Nitroglycerin as a comparative experimental model of migraine pain: From animal to human and back

Demartini, Chiara; Greco, Rosaria; Zanaboni, Anna Maria; Sances, Grazia; Icco, Roberto De; Borsook, David; Tassorelli, Cristina

doi:10.1016/j.pneurobio.2019.02.002

Cited by 83 publications

(76 citation statements)

References 291 publications

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“…We used the NTG model in this study as it is a well-validated model of migraine [33]. NTG is a known human migraine trigger and has been used as a human experimental model of migraine [34].…”

Section: Discussionmentioning

confidence: 99%

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Bertels

Grewal

Dripps

et al. 2020

Preprint

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Migraine is the third most prevalent disease worldwide and current therapies provide only partial relief. Greater insight into molecular migraine mechanisms would create novel therapies. Cytoskeletal flexibility is fundamental to neuronal-plasticity and is dependent on microtubule dynamicity. Histone-deacetylase-6 (HDAC6) decreases microtubule dynamics by deacetylating its primary substrate, α-tubulin. We use validated models of chronic migraine to show that HDAC6-inhibition is an effective migraine treatment and reveal an undiscovered cytoarchitectural basis for migraine chronicity. The human migraine trigger, nitroglycerin, produced chronic migraine-associated pain and decreased neurite growth in pain-processing regions, and these were reversed by HDAC6 inhibition.Cortical spreading depression (CSD), a physiological correlate of migraine aura, also caused decreased cortical neurite growth, while administration of HDAC6-inhibitor restored neuronal complexity and decreased CSD. Our results demonstrate that disruptions in neuronal cytoarchitecture are a feature of chronic migraine, and evolving migraine therapies might include agents that restore microtubule stability and neuronal plasticity.

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Section: Discussionmentioning

confidence: 99%

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Bertels

Grewal

Dripps

et al. 2020

Preprint

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“…Headaches are a predominate side effect from therapeutic use of organic nitrates, which are prodrugs for NO, cause vasodilation of blood vessels in the brain, and "immediate" mild-to-medium severity headaches or "delayed" migraines which involves cGMP or NO dependent S-nitrosylation-mediated changes in ion channel function 73 . Nitroglycerin has been used to model migraines in multiple species including fish 74,75 .…”

Section: Discussionmentioning

confidence: 99%

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

García-Jaramillo

Beaver

Truong

et al. 2020

Preprint

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IntroductionDietary nitrate lowers blood pressure and improves athletic performance in humans, yet data supporting observations that it may increase cerebral blood flow and improve cognitive performance are mixed. Here we tested the hypothesis that nitrate and nitrite treatment would improve indicators of learning and cognitive performance in a zebrafish (Danio rerio) model. We also explored the extent to which nitrate and nitrite treatment affected the brain metabolome in order to understand how nitrate and nitrite supplementation may affect indices of cognitive function.MethodsFish were exposed to sodium nitrate (606.9 mg/L), sodium nitrite (19.5 mg/L), or control water for 2-4 weeks and free swim, startle response, innate predator avoidance, social cohesion, and shuttle box assays were performed.ResultsNitrate and nitrite treatment did not change fish weight, length, predator avoidance, or distance and velocity traveled in an unstressed environment. Nitrate- and nitrite-treated fish initially experienced more negative reinforcement and increased time to decision in the shuttle box assay, which is consistent with a decrease in associative learning or executive function however, over multiple trials, all treatment groups demonstrated behaviors associated with learning. Nitrate and nitrite treatment significantly increased anxiety-like behavior but did not alter epinephrine, norepinephrine or dopamine levels. Targeted LC-MS/MS analysis revealed no significant increase in brain nitrate or nitrite concentrations with treatment. An untargeted metabolomics analysis found 47 metabolites whose abundance was significantly altered in the brain with nitrate and nitrite treatment including an 18-19% reduction in the neurotransmitter γ-aminobutyric acid (GABA), and 17-22% reduction in its precursor, glutamine, which may contribute to the increased anxiety-like behavior.ConclusionNitrate and nitrite treatment did not adversely affect multiple parameters of zebrafish health but was associated with mild anxiety-like behavior, changes in the brain metabolome, and caused a short-term decrease in executive function or associative learning.

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“…Nitroglycerin, also known as GTN, is a nitric oxide donor that can trigger migraine attacks in patients and is an established model in testing anti-migraine drugs, both in humans and in animals [41]. GTN injection in rodents is known to induce sensitization that can be seen behaviorally as well as upon activation along the trigeminal system [40].…”

Section: Effects Of Bitox/aa In the Gtn Migraine Modelmentioning

confidence: 99%

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine

Andreou

Leese

Greco³

et al. 2021

Neurotherapeutics

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With a prevalence of 15%, migraine is the most common neurological disorder and among the most disabling diseases, taking into account years lived with disability. Current oral medications for migraine show variable effects and are frequently associated with intolerable side effects, leading to the dissatisfaction of both patients and doctors. Injectable therapeutics, which include calcitonin gene–related peptide–targeting monoclonal antibodies and botulinum neurotoxin A (BoNT/A), provide a new paradigm for treatment of chronic migraine but are effective only in approximately 50% of subjects. Here, we investigated a novel engineered botulinum molecule with markedly reduced muscle paralyzing properties which could be beneficial for the treatment of migraine. This stapled botulinum molecule with duplicated binding domain—binary toxin-AA (BiTox/AA)—cleaves synaptosomal-associated protein 25 with a similar efficacy to BoNT/A in neurons; however, the paralyzing effect of BiTox/AA was 100 times less when compared to native BoNT/A following muscle injection. The performance of BiTox/AA was evaluated in cellular and animal models of migraine. BiTox/AA inhibited electrical nerve fiber activity in rat meningeal preparations while, in the trigeminovascular model, BiTox/AA raised electrical and mechanical stimulation thresholds in Aδ- and C-fiber nociceptors. In the rat glyceryl trinitrate (GTN) model, BiTox/AA proved effective in inhibiting GTN-induced hyperalgesia in the orofacial formalin test. We conclude that the engineered botulinum molecule provides a useful prototype for designing advanced future therapeutics for an improved efficacy in the treatment of migraine.

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Nitroglycerin as a comparative experimental model of migraine pain: From animal to human and back

Cited by 83 publications

References 291 publications

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Neuronal complexity is attenuated in chronic migraine and restored by HDAC6 inhibition

Nitrate and nitrite exposure increases anxiety-like behavior and alters brain metabolomic profile in zebrafish

Double-Binding Botulinum Molecule with Reduced Muscle Paralysis: Evaluation in In Vitro and In Vivo Models of Migraine

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