Hypoxia facilitates neurogenic dural plasma protein extravasation in mice: a novel animal model for migraine pathophysiology

Abstract

Migraine animal models generally mimic the onset of attacks and acute treatment processes. A guinea pig model used the application of meta-chlorophenylpiperazine (mCPP) to trigger immediate dural plasma protein extravasation (PPE) mediated by 5-HT2B receptors. This model has predictive value for antimigraine drugs but cannot explain the delayed onset of efficacy of 5-HT2B receptor antagonists when clinically used for migraine prophylaxis. We found that mCPP failed to induce dural PPE in mice. Considering the role 5-HT2B receptors play in hypoxia-induced pulmonary vessel muscularization, we were encouraged to keep mice under hypoxic conditions and tested whether this treatment will render them susceptible to mCPP-induced dural PPE. Following four-week of hypoxia, PPE, associated with increased transendothelial transport, was induced by mCPP. The effect was blocked by sumatriptan. Chronic application of 5-HT2B receptor or nitric oxide synthase blockers during hypoxia prevented the development of susceptibility. Here we present a migraine model that distinguishes between a migraine-like state (hypoxic mice) and normal, normoxic mice and mimics processes that are related to chronic activation of 5-HT2B receptors under hypoxia. It seems striking, that chronic endogenous activation of 5-HT2B receptors is crucial for the sensitization since 5-HT2B receptor antagonists have strong, albeit delayed migraine prophylactic efficacy.

Prognostic value of hypoxia-inducible factor-1 alpha and prolyl 4-hydroxylase beta polypeptide overexpression in gastric cancer

“…Regardless of the initiation site, tumor metastasis is promoted by HIF signaling; specifically, HIF-1 and HIF-2 coordinate to stabilize this pathway and maintain homeostasis of the hypoxic microenvironment[ 20 ]. As a key transcription factor, HIF-1α is involved in each step of the tumor metastatic cascade: from epithelial-mesenchymal transition (EMT)[ 7 ], intravasation[ 21 ], extravasation[ 22 ], the establishment of premetastatic niche to survival at a distant site[ 23 ]. In vitro and in vivo experiments have shown that downregulation of HIF-1α expression can significantly inhibit the malignancy phenotype of GC[ 24 , 25 ].…”

Structure, Function, and Pharmaceutical Ligands of 5-Hydroxytryptamine 2B Receptor

“…In guinea pigs, selective 5-HT 2B R antagonists have been found to inhibit the 5-HT 2B R/5-HT 2C R agonist meta-chlorophenylpiperazine (mCPP) or the 5-HT 2B R agonist BW723C686-induced dural plasma protein extravasation (PPE), an indicator for migraine attacks in animal models [79]. In addition, 5-HT 2B R antagonism also prevented mCPP-induced dural PPE under hypoxia in mice [80].…”

Putative role of 5-HT2B receptors in migraine pathophysiology

“…observed an mCPP-induced PPE that was associated with increased transcellular transport of dissolved substances (e.g. horseradish peroxidase, HRP) in endothelial cells with no damage of fenestrae or tight junction integrity in mice dura mater (38). Other studies showed both transcellular and para-cellular transport through the endothelial junction and clefts (39).…”

“…The mechanism for this shift could not be explained by an increased expression of 5-HT 2B receptors or other proteins involved. Learning more about the underlying cellular mechanisms of this phenomenon is demanding and could explain why the exclusively chronic treatment with 5-HT 2B receptor antagonists leads to a reduction of migraine attacks (38).…”