Hyperhomocysteinemia increases susceptibility to cortical spreading depression associated with photophobia, mechanical allodynia, and anxiety in rats

Gerasimova, E.; Burkhanova, Gulshat; Chernova, Kseniya; Захаров, А. В.; Еникеев, Д. А.; Khaertdinov, N. N.; Giniatullin, Rashid; Ситдикова, Г. Ф.

doi:10.1016/j.bbr.2021.113324

Cited by 11 publications

(8 citation statements)

References 54 publications

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“…The higher excitability of TG afferents in rats with hHCY was further supported by a higher baseline activity of the TG nerve, which is also similar to previous findings in the hippocampus and somatosensory cortex of rats with prenatal hHCY 30,62 . Cluster analysis of APs was used to assess indirectly the activity of nerve fibers of different types according to Zakharov et al 38 .…”

Section: Discussionsupporting

confidence: 82%

“…We have recently shown that rats with prenatal hHCY display mechanical allodynia, photophobia, and a lower threshold of cortical spreading depression generation, supporting the clinical data of the predisposition of patients with hHCY to migraine with aura 30 . Moreover, rats with hHCY were more sensitive in the model of chronic nitroglycerine‐induced migraine 31 .…”

Section: Introductionsupporting

confidence: 76%

“…homocysteine, mast cell, meningeal trigeminal afferents, migraine, NMDA receptors, trigeminal ganglion neurons spreading depression generation, supporting the clinical data of the predisposition of patients with hHCY to migraine with aura. 30 Moreover, rats with hHCY were more sensitive in the model of chronic nitroglycerine-induced migraine. 31 These data suggest the involvement of peripheral mechanisms in the sensitivity to migrainelike symptoms of hHCY animals.…”

Section: Introductionmentioning

confidence: 99%

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Implications of high homocysteine levels in migraine pain: An experimental study of the excitability of peripheral meningeal afferents in rats with hyperhomocysteinemia

Ermakova,

Shaidullova,

Gafurov

et al. 2024

Headache

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ObjectivesInvestigation of chronic homocysteine action on the excitability and N‐methyl‐D‐aspartate (NMDA) sensitivity of the peripheral trigeminovascular system of rats.BackgroundMigraine is a neurological disease that affects 15%–20% of the general population. Epidemiological observations show that an increase of the sulfur‐containing amino acid homocysteine in plasma—called hyperhomocysteinemia—is associated with a high risk of migraine, especially migraine with aura. In animal studies, rats with hyperhomocysteinemia demonstrated mechanical allodynia, photophobia, and anxiety, and higher sensitivity to cortical spreading depression. In addition, rats with hyperhomocysteinemia were more sensitive in a model of chronic migraine induced by nitroglycerin which indicated the involvement of peripheral nociceptive mechanisms. The present work aimed to analyze the excitability of meningeal afferents and neurons isolated from the trigeminal ganglion of rats with prenatal hyperhomocysteinemia.MethodsExperiments were performed on male rats born from females fed with a methionine‐rich diet before and during pregnancy. The activity of meningeal afferents was recorded extracellularly in hemiskull preparations ex vivo and action potentials were characterized using cluster analysis. The excitability of trigeminal ganglion neurons was assessed using whole‐cell patch clamp recording techniques and calcium imaging studies. Meningeal mast cells were stained using toluidine blue.ResultsThe baseline extracellular recorded electrical activity of the trigeminal nerve was higher in the hyperhomocysteinemia group with larger amplitude action potentials. Lower concentrations of KCl caused an increase in the frequency of action potentials of trigeminal afferents recorded in rat hemiskull ex vivo preparations. In trigeminal ganglion neurons of rats with hyperhomocysteinemia, the current required to elicit at least one action potential (rheobase) was lower, and more action potentials were induced in response to stimulus of 2 × rheobase. In controls, short‐term application of homocysteine and its derivatives increased the frequency of action potentials of the trigeminal nerve and induced Ca2+ transients in neurons, which are associated with the activation of NMDA receptors. At the same time, in rats with hyperhomocysteinemia, we did not observe an increased response of the trigeminal nerve to NMDA. Similarly, the parameters of Ca2+ transients induced by NMDA, homocysteine, and its derivatives were not changed in rats with hyperhomocysteinemia. Acute incubation of the meninges in homocysteine and homocysteinic acid did not change the state of the mast cells, whereas in the model of hyperhomocysteinemia, an increased degranulation of mast cells in the meninges was observed.ConclusionsOur results demonstrated higher excitability of the trigeminal system of rats with hyperhomocysteinemia. Together with our previous finding about the lower threshold of generation of cortical spreading depression in rats with hyperhomocysteinemia, the present data provide evidence of homocysteine as a factor that increases the sensitivity of the peripheral migraine mechanisms, and the control of homocysteine level may be an important strategy for reducing the risk and/or severity of migraine headache attacks.

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Section: Discussionsupporting

confidence: 82%

Section: Introductionsupporting

confidence: 76%

Section: Introductionmentioning

confidence: 99%

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Implications of high homocysteine levels in migraine pain: An experimental study of the excitability of peripheral meningeal afferents in rats with hyperhomocysteinemia

Ermakova,

Shaidullova,

Gafurov

et al. 2024

Headache

Self Cite

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“…Hcy is synthesized in humans from methionine, its precursor, throughout a complex metabolic pathway that involves several essential enzymes and co-factors [ 232 ]. Different degrees of hyperhomocysteinemia are usually present alongside the absence of one or more enzymes and co-factors [ 233 , 234 ].…”

Section: The Potential Circulating Biomarkers Described In Migraine P...mentioning

confidence: 99%

“…Concerning CSF, according to one study [ 246 ], patients with aura have higher CSF Hcy levels than patients without aura. The elevated levels of Hcy enhance migraine symptoms such as increased cortical excitability, mechanical allodynia, photophobia, and anxiety in rats [ 234 , 247 ].…”

Section: The Potential Circulating Biomarkers Described In Migraine P...mentioning

confidence: 99%

Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings

Demartini

Francavilla

Zanaboni

et al. 2023

IJMS

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In recent years, numerous efforts have been made to identify reliable biomarkers useful in migraine diagnosis and progression or associated with the response to a specific treatment. The purpose of this review is to summarize the alleged diagnostic and therapeutic migraine biomarkers found in biofluids and to discuss their role in the pathogenesis of the disease. We included the most informative data from clinical or preclinical studies, with a particular emphasis on calcitonin gene-related peptide (CGRP), cytokines, endocannabinoids, and other biomolecules, the majority of which are related to the inflammatory aspects and mechanisms of migraine, as well as other actors that play a role in the disease. The potential issues affecting biomarker analysis are also discussed, such as how to deal with bias and confounding data. CGRP and other biological factors associated with the trigeminovascular system may offer intriguing and novel precision medicine opportunities, although the biological stability of the samples used, as well as the effects of the confounding role of age, gender, diet, and metabolic factors should be considered.

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Maternal hyperhomocysteinemia increases seizures susceptibility of neonatal rats

et al. 2023

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Hyperhomocysteinemia increases susceptibility to cortical spreading depression associated with photophobia, mechanical allodynia, and anxiety in rats

Cited by 11 publications

References 54 publications

Implications of high homocysteine levels in migraine pain: An experimental study of the excitability of peripheral meningeal afferents in rats with hyperhomocysteinemia

Implications of high homocysteine levels in migraine pain: An experimental study of the excitability of peripheral meningeal afferents in rats with hyperhomocysteinemia

Biomarkers of Migraine: An Integrated Evaluation of Preclinical and Clinical Findings

Maternal hyperhomocysteinemia increases seizures susceptibility of neonatal rats

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