GLP-1R knockdown abrogates the protective effects of liraglutide on ischaemic stroke via inhibition of M2 polarisation and activation of NLRP3 inflammasome by reducing Nrf2 activation

• Published in: Neuropharmacology Vol. 237; p. 109603
• Main Authors: Tu, Xian-kun, Chen, Ping-ping, Chen, Jing-yi, Ding, Yi-hang, Chen, Quan, Shi, Song-sheng
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.10.2023
• Subjects: GLP-1R; Ischemic stroke; Liraglutide; Neuroprotection; Nrf2; Neuroprotection; Ischemic stroke; Nrf2; Liraglutide; GLP-1R
• ISSN: 0028-3908; 1873-7064
• DOI: 10.1016/j.neuropharm.2023.109603

Liraglutide has been recently discovered to penetrate the blood–brain barrier to exert neuroprotective effects. However, relevant mechanisms of the protective effects of liraglutide on ischaemic stroke remain to be elucidated. This study examined the mechanism of GLP-1R in regulating the protective effect of liraglutide against ischaemic stroke. Middle cerebral artery occlusion (MCAO) male Sprague-Dawley rat model with/without GLP-1R or Nrf2 knockdown was established and subjected to liraglutide treatment. Then neurological deficit and brain oedema of rats was evaluated and brain tissues were subjected to TTC, Nissl, TUNEL and immunofluorescence staining. Rat primary microglial cells firstly underwent lipopolysaccharide (LPS) treatment, then GLP-1R or Nrf2 knockdown treatment, and finally Liraglutide treatment to research the NLRP3 activation. As a result, Liraglutide protected rats' brain tissues after MCAO, which attenuated brain oedema, infarct volume, neurological deficit score, neuronal apoptosis and Iba1 expression but enhanced live neurons. However, GLP-1R knockdown abrogated these protective effects of liraglutide on MCAO rats. According to in vitro experiments, Liraglutide promoted M2 polarisation, activated Nrf2 and inhibited NLRP3 activation in LPS-induced microglial cells, but GLP-1R or Nrf2 knockdown reversed these effects of Liraglutide on LPS-induced microglial cells. Further, Nrf2 knockdown counteracted the protection of liraglutide on MCAO rats, whereas sulforaphane (agonist of Nrf2) counteracted the effect of Nrf2 knockdown on liraglutide-treated MCAO rats. Collectively, GLP-1R knockdown abrogated the protection of liraglutide on MCAO rats by activating NLRP3 via inactivating Nrf2. [Display omitted] •Liraglutide attenuated brain damage in MCAO rat.•Loss of GLP-1R or Nrf2 abrogated protection of liraglutide on brain of MCAO rat.•Liraglutide inactivated NLRP3 inflammasome in microglial cells.•Liraglutide promoted M2 polarisation of microglial cells.•GLP-1R loss abrogated the protection of liraglutide on MCAO by inactivating Nrf2.