title: Prokineticins are neuroprotective in models of cerebral ischemia and ischemic tolerance in vitro.
abstract: Bv8/prokineticin 2 (PK2) is a member of a bioactive family of peptides that regulate multiple functions in the CNS including hyperalgesia, neurogenesis, neuronal survival and inflammation. Recent studies have associated PK2 and prokineticin receptors (PKR) with human diseases, but because their role in neuropathology is still debated we examined whether prokineticins exert a protective or deleterious role in models of cerebral ischemia and ischemic tolerance in vitro. In order to mimic cerebral ischemia, we exposed primary murine cortical cell cultures or rat organotypic hippocampal slices to appropriate periods of oxygen-glucose deprivation (OGD), which leads to neuronal damage 24 h later. Ischemic tolerance was induced by exposing hippocampal slices to a preconditioning subtoxic pharmacological stimulus (3 μM NMDA for 1 h) 24 h before the exposure to OGD. Bv8 (10-100 nM) attenuated OGD injury in cortical cultures and hippocampal slices, and the effect was prevented by the PKR antagonist PC7. The development of OGD tolerance was associated with an increase in the expression of PK2, PKR1 and PKR2 mRNA and proteins and was prevented by addition of the antagonist PC7 into the medium during preconditioning. Both Bv8 at protective concentrations and the NMDA preconditioning stimulus promoted the phosphorylation of ERK1/2 and Akt. These findings indicate that the prokineticin system can be up-regulated by a defensive preconditioning subtoxic NMDA stimulus and that PK2 may act as an endogenous neuroprotective factor through the activation of the ERK1/2 and Akt transduction pathways.
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy. Electronic address: elisa.landucci@unifi.it.
authors.forename: Elisa
authors.initials: E
authors.lastname: Landucci
authors.affiliation: Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Rome "La Sapienza", Piazza A. Moro 5, 00185 Rome, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Lattanzi
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Gerace
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
authors.forename: Tania
authors.initials: T
authors.lastname: Scartabelli
authors.affiliation: Department of Life and Environmental Sciences, Unit of Pharmaceutical, Pharmacological and Nutraceutical Sciences, University of Cagliari, Via Ospedale 72, 09124 Cagliari, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.affiliation: Department of Human Physiology and Pharmacology "Vittorio Erspamer", University of Rome "La Sapienza", Piazza A. Moro 5, 00185 Rome, Italy.
authors.forename: Lucia
authors.initials: L
authors.lastname: Negri
authors.affiliation: Department of Health Sciences, Section of Clinical Pharmacology and Oncology, University of Florence, Viale G. Pieraccini 6, 50139 Florence, Italy.
authors.forename: Domenico E
authors.initials: DE
authors.lastname: Pellegrini-Giampietro
mesh_terms: D000818:Animals; D001001:Anura; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D002545:Brain Ischemia / Q000378:metabolism* / Q000517:prevention & control; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005768:Gastrointestinal Hormones / Q000096:biosynthesis* / Q000494:pharmacology / Q000627:therapeutic use; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D009479:Neuropeptides / Q000096:biosynthesis* / Q000494:pharmacology / Q000627:therapeutic use; D018696:Neuroprotective Agents / Q000378:metabolism* / Q000627:therapeutic use; D009924:Organ Culture Techniques; D051381:Rats
chemical_list: D005768:Gastrointestinal Hormones; D009479:Neuropeptides; D018696:Neuroprotective Agents; C486587:Prok2 protein, rat; C513686:prokineticin 2, rat
keywords: Bv8; Ischemic tolerance; Neuroprotection; Oxygen-glucose deprivation; Preconditioning; Prokineticins