Phaseic Acid, an Endogenous and Reversible Inhibitor of Glutamate Receptors in Mouse Brain

Sheng Tao Hou; Susan X. Jiang; L. Irina Zaharia; Xiumei Han; Chantel L. Benson; Jacqueline Slinn; Suzanne R. Abrams

doi:10.1074/jbc.M116.756429

Phaseic Acid, an Endogenous and Reversible Inhibitor of Glutamate Receptors in Mouse Brain*

From the ^‡Brain Research Centre and Department of Biology, Southern University of Science and Technology, 1088 Xueyuan Boulevard, Nanshan District, Shenzhen, 518055 Guangdong Province, China,
^§Experimental NeuroTherapeutics, Human Health Therapeutics Portfolio, National Research Council Canada, 1200 Montreal Road, Building M54, Ottawa K1A 0R6, Ontario, Canada,
^‖Aquatic and Crop Resource Development, National Research Council Canada, 110 Gymnasium Place, Saskatoon, Saskatchewan S7N 0W9, Canada, and
the ^¶Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ontario K1H 8M5, Canada

↵1 To whom correspondence should be addressed: Brain Research Centre and Dept. of Biology, Southern University of Science and Technology, 1088 Xueyuan Blvd., Nanshan District, Shenzhen, 518055 Guangdong Province, China. Tel.: 86-755-8801-8418; E-mail: hou.st{at}sustc.edu.cn.

Edited by F. Anne Stephenson

↵2 Present address: Saskatchewan Structural Sciences Centre, Rm. 190 Thorvaldson Bldg., 110 Science Place, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5C9, Canada.

Abstract

Phaseic acid (PA) is a phytohormone regulating important physiological functions in higher plants. Here, we show the presence of naturally occurring (−)-PA in mouse and rat brains. (−)-PA is exclusively present in the choroid plexus and the cerebral vascular endothelial cells. Purified (−)-PA has no toxicity and protects cultured cortical neurons against glutamate toxicity through reversible inhibition of glutamate receptors. Focal occlusion of the middle cerebral artery elicited a significant induction in (−)-PA expression in the cerebrospinal fluid but not in the peripheral blood. Importantly, (−)-PA induction only occurred in the penumbra area, indicting a protective role of PA in the brain. Indeed, elevating the (−)-PA level in the brain reduced ischemic brain injury, whereas reducing the (−)-PA level using a monoclonal antibody against (−)-PA increased ischemic injury. Collectively, these studies showed for the first time that (−)-PA is an endogenous neuroprotective molecule capable of reversibly inhibiting glutamate receptors during ischemic brain injury.

Footnotes

↵* This work was supported by National Natural Science Foundation of China Grant 81571287, Shenzhen Science and Technology Innovation Committee Basic Science Research Grants JCYJ20140417105742709 and JCYJ20160301112230218, State Key Laboratory of Neuroscience Open Competition Grant SKLN-201403, Southern University of Science and Technology (SUSTech) Peacock Program Start-up Fund Grant 22/Y01226109, and SUSTech Brain Research Centre Fund (to S. T. H.). The authors declare that they have no conflicts of interest with the contents of this article.