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Sigma–1 receptor activation alleviates blood–brain barrier disruption post cerebral ischemia stroke by stimulating the GDNF–GFRα1–RET pathway

Sigma–1 receptor activation alleviates blood–brain barrier disruption post cerebral ischemia stroke by stimulating the GDNF–GFRα1–RET pathway

By Danyang Liu, Luxi Yang, Peng Liu, Xuefei Ji, Xiaoxiao Qi, Ziqi Wang, Tianyan Chi, and Libo Zou

Excerpt from the article published in Experimental Neurology, Volume 347, 2022, DOI: https://doi.org/10.1016/j.expneurol.2021.113867.

Editors’ Highlights

Sigma-1 receptor agonists could play an effective therapeutic role in preventing BBB damage in ischemic stroke and other cardiovascular conditions.

Autors’ Highlights

  • Sigma 1 receptor activate in the blood brain barrier associated astrocyte.
  • Sigma 1 receptor activation promotes glia-derived neurotrophic factor secretion.
  • Sigma 1 receptor activation facilitates GDNF receptor complex formation.
  • Sigma 1 receptor binds to GDNF receptor on the endothelial cell plasma membrane.

Abstract

Blood–brain barrier (BBB) disruption is one of the most important pathological manifestations of ischemic stroke. Reducing BBB collapse is effective in alleviating brain parenchymal injury and cognitive dysfunction. Our previous study reported that Sigma–1 receptor (Sig–1R) activation in cerebral microvascular endothelial cells(CMECs) ameliorated BBB impairment, but the detailed mechanism remains unclear. In this study, we investigated Sig–1R activation as a BBB integrity promoter via many post ischemic stroke pathways. Sig–1R activation in BBB–associated astrocytes can increase glia–derived neurotrophic factor (GDNF) secretion in bilateral common carotid artery occlusion (BCCAO) mice. Upregulated GDNF activates its receptors in CMECs to promote BBB integrity, and activated Sig–1R in CMECs facilitates this process. In vitro experiments have found that Sig–1R activation in CMECs promotes the interaction between the GDNF α1 receptor and transduction rearrangement gene, increasing PI3K–AKT–junction protein signaling pathway expression. Sig–1R activation could be an effective therapeutic method for preventing BBB damage in ischemic stroke and other neurological conditions.