Peroxynitrite Contributes to Behavioral Responses, Increased Trigeminal Excitability, and Changes in Mitochondrial Function in a Preclinical Model of Migraine

Abstract

Administration of a nitric oxide (NO) donor triggers migraine attacks but mechanisms by which this occurs are unknown. Reactive nitroxidative species, including NO and peroxynitrite (PN), have been implicated in nociceptive sensitization and neutralizing PN is anti-nociceptive. We determined whether PN contributes to nociceptive responses in two distinct models of migraine headache. Female and male mice were subjected to three consecutive days of restraint stress or to dural stimulation with the pro-inflammatory cytokine interleukin-6. Following resolution of the initial post-stimulus behavioral responses, animals were tested for hyperalgesic priming using a normally non-noxious dose of the NO donor sodium nitroprusside (SNP) or dural pH 7.0, respectively. We measured periorbital von Frey and grimace responses in both models and measured stress-induced changes in 3-nitrotyrosine (3-NT) expression (a marker for PN activity) and trigeminal ganglia (TG) mitochondrial function. Additionally, we recorded TG neuronal activity in response to the PN generator SIN-1. We then tested the effects of the PN decomposition catalysts, FeTMPyP and FeTPPS, or the PN scavenger MnTBAP against these behavioral, molecular, and neuronal changes. Neutralizing PN attenuated stress-induced periorbital hypersensitivity and priming to SNP, with no effect on priming to dural pH 7.0. These compounds also prevented stress-induced increases in 3-NT expression in both the TG and dura mater and attenuated TG neuronal hyperexcitability caused by SIN-1. Surprisingly, FeTMPyP attenuated changes in TG mitochondrial function caused by SNP in stressed males only. Together, these data strongly implicate PN in migraine mechanisms and highlight the therapeutic potential of targeting PN.SIGNIFICANCE STATEMENT:Among the most reliable experimental triggers of migraine are nitric oxide donors. Mechanisms by which nitric oxide triggers attacks are unclear but may be due to reactive nitroxidative species such as peroxynitrite. Utilizing mouse models of migraine headache, we show that peroxynitrite-modulating compounds attenuate behavioral, neuronal, and molecular changes caused by repeated stress and nitric oxide donors (two of the most common triggers of migraine in humans). Additionally, our results show a sex-specific regulation of mitochondrial function by peroxynitrite following stress, providing novel insight into the ways in which peroxynitrite may contribute to migraine-related mechanisms. Critically, our data underscore the potential in targeting peroxynitrite formation as a novel therapeutic for the treatment of migraine headache.

FeTPPS, a Peroxynitrite Decomposition Catalyst, Ameliorates Nitrosative Stress in Human Spermatozoa

“…FeTPPS is a metalloporphyrin that belongs to a group of compounds known as peroxynitrite decomposition catalysts, whose therapeutic potential is currently being developed to be applied to different clinical conditions [ 2 , 16 , 18 , 19 , 26 ]. Here, we demonstrate the beneficial effects of FeTPPS in antagonizing the adverse effects of peroxynitrite-mediated nitrosative stress in sperm cells, evidenced by an improvement of ATP, motility, MMP, thiol status, viability, and DNA fragmentation.…”

In Vitro Pharmacological Modulation of PIEZO1 Channels in Frontal Cortex Neuronal Networks

“…Recordings were taken using a pipette solution containing (in mM): 135 KCl, 10 HEPES, 4 ATP-Mg, 0.9 GTP-Na, 0.5 EGTA, and 5 NaCl adjusted to a pH of 7.4 with an osmolarity ranging from 305–320. The external bath solution contained (in mM): 135 NaCl, 5 KCl, 2 CaCl 2 , 1 MgCl 2 , 20 mM sucrose, 10 glucose, and 10 HEPES, with a pH of 7.4 and osmolarity ranging from 310–320 mOsm/L [ 37 ]. The cell capacitance, whole-cell compensation, fast and slow capacitance, resting membrane potential, leak current, pipette resistance, and offset were recorded for each cell.…”

Provocation of attacks to discover migraine signaling mechanisms and new drug targets: early history and future perspectives - a narrative review

“…4 ). In animal experiments the latter pathway plays an important role [ 80 ]. In humans, the question was studied using sildenafil which is an inhibitor of Phosphodiesterase-5 (PDE-5) whichbreaks down cGMP.…”