989
2. Cofilin as a promising therapeutic target for ischemic and hemorrhagic stroke;Alhadidi Q.;Translational Stroke Research,2016
3. The role of cofilin in age‐related neuroinflammation;Alsegiani A. S.;Neural Regeneration Research,2020
4. ADF/cofilin mediates Actin cytoskeletal alterations in LLC‐PK cells during ATP depletion;Ashworth S. L.;American Journal of Physiology. Renal Physiology,2003
5. Cofilin inhibitor protects against traumatic brain injury‐induced oxidative stress and neuroinflammation;Bahader G. A.;Biology (Basel),2023