Lysophosphatidic acid increased infarct size in the early stage of cerebral ischemia-reperfusion with increased BBB permeability.

Abstract

BACKGROUND:

We investigated whether exogenous lysophosphatidic acid (LPA), a phospholipid extracellular signaling molecule, would increase infarct size and blood-brain barrier (BBB) disruption during the early stage of cerebral ischemia-reperfusion, and whether it works through Akt-mTOR-S6K1 intracellular signaling.

MATERIAL AND METHODS:

Rats were given either vehicle or LPA 1 mg/kg iv three times during reperfusion after one hour of middle cerebral artery (MCA) occlusion. In another group, prior to administration of LPA, 30 mg/kg of PF-4708671, an S6K1 inhibitor, was injected. After one hour of MCA occlusion and two hours of reperfusion the transfer coefficient (Ki) of 14C-α-aminoisobutyric acid and the volume of 3H-dextran distribution were determined to measure the degree of BBB disruption. At the same time, the size of infarct was determined and western blot analysis was performed to determine the levels of phosphorylated Akt (p-Akt) and phosphorylated S6 (pS6).

RESULTS:

LPA increased the Ki in the ischemic-reperfused cortex (+43%) when compared with Control rats and PF-4708671 pretreatment prevented the increase of Ki by LPA. LPA increased the percentage of cortical infarct out of total cortical area (+36%) and PF-4708671 pretreatment prevented the increase of the infarct size. Exogenous LPA did not significantly change the levels of p-Akt as well as pS6 in the ischemic-reperfused cortex.

CONCLUSION:

Our data demonstrate that the increase in BBB disruption could be one of the reasons of the increased infarct size by LPA. S6K1 may not be the major target of LPA. A decrease of LPA during early cerebral ischemia-reperfusion might be beneficial for neuronal survival.

• Authors: Oak Z Chi, Scott J Mellender, Geza K Kiss, Antonio Chiricolo, Xia Liu, Nikhil Patel, Estela Jacinto, Harvey R Weiss
• Journal: Journal of stroke and cerebrovascular diseases : the official journal of National Stroke Association (J Stroke Cerebrovasc Dis) Vol. 29 Issue 10 Pg. 105029 (Oct 2020) ISSN: 1532-8511 [Electronic] United States
• PMID: 32912542 (Publication Type: Journal Article)
• Copyright: Copyright © 2020 Elsevier Inc. All rights reserved.

Chemical References

• Lysophospholipids
• Proto-Oncogene Proteins c-akt
• Ribosomal Protein S6 Kinases
• Rps6kb1 protein, rat
• lysophosphatidic acid

Topics

• Animals
• Blood-Brain Barrier (drug effects, physiopathology)
• Capillary Permeability (drug effects)
• Cerebral Cortex (drug effects, enzymology, pathology)
• Disease Models, Animal
• Infarction, Middle Cerebral Artery (enzymology, pathology, physiopathology, therapy)
• Lysophospholipids (toxicity)
• Male
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• Rats, Inbred F344
• Reperfusion
• Reperfusion Injury (chemically induced, enzymology, pathology, physiopathology)
• Ribosomal Protein S6 Kinases (metabolism)