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Reactive oxygen species induce procalcitonin expression in trigeminal ganglia glia
Journal article   Peer reviewed

Reactive oxygen species induce procalcitonin expression in trigeminal ganglia glia

Ann C Raddant and Andrew F Russo
Headache, Vol.54(3), pp.472-484
03/2014
DOI: 10.1111/head.12301
PMCID: PMC3947709
PMID: 24512072
url
http://doi.org/10.1111/head.12301View
Open Access

Abstract

To examine calcitonin gene-related peptide (CGRP) gene expression under inflammatory conditions using trigeminal ganglia organ cultures as an experimental system. These cultures have increased proinflammatory signaling that may mimic neurogenic inflammation in the migraine state. The trigeminal nerve sends peripheral pain signals to the central nervous system during migraine. Understanding the dynamic processes that occur within the trigeminal nerve and ganglion may provide insights into events that contribute to migraine pain. A neuropeptide of particular interest is CGRP, which can be elevated and play a causal role in migraine. However, most studies have overlooked a second splice product of the Calca gene that encodes calcitonin (CT), a peptide hormone involved in calcium homeostasis. Importantly, a precursor form of CT called procalcitonin (proCT) can act as a partial agonist at the CGRP receptor and elevated proCT has recently been reported during migraine. We used a trigeminal ganglion whole organ explant model, which has previously been demonstrated to induce pro-inflammatory agents in vitro. Quantitative polymerase chain reaction and immunohistochemistry were used to evaluate changes in messenger ribonucleic acid (mRNA) and protein levels of CGRP and proCT. Whole mouse trigeminal ganglia cultured for 24 hours showed a 10-fold increase in CT mRNA, with no change in CGRP mRNA. A similar effect was observed in ganglia from adult rats. ProCT immunoreactivity was localized in glial cells. Cutting the tissue blunted the increase in CT, suggesting that induction required the close environment of the intact ganglia. Consistent with this prediction, there were increased reactive oxygen species in the ganglia, and the elevated CT mRNA was reduced by antioxidant treatment. Surprisingly, reactive oxygen species were increased in neurons, not glia. These results demonstrate that reactive oxygen species can activate proCT expression from the CGRP gene in trigeminal glia by a paracrine regulatory mechanism. We propose that this glial recruitment pathway may occur following cortical spreading depression and neurogenic inflammation to increase CGRP nociceptive actions in migraine.
 Immunohistochemistry Reactive Oxygen Species - metabolism Calcitonin - biosynthesis Mice, Inbred C57BL Cells, Cultured Rats Trigeminal Ganglion - metabolism Male Reverse Transcriptase Polymerase Chain Reaction Rats, Sprague-Dawley Migraine Disorders - metabolism Animals Protein Precursors - biosynthesis Neuroglia - metabolism Mice Calcitonin Gene-Related Peptide - metabolism

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