Effects of PAK1/LIMK1/Cofilin-mediated Actin Homeostasis on Axonal Injury after Experimental Intracerebral Hemorrhage.

Abstract

Intracerebral hemorrhage (ICH) is a hemorrhagic stroke with a high mortality and disability rate. Neurological impairment after ICH is closely associated with neuronal axon damage. Serine/threonine-protein kinase p21 activated kinase 1 (PAK1) participates in cytoskeletal remodeling and regulates the F-actin and G-actin ratio in neuronal axons, but the function of PAK1 after ICH remains unclear. We established an in vivo rat ICH model by autologous whole blood injection into the right basal ganglia and an in vitro neuron oxyhemoglobin intervention. The results showed that the phosphorylated PAK1 level increased while the PAK1 expression level unchanged after ICH, After PAK1 knockdown, PAK1 and phosphorylated PAK1 levels were both reduced. Meanwhile, downstream proteins LIMK1 and cofilin expression levels were unchanged while phosphorylated LIMK1 and phosphorylated cofilin were decreased. F-actin/G-actin ratio decreased after PAK1 knockdown. Moreover, PAK1 knockdown improved short- and long-term neurobehavioral impairments in rats. In vitro, phosphorylated PAK1 expression increased after oxyhemoglobin intervention. After PAK1 knockdown, the axon length of neurons increased while F-actin/G-actin ratio decreased. Spersman correlation analysis showed a negative correlation between phospho-PAK1 fluorescence intensity and neuronal axon length. Knockdown of PAK1 increased the live/dead cell ratio and promoted neurons survival. Our study showed that PAK1 is involved in ICH early secondary brain injury by affecting F-actin/G-actin ratio through the PAK1/LIMK1/cofilin pathway. PAK1 may be an essential target for early secondary brain injury intervention after ICH.

• Authors: Muyun Luo, Zongqi Wang, Jie Wu, Xueshun Xie, Wanchun You, Zhengquan Yu, Haitao Shen, Xiang Li, Haiying Li, Yanfei Liu, Zhong Wang, Gang Chen
• Journal: Neuroscience (Neuroscience) Vol. 490 Pg. 155-170 (05 10 2022) ISSN: 1873-7544 [Electronic] United States
• PMID: 35306145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2022 IBRO. Published by Elsevier Ltd. All rights reserved.

Chemical References

• Actin Depolymerizing Factors
• Actins
• Oxyhemoglobins
• Lim Kinases
• Limk1 protein, rat
• p21-Activated Kinases

Topics

• Actin Depolymerizing Factors (metabolism)
• Actins (metabolism)
• Animals
• Axons (metabolism)
• Brain Injuries (metabolism)
• Cerebral Hemorrhage (metabolism)
• Homeostasis
• Lim Kinases (metabolism)
• Oxyhemoglobins (metabolism)
• Phosphorylation
• Rats
• p21-Activated Kinases (metabolism)