Acyl‐CoA synthetase long chain family member 4 plays detrimental role in early brain injury after subarachnoid hemorrhage in rats by inducing ferroptosis

• Published in: CNS neuroscience & therapeutics Vol. 27; no. 4; pp. 449 - 463
• Main Authors: Qu, Xiao‐feng, Liang, Tian‐yu, Wu, De‐gang, Lai, Nian‐sheng, Deng, Ru‐ming, Ma, Chao, Li, Xiang, Li, Hai‐ying, Liu, Yi‐zhi, Shen, Hai‐tao, Chen, Gang
• Format: Journal Article
• Language: English
• Published: England John Wiley & Sons, Inc 01-04-2021; John Wiley and Sons Inc
• Subjects: acyl‐CoA synthetase long chain family member 4; Aneurysms; Animals; Apoptosis; Blood-brain barrier; Brain Injuries - metabolism; Brain Injuries - pathology; Brain injury; Coenzyme A Ligases - biosynthesis; Cognitive ability; early brain injury; Edema; Enzymes; Experiments; Fatty acids; Ferroptosis; Ferroptosis - physiology; Labeling; Male; Maze Learning - physiology; Metabolism; Original; Oxidative stress; Permeability; Rats; Rats, Sprague-Dawley; Rodents; Subarachnoid hemorrhage; Subarachnoid Hemorrhage - metabolism; Subarachnoid Hemorrhage - pathology; Traumatic brain injury; acyl-CoA synthetase long chain family member 4; ferroptosis; subarachnoid hemorrhage; early brain injury
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.13548

Aims
Acyl‐CoA synthetase long chain family member 4 (ACSL4) is closely related to tumor genesis and development in certain tissues. However, the function of ACSL4 in early brain injury (EBI) caused by subarachnoid hemorrhage (SAH) is unclear. In this study, we investigated the expression patterns and role of ACSL4 in SAH and post‐SAH EBI using a rat model of SAH.
Methods
The rat model of SAH was induced by autologous blood injection into the prechiasmatic cistern of rats. We also used two specific inhibitors of ferroptosis (Ferrostatin‐1 and Liproxstatin‐1) to investigate the role of ferroptosis in EBI.
Results
We found that ACSL4 levels in brain tissue increased significantly in post‐SAH EBI. Inhibiting the expression of ACSL4 using small interfering RNAs alleviated inflammation, blood‐brain barrier (BBB) impairment, oxidative stress, brain edema, and behavioral and cognitive deficits, and increased the number of surviving neurons, after SAH. Similar effects were obtained by suppressing ferroptosis.
Conclusions
ACSL4 exacerbated SAH‐induced EBI by mediating ferroptosis. These findings may provide a theoretical basis for potential therapy aimed at alleviating post‐SAH EBI.
ACSL4 levels in brain tissue of rats increase significantly in EBI and brain damage after SAH could be reduced by down‐regulation of ACSL4. ACSL4 could trigger ferroptosis and aggravate brain damage via catalyzing lipid metabolism. It may provide a theoretical basis for potential therapy to alleviate EBI after SAH