Biomol Ther.  2024 May;32(3):319-328. 10.4062/biomolther.2024.052.

Lysophosphatidic Acid Receptor 1 Plays a Pathogenic Role in Permanent Brain Ischemic Stroke by Modulating Neuroinflammatory Responses

• Tiwari S
• Basnet N
• Choi JW

• KMID: 2555691
• DOI: http://doi.org/10.4062/biomolther.2024.052

Abstract

Lysophosphatidic acid receptor 1 (LPA₁) plays a critical role in brain injury following a transient brain ischemic stroke. However, its role in permanent brain ischemic stroke remains unknown. To address this, we investigated whether LPA₁could contribute to brain injury of mice challenged by permanent middle cerebral artery occlusion (pMCAO). A selective LPA₁ antagonist (AM152) was used as a pharmacological tool for this investigation. When AM152 was given to pMCAO-challenged mice one hour after occlusion, pMCAO-induced brain damage such as brain infarction, functional neurological deficits, apoptosis, and blood-brain barrier disruption was significantly attenuated. Histological analyses demonstrated that AM152 administration attenuated microglial activation and proliferation in injured brain after pMCAO challenge. AM152 administration also attenuated abnormal neuroinflammatory responses by decreasing expression levels of pro-inflammatory cytokines while increasing expression levels of anti-inflammatory cytokines in the injured brain. As underlying effector pathways, NF-ĸB, MAPKs (ERK1/2, p38, and JNKs), and PI3K/Akt were found to be involved in LPA₁-dependent pathogenesis. Collectively, these results demonstrate that LPA₁can contribute to brain injury by permanent ischemic stroke, along with relevant pathogenic events in an injured brain.

Keyword

Lysophosphatidic acid receptor 1 (LPA ₁ ); AM152; Permanent brain ischemic stroke; Permanent middle cerebral artery occlusion (pMCAO); Microglia; Pro-inflammatory cytokines