Knockdown and inhibition of hippocampal GPR17 attenuates lipopolysaccharide-induced cognitive impairment in mice.

Previously we reported that inhibition of GPR17 prevents amyloid β 1-42 (Aβ1-42)-induced cognitive impairment in mice. However, the role of GPR17 on cognition is still largely unknown. Herein, we used a mouse model of cognitive impairment induced by lipopolysaccharide (LPS) to further investigate the role of GPR17 in cognition and its potential mechanism. The mice were pretreated with GPR17 shRNA lentivirus and cangrelor by microinjection into the dentate gyrus (DG) region of the hippocampus. After 21 days, LPS (0.25 mg/kg, i.p.) was administered for 7 days. Animal behavioral tests as well as pathological and biochemical assays were performed to evaluate the cognitive function in mice. LPS exposure resulted in a significant increase in GPR17 expression at both protein and mRNA levels in the hippocampus. Gene reduction and pharmacological blockade of GPR17 improved cognitive impairment in both the Morris water maze and novel object recognition tests. Knockdown and inhibition of GPR17 inhibited Aβ production, decreased the expression of NF-κB p65, increased CREB phosphorylation and elevated BDNF expression, suppressed the accumulation of pro-inflammatory cytokines, inhibited Glial cells (microglia and astrocytes) activation, and increased Bcl-2, PSD-95, and SYN expression, reduced Bax expression as well as decreased caspase-3 activity and TUNEL-positive cells in the hippocampus of LPS-treated mice. Notably, knockdown and inhibition of GPR17 not only provided protective effects against cholinergic dysfunction but also facilitated the regulation of oxidative stress. In addition, cangrelor pretreatment can effectively inhibit the expression of inflammatory cytokines by suppressing NF-κB/CREB/BDNF signaling in BV-2 cells stimulated by LPS. However, activation of hippocampal GPR17 with MDL-29951 induced cognitive impairment in normal mice. These observations indicate that GPR17 may possess a neuroprotective effect against LPS-induced cognition deficits, and neuroinflammation by modulation of NF-κB/CREB/BDNF signaling in mice, indicating that GPR17 may be a promising new target for the prevention and treatment of AD. © 2023. The Author(s).

Citation

Yusheng Liang, Xu Kang, Haiwang Zhang, Heng Xu, Xian Wu. Knockdown and inhibition of hippocampal GPR17 attenuates lipopolysaccharide-induced cognitive impairment in mice. Journal of neuroinflammation. 2023 Nov 21;20(1):271

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PMID: 37990234

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