2. Academic Validation
  3. The Aldose Reductase Inhibitor Epalrestat Maintains Blood-Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

The Aldose Reductase Inhibitor Epalrestat Maintains Blood-Brain Barrier Integrity by Enhancing Endothelial Cell Function during Cerebral Ischemia

  • Mol Neurobiol. 2023 Jul;60(7):3741-3757. doi: 10.1007/s12035-023-03304-z.
Tongshuai Zhang # 1,  Jinrong Wu # 2,  Xinmin Yao # 3,  Yao Zhang 1,  Yue Wang 4,  Yang Han 1,  Yun Wu 5,  Zhenyu Xu 1,  Jing Lan 1,  Siyu Han 1,  Haifeng Zou 1,  Qixu Sun 6,  Dandan Wang 7,  Jingyu Zhang 8,  Guangyou Wang 9
Affiliations

Affiliations

  • 1 Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China.
  • 2 Department of Anaesthesiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
  • 3 Traditional Chinese Medicine, Heilongjiang University of Chinese Medicine, Harbin, 150040, Heilongjiang, China.
  • 4 Department of Anesthesiology, Second Affiliated Hospital of Air Force Medical University, Xi'an, 710032, Shaanxi, China.
  • 5 The Medical Department of Neurology, The Second Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China.
  • 6 Department of Gastroenterology, Penglai People's Hospital, Yantai, 264117, Shandong, China.
  • 7 Wu Lian De Memorial Hospital, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China. wangdandan1973@126.com.
  • 8 The Medical Department of Neurology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, China. zhangjingyuyx@163.com.
  • 9 Department of Neurobiology, Heilongjiang Provincial Key Laboratory of Neurobiology, Harbin Medical University, Harbin, 150081, Heilongjiang, China. wangguangyou@hrbmu.edu.cn.
  • # Contributed equally.
PMID: 36940077 DOI: 10.1007/s12035-023-03304-z
Abstract

Excessive activation of Aldose Reductase (AR) in the brain is a risk factor for aggravating cerebral ischemia injury. Epalrestat is the only AR inhibitor with proven safety and efficacy, which is used in the clinical treatment of diabetic neuropathy. However, the molecular mechanisms underlying the neuroprotection of epalrestat remain unknown in the ischemic brain. Recent studies have found that blood-brain barrier (BBB) damage was mainly caused by increased Apoptosis and Autophagy of brain microvascular endothelial cells (BMVECs) and decreased expression of tight junction proteins. Thus, we hypothesized that the protective effect of epalrestat is mainly related to regulating the survival of BMVECs and tight junction protein levels after cerebral ischemia. To test this hypothesis, a mouse model of cerebral ischemia was established by permanent middle cerebral artery ligation (pMCAL), and the mice were treated with epalrestat or saline as a control. Epalrestat reduced the ischemic volume, enhanced BBB function, and improved the neurobehavior after cerebral ischemia. In vitro studies revealed that epalrestat increased the expression of tight junction proteins, and reduced the levels of cleaved-caspase3 and LC3 proteins in mouse BMVECs (bEnd.3 cells) exposed to oxygen-glucose deprivation (OGD). In addition, bicalutamide (an Akt Inhibitor) and rapamycin (an mTOR Inhibitor) increased the epalrestat-induced reduction in Apoptosis and Autophagy related protein levels in bEnd.3 cells with OGD treatment. Our findings suggest that epalrestat improves BBB function, which may be accomplished by reducing AR activation, promoting tight junction proteins expression, and upregulating Akt/mTOR signaling pathway to inhibit Apoptosis and Autophagy in BMVECs.

Keywords

Aldose reductase (AR); Autophage; Blood brain barrier (BBB); Brain microvascular endothelial cells (BMVECs); Cerebral ischemia; Epalrestat.

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