2. Academic Validation
  3. Delayed simvastatin treatment improves neurological recovery after cryogenic traumatic brain injury through downregulation of ELOVL1 by inhibiting mTOR signaling

Delayed simvastatin treatment improves neurological recovery after cryogenic traumatic brain injury through downregulation of ELOVL1 by inhibiting mTOR signaling

  • Brain Res Bull. 2024 Oct 15:217:111072. doi: 10.1016/j.brainresbull.2024.111072.
Jing Huo 1,  Lin Feng 1,  Yao Cheng 1,  Yu-Lu Miao 2,  Wen Liu 3,  Miao-Miao Hou 4,  Hui-Feng Zhang 1,  Cai-Hong Yang 1,  Yan Li 5,  Ming-Sheng Zhang 6,  Yan-Ying Fan 7
Affiliations

Affiliations

  • 1 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Jinzhong, Shanxi 030600, China.
  • 2 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Jinzhong, Shanxi 030600, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
  • 3 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China.
  • 4 Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Third Hospital of Shanxi Medical University, Tongji Shanxi Hospital, Taiyuan 030032, China.
  • 5 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Jinzhong, Shanxi 030600, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China. Electronic address: sxliyan@sxmu.edu.cn.
  • 6 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Jinzhong, Shanxi 030600, China. Electronic address: zms@sxmu.edu.cn.
  • 7 Department of Pharmacology, School of Basic Medical Science, Shanxi Medical University, Jinzhong, Shanxi 030600, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan 030001, China. Electronic address: fanyanying@sxmu.edu.cn.
PMID: 39243948 DOI: 10.1016/j.brainresbull.2024.111072
Abstract

Statins are well-tolerated and widely available lipid-lowering medications with neuroprotective effects against traumatic brain injury (TBI). However, whether delayed statin therapy starting in the subacute phase promotes recovery after TBI is unknown. Elongation of the very long-chain fatty acid protein 1 (ELOVL1) is involved in astrocyte-mediated neurotoxicity, but its role in TBI and the relationship between ELOVL1 and statins are unclear. We hypothesized that delayed simvastatin treatment promotes neurological functional recovery after TBI by regulating the ELOVL1-mediated production of very long-chain fatty acids (VLCFAs). ICR male mice received daily intragastric administration of 1, 2 or 5 mg/kg simvastatin on Days 1-14, 3-14, 5-14, or 7-14 after cryogenic TBI (cTBI). The results showed that simvastatin promoted motor functional recovery in a dose-dependent manner, with a wide therapeutic window of at least 7 days postinjury. Meanwhile, simvastatin inhibited astrocyte and microglial overactivation and glial scar formation, and increased total dendritic length, neuronal complexity and spine density on day 14 after cTBI. The up-regulation of ELOVL1 expression and saturated VLCFAs concentrations in the cortex surrounding the lesion caused by cTBI was inhibited by simvastatin, which was related to the inhibition of the mTOR signaling. Overexpression of ELOVL1 in astrocytes surrounding the lesion using HBAAV2/9-GFAP-m-ELOVL1-3xFlag-EGFP partially attenuated the benefits of simvastatin. These results showed that delayed simvastatin treatment promoted functional recovery and brain tissue repair after TBI through the downregulation of ELOVL1 expression by inhibiting mTOR signaling. Astrocytic ELOVL1 may be a potential target for rehabilitation after TBI.

Keywords

Brain tissue repair; Delayed simvastatin treatment; ELOVL1; Therapeutic window; Traumatic brain injury.

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