2. Academic Validation
  3. LAMC1 attenuates neuronal apoptosis via FAK/PI3K/AKT signaling pathway after subarachnoid hemorrhage

LAMC1 attenuates neuronal apoptosis via FAK/PI3K/AKT signaling pathway after subarachnoid hemorrhage

  • Exp Neurol. 2024 Jun:376:114776. doi: 10.1016/j.expneurol.2024.114776.
Qiaowei Wu 1,  Kaikun Yuan 1,  Yanting Yao 2,  Jinbiao Yao 1,  Jiang Shao 1,  Yuxiao Meng 1,  Pei Wu 3,  Huaizhang Shi 4
Affiliations

Affiliations

  • 1 Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China.
  • 2 Department of Neurosurgery, Beidahuang Group General Hospital, Harbin, Heilongjiang, China.
  • 3 Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. Electronic address: [email protected].
  • 4 Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China. Electronic address: [email protected].
PMID: 38609046 DOI: 10.1016/j.expneurol.2024.114776
Abstract

Background and purpose: The poor prognosis in patients with subarachnoid hemorrhage (SAH) is often attributed to neuronal Apoptosis. Recent evidence suggests that Laminin subunit gamma 1 (LAMC1) is essential for cell survival and proliferation. However, the effects of LAMC1 on early brain injury after SAH and the underlying mechanisms are unknown. The current study aimed to reveal the anti-neuronal apoptotic effect and the potential mechanism of LAMC1 in the rat and in the in vitro SAH models.

Methods: The SAH model of Sprague-Dawley rats was established by endovascular perforation. Recombinant LAMC1 (rLAMC1) was administered intranasally 30 min after modeling. LAMC1 small interfering RNA (LAMC1 siRNA), focal adhesion kinase (FAK)-specific inhibitor Y15 and PI3K-specific inhibitor LY294002 were administered before SAH modeling to explore the neuroprotection mechanism of rLAMC1. HT22 cells were cultured and stimulated by oxyhemoglobin to establish an in vitro model of SAH. Subsequently, SAH grades, neurobehavioral tests, brain water content, blood-brain barrier permeability, western blotting, immunofluorescence, TUNEL, and Fluoro-Jade C staining were performed.

Results: The expression of endogenous LAMC1 was markedly decreased after SAH, both in vitro and in vivo. rLAMC1 significantly reduced the brain water content and blood-brain barrier permeability, improved short- and long-term neurobehavior, and decreased neuronal Apoptosis. Furthermore, rLAMC1 treatment significantly increased the expression of p-FAK, p-PI3K, p-AKT, Bcl-xL, and Bcl-2 and decreased the expression of Bax and cleaved Caspase -3. Conversely, knockdown of endogenous LAMC1 aggravated the neurological impairment, suppressed the expression of Bcl-xL and Bcl-2, and upregulated the expression of Bax and cleaved Caspase-3. Additionally, the administration of Y15 and LY294002 abolished the protective roles of rLAMC1. In vitro, rLAMC1 significantly reduced neuronal Apoptosis, and the protective effects were also abolished by Y15 and LY294002.

Conclusion: Exogenous LAMC1 treatment improved neurological deficits after SAH in rats, and attenuated neuronal Apoptosis in both in vitro and in vivo SAH models, at least partially through the FAK/PI3K/Akt pathway.

Keywords

Early brain injury; Focal adhesion kinase; Laminin subunit gamma 1; Neuronal apoptosis; Subarachnoid hemorrhage.

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