Cofilin Inhibition by Limk1 Reduces Rod Formation and Cell Apoptosis after Ischemic Stroke. (15th September 2020)

• Record Type: Journal Article
• Authors: Chen, Bin; Lin, Wanqing; Qi, Wan; Li, Shibin; Hong, Zhenfeng; Zhao, Hongjia
• Is Part Of: Neuroscience. Volume 444(2020)
• Page Start: 64
• Page End: 75
• Publication Date: 2020-09-15
• Subjects: ATP-D ATP depletion -- DAPI 4′, 6-Diamidino-2-phenylindole -- ECA external carotid artery -- MAP2 microtubule-associated protein-2 -- NeuN neuronal nuclei -- tMCAO transient middle cerebral artery occlusion -- TTC 2, 3, 5-Triphenyl tetrazolium chloride -- TUNEL TdT-mediated dUTP Nick-End Labeling; cofilin rod -- apoptosis -- tMCAO -- Limk1 -- ischemic stroke; Neurochemistry -- Periodicals; Neurophysiology -- Periodicals; Neurology -- Periodicals; Neurochimie -- Périodiques; Neurophysiologie -- Périodiques; Neurochemistry; Neurophysiology; Electronic journals; Periodicals; Electronic journals; 612.8
• DOI: 10.1016/j.neuroscience.2020.07.019
• Languages: English
• ISSNs: 0306-4522

Abstract

Highlights: ATP depletion induced cofilin rod formation and neuronal apoptosis. Infarct volume increased from 2 h to 24 h, then became stable from 24 h to 7 d after tMCAO. Rod formation and cell apoptosis was gradually induced in the ischemic penumbra and core areas of tMCAO rats. Inhibition of cofilin by Limk1 reduced rod formation and cofilin mediated-apoptosis at 24 h after tMCAO. Abstract: Cofilin, a cytoskeletal actin severing protein, is essential for the initiation phase of apoptosis. The formation of cofilin rods (containing 1:1 cofilin:actin) has been studied in cultured mammalian neurons under conditions of excessive glutamate, ATP depletion (ATP-D) or oxidative stress. These conditions simulate the pathologies occurring during ischemic stroke. In this study, we investigated the potential involvement of cofilin during ischemic-stroke induced apoptosis. Transient middle cerebral artery occlusion (tMCAO) was performed to establish an experimental model of ischemic stroke. We used 2, 3, 5-Triphenyltetrazolium Chloride (TTC) and immunostaining of the neuronal marker neuronal nuclei (NeuN) to evaluate the evolving phases of infarction in rats subjected tMCAO. Immunostaining and TdT-mediated dUTP Nick-End Labeling (TUNEL) apoptosis staining were collaboratively used to examine cofilin rod formation and cell apoptosis in response to ischemia at different time points (2 h, 8 h, 24 h and 7 d). Our results showed that infarct volume increased initially, between the first 2 h to 24 h and became stabilized 24 h to 7 d after tMCAO. The formation of cofilin rods significantly increased in the cortical core (from 2 h) and penumbra (from 8 h), peaking at 24 h and gradually diminishing 7 d after tMCAO. Progressive accumulation of cofilin rods subsequently induced microtubule-associated protein-2 (MAP2) degradation and ischemic cell apoptosis in the infarct cortex after stroke. To further corroborate the role of activated cofilin in ischemic stroke, inhibition of cofilin by LIM kinase (Limk1) over-expression was performed. Lmik1 reduced cofilin rod formation and MAP2 degradation, and consequently, attenuated cofilin mediated-apoptosis 24 h after tMCAO. From this evidence we conclude that cofilin plays a role in the onset of ischemic-induced apoptosis and may be efficacious in future studies as a drug target for ischemic stroke.