2. Academic Validation
  3. The astrocytic TRPA1 channel mediates an intrinsic protective response to vascular cognitive impairment via LIF production

The astrocytic TRPA1 channel mediates an intrinsic protective response to vascular cognitive impairment via LIF production

  • Sci Adv. 2023 Jul 21;9(29):eadh0102. doi: 10.1126/sciadv.adh0102.
Masashi Kakae 1 2,  Hiroki Nakajima 1,  Shota Tobori 1,  Ayaka Kawashita 1,  Jun Miyanohara 1,  Misa Morishima 1,  Kazuki Nagayasu 1,  Takayuki Nakagawa 2 3,  Eiji Shigetomi 4 5,  Schuichi Koizumi 4 5,  Yasuo Mori 6,  Shuji Kaneko 1,  Hisashi Shirakawa 1
Affiliations

Affiliations

  • 1 Department of Molecular Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan.
  • 2 Department of Clinical Pharmacology and Pharmacotherapy, School of Pharmaceutical Sciences, Wakayama Medical University, Wakayama, Japan.
  • 3 Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan.
  • 4 Department of Neuropharmacology, Interdisciplinary Graduate School of Medicine, University of Yamanashi, Yamanashi, Japan.
  • 5 Yamanashi GLIA Center, University of Yamanashi, Yamanashi, Japan.
  • 6 Department of Synthetic Chemistry and Biological Chemistry, Graduate School of Engineering, Kyoto University, Kyoto, Japan.
PMID: 37478173 DOI: 10.1126/sciadv.adh0102
Abstract

Vascular cognitive impairment (VCI) refers to cognitive alterations caused by vascular disease, which is associated with various types of dementia. Because chronic cerebral hypoperfusion (CCH) induces VCI, we used bilateral common carotid artery stenosis (BCAS) mice as a CCH-induced VCI model. Transient receptor potential ankyrin 1 (TRPA1), the most redox-sensitive TRP Channel, is functionally expressed in the brain. Here, we investigated the pathophysiological role of TRPA1 in CCH-induced VCI. During early-stage CCH, cognitive impairment and white matter injury were induced by BCAS in TRPA1-knockout but not wild-type mice. TRPA1 stimulation with cinnamaldehyde ameliorated BCAS-induced outcomes. RNA sequencing analysis revealed that BCAS increased Leukemia Inhibitory Factor (LIF) in astrocytes. Moreover, hydrogen peroxide-treated TRPA1-stimulated primary astrocyte cultures expressed LIF, and culture medium derived from these cells promoted oligodendrocyte precursor cell myelination. Overall, TRPA1 in astrocytes prevents CCH-induced VCI through LIF production. Therefore, TRPA1 stimulation may be a promising therapeutic approach for VCI.

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