title: Prokineticin 2 is an endangering mediator of cerebral ischemic injury.
abstract: Stroke causes brain dysfunction and neuron death, and the lack of effective therapies heightens the need for new therapeutic targets. Here we identify prokineticin 2 (PK2) as a mediator for cerebral ischemic injury. PK2 is a bioactive peptide initially discovered as a regulator of gastrointestinal motility. Multiple biological roles for PK2 have been discovered, including circadian rhythms, angiogenesis, and neurogenesis. However, the role of PK2 in neuropathology is unknown. Using primary cortical cultures, we found that PK2 mRNA is up-regulated by several pathological stressors, including hypoxia, reactive oxygen species, and excitotoxic glutamate. Glutamate-induced PK2 expression is dependent on NMDA receptor activation and extracellular calcium. Enriched neuronal culture studies revealed that neurons are the principal source of glutamate-induced PK2. Using in vivo models of stroke, we found that PK2 mRNA is induced in the ischemic cortex and striatum. Central delivery of PK2 worsens infarct volume, whereas PK2 receptor antagonist decreases infarct volume and central inflammation while improving functional outcome. Direct central inhibition of PK2 using RNAi also reduces infarct volume. These findings indicate that PK2 can be activated by pathological stimuli such as hypoxia-ischemia and excitotoxic glutamate and identify PK2 as a deleterious mediator for cerebral ischemia.
authors.affiliation: Department of Biological Sciences, Stanford University, Stanford, CA 94305, USA. mycheng@stanford.edu
authors.forename: Michelle Y
authors.initials: MY
authors.lastname: Cheng
authors.forename: Alex G
authors.initials: AG
authors.lastname: Lee
authors.forename: Collin
authors.initials: C
authors.lastname: Culbertson
authors.forename: Guohua
authors.initials: G
authors.lastname: Sun
authors.forename: Rushi K
authors.initials: RK
authors.lastname: Talati
authors.forename: Nathan C
authors.initials: NC
authors.lastname: Manley
authors.forename: Xiaohan
authors.initials: X
authors.lastname: Li
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
authors.forename: David M
authors.initials: DM
authors.lastname: Lyons
authors.forename: Qun-Yong
authors.initials: QY
authors.lastname: Zhou
authors.forename: Gary K
authors.initials: GK
authors.lastname: Steinberg
authors.forename: Robert M
authors.initials: RM
authors.lastname: Sapolsky
mesh_terms: D000818:Animals; D002545:Brain Ischemia / Q000503:physiopathology*; D005768:Gastrointestinal Hormones / Q000235:genetics / Q000502:physiology*; D009479:Neuropeptides / Q000235:genetics / Q000502:physiology*; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D015854:Up-Regulation
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; D012333:RNA, Messenger; C513686:prokineticin 2, rat