Inhibition of LPA₅ Activity Provides Long-Term Neuroprotection in Mice with Brain Ischemic Stroke

Abstract

Stroke is a leading cause of long-term disability in ischemic survivors who are suffering from motor, cognitive, and memory impairment. Previously, we have reported suppressing LPA 5 activity with its specific antagonist can attenuate acute brain injuries after ischemic stroke. However, it is unclear whether suppressing LPA 5 activity can also attenuate chronic brain injuries after ischemic stroke. Here, we explored whether effects of LPA 5 antagonist, TCLPA5, could persist a longer time after brain ischemic stroke using a mouse model challenged with tMCAO. TCLPA5 was administered to mice every day for 3 days, starting from the time immediately after reperfusion. TCLPA5 administration improved neurological function up to 21 days after tMCAO challenge. It also reduced brain tissue loss and cell apoptosis in mice at 21 days after tMCAO challenge. Such long-term neuroprotection of TCLPA5 was associated with enhanced neurogenesis and angiogenesis in post-ischemic brain, along with upregulated expression levels of vascular endothelial growth factor. Collectively, results of the current study indicates that suppressing LPA 5 activity can provide long-term neuroprotection to mice with brain ischemic stroke.

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

“…Given data that RAGE could be upregulated in injured brains after tMCAO challenge ( Figure 1 ), we determined whether LPA 5 could be associated with such RAGE upregulation. To address this, we employed TCLPA5, an LPA 5 antagonist, which could attenuate brain injuries after tMCAO challenge [ 9 , 10 ]. We chose 3 days after tMCAO challenge as the time point for analysis because RAGE upregulation was clearly observed at this time point ( Figure 1 a,b).…”

“…Suppressing LPA 5 activity with its antagonist, TCLPA5, can attenuate such acute brain injuries and neuroinflammatory responses in mice after ischemic challenge [ 9 ]. In addition, it can attenuate chronic brain injuries in mice after ischemic challenge by enhancing neurogenesis and angiogenesis [ 10 ]. These two independent studies clearly suggest that LPA 5 can play pathogenic roles in brain injuries during both acute and chronic phases after ischemic stroke.…”

“…Thus, several efforts have been made to develop drugs by targeting LPA signaling including its receptors [ 2 , 3 , 4 ]. In brain ischemic stroke, the importance of receptor-mediated LPA signaling has been suggested [ 5 , 6 , 7 , 8 , 9 , 10 ]. Amounts of LPA can be increased in both human patients [ 5 ] and animals with stroke [ 6 , 7 ].…”

“…Amounts of LPA can be increased in both human patients [ 5 ] and animals with stroke [ 6 , 7 ]. Moreover, its receptors LPA 1 [ 8 ] and LPA 5 [ 9 , 10 ] have been demonstrated to contribute to ischemic brain injuries. In particular, LPA 5 has been suggested to play a pathogenic role in brain ischemic stroke because it can be upregulated in the ischemic core regions after ischemic challenge [ 9 ] and suppressing its activity with TCLPA5, a selective LPA 5 antagonist, can lead to neuroprotection against ischemic brain injuries during both acute and chronic phases [ 9 , 10 ].…”

Lysophosphatidic Acid Receptor 5 (LPA5) Knockout Ameliorates the Neuroinflammatory Response In Vivo and Modifies the Inflammatory and Metabolic Landscape of Primary Microglia In Vitro

“…LPA 5 [ 15 ] and LPA 6 [ 16 , 17 ] are highly expressed in BV-2 cells and primary murine microglia [ 18 , 19 ], although LPA receptor expression in the brain is subject to developmental regulation [ 6 , 20 ] and depends on the genetic background of the animal model used [ 21 ]. LPA 5 is considered to be a driving factor for acute and chronic ischemic injuries in the mouse transient middle cerebral artery occlusion (tMCAO) stroke model, and the LPA 5 antagonist TCLPA5 has been shown to confer acute and long-term protection in this injury model [ 22 , 23 ]. These findings were ascribed to a pathogenic role of LPA 5 closely associated with microglia activation in injured brains [ 22 ], likely via RAGE-dependent pathways [ 24 ].…”