title: Pro-nociceptive migraine mediator CGRP provides neuroprotection of sensory, cortical and cerebellar neurons via multi-kinase signaling.
abstract: Background Blocking the pro-nociceptive action of CGRP is one of the most promising approaches for migraine prophylaxis. The aim of this study was to explore a role for CGRP as a neuroprotective agent for central and peripheral neurons. Methods The viability of isolated rat trigeminal, cortical and cerebellar neurons was tested by fluorescence vital assay. Engagement of Nrf2 target genes was analyzed by qPCR. The neuroprotective efficacy of CGRP in vivo was tested in mice using a permanent cerebral ischemia model. Results CGRP prevented apoptosis induced by the amino acid homocysteine in all three distinct neuronal populations. Using a set of specific kinase inhibitors, we show the role of multi-kinase signaling pathways involving PKA and CaMKII in neuronal survival. Forskolin triggered a very similar signaling cascade, suggesting that cAMP is the main upstream trigger for multi-kinase neuroprotection. The specific CGRP antagonist BIBN4096 reduced cellular viability, lending further support to the proposed neuroprotective function of CGRP. Importantly, CGRP was neuroprotective against permanent ischemia in mice. Conclusion Our data show an unexpected 'positive' role for the endogenous pro-nociceptive migraine mediator CGRP, suggesting more careful examination of migraine prophylaxis strategy based on CGRP antagonism although it should be noted that homocysteine induced apoptosis in primary neuronal cell culture might not necessarily reproduce all the features of cell loss in the living organism.
authors.affiliation: 1 Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.|2 Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Laboratory of Comparative Neurophysiology, Saint-Petersburg, Russia.
authors.forename: Polina A
authors.initials: PA
authors.lastname: Abushik
authors.affiliation: 1 Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Geneviève
authors.initials: G
authors.lastname: Bart
authors.affiliation: 1 Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Paula
authors.initials: P
authors.lastname: Korhonen
authors.affiliation: 3 Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Hanna
authors.initials: H
authors.lastname: Leinonen
authors.affiliation: 1 Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Raisa
authors.initials: R
authors.lastname: Giniatullina
authors.affiliation: 2 Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Laboratory of Comparative Neurophysiology, Saint-Petersburg, Russia.
authors.forename: Dmitry A
authors.initials: DA
authors.lastname: Sibarov
authors.affiliation: 3 Department of Biotechnology and Molecular Medicine, University of Eastern Finland, Kuopio, Finland.
authors.forename: Anna-Liisa
authors.initials: AL
authors.lastname: Levonen
authors.affiliation: 1 Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Malm
authors.affiliation: 2 Sechenov Institute of Evolutionary Physiology and Biochemistry of the Russian Academy of Sciences, Laboratory of Comparative Neurophysiology, Saint-Petersburg, Russia.
authors.forename: Sergei M
authors.initials: SM
authors.lastname: Antonov
authors.affiliation: 1 Department of Neurobiology, University of Eastern Finland, Kuopio, Finland.|4 Laboratory of Neurobiology, Department of Physiology, Kazan Federal University, Kazan, Russia.
authors.forename: Rashid
authors.initials: R
authors.lastname: Giniatullin
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D002531:Cerebellum / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology*; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008881:Migraine Disorders / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000201:enzymology*; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use; D059225:Nociception / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D011984:Sensory Receptor Cells / Q000187:drug effects / Q000201:enzymology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D012668:Trigeminal Ganglion / Q000000981:diagnostic imaging / Q000187:drug effects / Q000201:enzymology
chemical_list: D018696:Neuroprotective Agents; D015740:Calcitonin Gene-Related Peptide
keywords: CGRP; CaMKII; cAMP; cerebellum; cortex; ischemia; migraine; neuroprotection; trigeminal ganglion