Receptor for Advanced Glycation End Products Is Involved in LPA₅-Mediated Brain Damage after a Transient Ischemic Stroke

Lysophosphatidic acid receptor 5 (LPA₅) has been recently identified as a novel pathogenic factor for brain ischemic stroke. However, its underlying mechanisms remain unclear. Here, we determined whether the receptor for advanced glycation end products (RAGE) could be involved in LPA₅-mediated brain injuries after ischemic challenge using a mouse model of transient middle cerebral artery occlusion (tMCAO). RAGE was upregulated in the penumbra and ischemic core regions after tMCAO challenge. RAGE upregulation was greater at 3 days than that at 1 day after tMCAO challenge. It was mostly observed in Iba1-immunopositive cells of a post-ischemic brain. Suppressing LPA₅ activity with its antagonist, TCLPA5, attenuated RAGE upregulation in the penumbra and ischemic core regions, particularly on Iba1-immunopositive cells, of injured brains after tMCAO challenge. It also attenuated blood-brain barrier disruption, one of the core pathogenesis upon RAGE activation, after tMCAO challenge. As an underlying signaling pathways, LPA₅ could contribute to the activation of ERK1/2 and NF-κB in injured brains after tMCAO challenge. Collectively, the current study suggests that RAGE is a possible mediator for LPA₅-dependent ischemic brain injury.