Delayed administration of rapamycin inhibits glial scar formation through upregulating matrilin-3 in an autophagy-dependent manner in ischemic stroke

  • Neurosci Lett. 2025 Jul 29:865:138333. doi: 10.1016/j.neulet.2025.138333.
Yi Guo  1 ,  Aiping Qin  2 ,  Li Sun  3 ,  Jinzhi He  1 ,  Yuping Shan  1 ,  Xinyi Wang  1 ,  Tongxin Zhang  1 ,  Min Li  1 ,  Yuqi Ma  1 ,  Shigang Qiao  4 ,  Huiling Zhang  5
Affiliations
  • 1. Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China.
  • 2. Department of Pharmacy, Jiangsu Health Vocational College, Nanjing 210000, China.
  • 3. Department of Neurology, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou 215200, China.
  • 4. Kunshan Hospital of Chinese Medicine, Affiliated Hospital of Yangzhou University, Kunshan, Jiangsu 215300, China. Electronic address: [email protected].
  • 5. Jiangsu Key Laboratory of Drug Discovery and Translational Research for Brain Diseases, College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu 215123, China; Department of Neurology, Suzhou Ninth People's Hospital, Suzhou Ninth Hospital Affiliated to Soochow University, Soochow University, Suzhou 215200, China. Electronic address: [email protected].
PMID: 40744138 DOI: 10.1016/j.neulet.2025.138333
Abstract

Glial scar formation is one of the major pathological mechanisms following ischemic stroke. Rapamycin is a potent specific mTOR Inhibitor and an Autophagy activator. Although it has neuroprotective effects against acute ischemic stroke, it is unknown whether delayed administration of rapamycin can reduce ischemic stroke-induced pathogenesis such as glial scar formation, independent on its effects of acute administration. We recently reported that matrilin-3, an extracellular matrix component, provides neuroprotection in ischemic stroke by suppressing astrocyte-mediated neuroinflammation and glial scar formation. Here, in rat models of middle cerebral artery occlusion and reperfusion (I/R), rapamycin was administered for consecutive 7 or 14 days starting at day 1 post-reperfusion; and in an oxygen-glucose deprivation and reoxygenation (OGD/Re)-induced primary astrocyte or human astrocyte injury model, rapamycin was given upon reoxygenation. We found that rapamycin improved I/R-mediated rats' neurological dysfunction, accompanied by reduced glial scar formation and neuronal loss. To our surprise, rapamycin increased the levels of matrilin-3 in the peri-infarct region of rats and in OGD/Re-treated astrocytes associating with restoring autophagic flux. In contrast, the Autophagy inhibitors wortmannin and bafilomycin A1 blocked autophagic flux, decreased the levels of matrilin-3 and enhanced glial scar formation, respectively. Overexpression of matrilin-3 significantly reduced the glial scar formation. Mechanistically, rapamycin could decrease the ADAMTS-4 and ADAMTS-5 levels, two hydrolases responsible for the breakdown of matrilin-3, thus upregulating the matrilin-3 levels. Our results reveal that delayed administration of rapamycin suppresses the glial scar formation by upregulating the astrocytic matrilin-3 related to restoring autophagic flux in ischemic stroke.

Keywords
ADAMTS-4/5; Astrocytes; Autophagy; Glial scar; Ischemic stroke; Matrilin-3; Rapamycin.
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