Reactive Oxygen Species Induce Procalcitonin Expression in Trigeminal Ganglia Glia

Abstract

Objective 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. Background 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, which encodes calcitonin (CT), a peptide hormone involved in calcium homeostasis. Importantly, a precursor form of calcitonin called procalcitonin (proCT) can act as a partial agonist at the CGRP receptor and elevated proCT has recently been reported during migraine. Methods We used a trigeminal ganglion whole organ explant model, which has previously been demonstrated to induce pro-inflammatory agents in vitro. Quantitative PCR and immunohistochemistry were used to evaluate changes in mRNA and protein levels of CGRP and proCT. Results Whole mouse trigeminal ganglia cultured for 24 h 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. Conclusions 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.

Calcitonin Gene-Related Peptide (CGRP): A New Target for Migraine

“…The significance of trigeminal ROS is supported by the ability of hydrogen peroxide to trigger CGRP release from cultured dorsal root ganglia neurons (139). ROS production following CSD could potentially be involved in epigenetic activation of the CGRP gene, as ROS can activate the gene in cultured trigeminal ganglia (140). Interestingly, the primary product of the CGRP gene in glia is procalcitonin, a CGRP-related peptide that has been reported to be elevated in migraine (141).…”

Hepatic Macrophages are the Cell Source of Hepatic Procalcitonin in Acute Liver Failure

“…Moreover, the liver is also considered a pivotal innate immune organ responsible for the biosynthesis of 80-90% of acute phase proteins, complement components, and other secreted pattern-recognition receptors of the innate immune system. One of the acute phase proteins, PCT, is a 13-kDa secreted protein found in various organs in sepsis, including the thyroid, liver, lung, small intestine, and kidney [3,5,7,11]. It is now known that serum PCT is highly upregulated after surgery and during bacterial infections, and the expression of PCT is induced by LPS and cytokines (TNF-α, IL- …”

“…In the 1990s, its association with sepsis was identified and since then PCT has become a diagnostic marker of systemic bacterial infection and is a deciding factor for antibiotic therapy [2]. PCT concentrations are elevated in serum in sepsis and PCT mRNA can be found in multiple tissues throughout the body [3][4][5]. Some research has shown that the liver expresses high levels of PCT mRNA in septic animals [3,6].…”

Induction of calcitonin gene-related peptide expression in rats by cortical spreading depression

“…Likewise, the ROS-responsive COX2 gene has been reported to be upregulated by CSD (16). Moreover, ROS-induced CGRP gene expression can be inhibited with antioxidant treatment in rat trigeminal ganglia (26). In light of these observations, we speculate that CSD-induced ROS production can lead to pro-inflammatory cascades that upregulate the CGRP gene.…”