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

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.

SPAK inhibitor ZT‐1a attenuates reactive astrogliosis and oligodendrocyte degeneration in a mouse model of vascular dementia

“…However, the specific toxic molecule(s) secreted by cytotoxic reactive astrocytes that induce OPC/OL death and inhibit OPC proliferation and differentiation are yet to be identified 29 . Interestingly, a recent study reported that the leukemia inhibitory factor (LIF) secreted from GFAP + astrocytes plays a protective role against BCAS‐induced memory impairment in WT C57BL/6J mice during early stage of VCID 37 . Kakae et al.…”

“…Data are mean ± SEM; one-way ANOVA, Tukey's post hoc test; n = 3-4; **p < 0.01. factor (LIF) secreted from GFAP + astrocytes plays a protective role against BCAS-induced memory impairment in WT C57BL/6J mice during early stage of VCID. 37 Kakae et al (2023) showed that astrocytic LIF enhanced differentiation of myelinating OL at 2 weeks after BCAS but not at 4 weeks after BCAS. 37 In our study, we found increased myelinating OL in ZT-1a-treated BCAS mice at 4 weeks after BCAS.…”

“…37 Kakae et al (2023) showed that astrocytic LIF enhanced differentiation of myelinating OL at 2 weeks after BCAS but not at 4 weeks after BCAS. 37 In our study, we found increased myelinating OL in ZT-1a-treated BCAS mice at 4 weeks after BCAS. Whether ZT-1a treatment affects astrocyte LIF secretion warrants further study.…”

“… 29 Interestingly, a recent study reported that the leukemia inhibitory factor (LIF) secreted from GFAP + astrocytes plays a protective role against BCAS‐induced memory impairment in WT C57BL/6J mice during early stage of VCID. 37 Kakae et al. (2023) showed that astrocytic LIF enhanced differentiation of myelinating OL at 2 weeks after BCAS but not at 4 weeks after BCAS.…”

Satellite Glial Cells Bridge Sensory Neuron Crosstalk in Visceral Pain and Cross-Organ Sensitization

“…TRPA1 is also expressed in sensory neurons and is responsive to a variety of stimuli including but not limit to mustard oil, allicin, and other chemical irritants, and serves as a sensor for noxious cold temperature (Guimaraes and Jordt, 2007). The functional role of TRPA1 in SGCs has not been confirmed, while TRPA1 expressed by astrocytes has a protective role against chronic cerebral hypoperfusion-induced vascular cognitive impairment through blockade of the production of leukemia inhibitory factor, a member of IL-6 cytokine family (Kakae et al, 2023). Another TRP channel in SGCs is TRPV4 which is activated by TRPV4-selective agonist GSK1016790A to elevate Ca 2+ influx (Rajasekhar et al, 2015).…”