2. Academic Validation
  3. Hypoxia ischemia results in blood brain barrier damage via Akt/GSK-3β/CREB pathway in neonatal rats

Hypoxia ischemia results in blood brain barrier damage via Akt/GSK-3β/CREB pathway in neonatal rats

  • Brain Res. 2023 Oct 18:148640. doi: 10.1016/j.brainres.2023.148640.
Chenmeng Liu 1,  Can Wang 1,  Haimo Zhang 1,  Xiaotian Gao 1,  Peilun Xiao 2,  Miao Yu 1,  Xin Wang 3,  Xizhen Wang 4,  Xiaoli Wang 5
Affiliations

Affiliations

  • 1 School of Medical Imaging, Weifang Medical University, Weifang 261053, China.
  • 2 Department of Anatomy, School of Basic Medicine, Weifang Medical University, Weifang 261053, China.
  • 3 Department of Neurosurgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
  • 4 Medical Imaging Center, Affiliated Hospital of Weifang Medical University, Weifang 261031, China. Electronic address: [email protected].
  • 5 School of Medical Imaging, Weifang Medical University, Weifang 261053, China. Electronic address: [email protected].
PMID: 37863169 DOI: 10.1016/j.brainres.2023.148640
Abstract

Previous studies have showed that the permeability of blood brain barrier (BBB) increased after hypoxia ischemia (HI). The current research uncovered the mechanism of altered BBB permeability after hypoxic-ischemic brain damage (HIBD) through Akt/GSK-3β/CREB signaling pathway in neonatal rats. Firstly, Magnetic resonance imaging (MRI) combined with hematoxylin & eosin (H&E) staining was used to assess brain injury. Initial findings showed abnormal signals in T2-weighted imaging (T2WI) and diffusion weighted imaging (DWI). Changes also happened in the morphology of nerve cells. Subsequently, we found that BBB damage is manifested as leakage of immunoglobulin G (IgG) and destruction of BBB-related proteins and ultrastructure. Meanwhile, the levels of matrix metalloproteinase-9 (MMP-9) significantly increased at 24 h after HIBD compared to a series of time points. Additionally, immunohistochemical (IHC) staining combined with WB was used to verify the function of the Akt/GSK-3β/CREB signaling pathway in BBB damage after HI in neonatal rats. Results showed that less Claudin-5, ZO-1, p-Akt, p-GSK-3β and p-CREB, along with more MMP-9 protein expression were visible on the damaged side of the cerebral cortex in the HIBD group in contrast to the sham and HIBD + SC79 groups. Together, our findings demonstrated that HI in neonatal rats might upregulate the levels of MMP-9 protein and downregulate the levels of Claudin-5 and ZO-1 by inhibiting the Akt/GSK-3β/CREB pathway, thus disrupting the BBB, which in turn aggravates brain damage after HI in neonatal rats.

Keywords

Akt/GSK-3β/CREB pathway; Blood brain barrier; Hypoxic-ischemic brain damage; Neonatal rats.

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