Hydrogen sulfide (H₂S) is endogenously produced from sulfur containing amino acids, including homocysteine and exerts neuroprotective effects. An increase of homocysteine during pregnancy impairs fetal growth and development of the offspring due to severe oxidative stress. We analyzed the effects of the H₂S donor—sodium hydrosulfide (NaHS) administered to female rats with hyperhomocysteinemia (hHcy) on behavioral impairments and levels of oxidative stress of their offspring. Rats born from females fed with control or high methionine diet, with or without H₂S donor injections were investigated. Rats with maternal hHcy exhibit increased levels of total locomotor activity and anxiety, decreased muscle endurance and motor coordination, abnormalities of fine motor control, as well as reduced spatial memory and learning. Oxidative stress in brain tissues measured by activity of glutathione peroxidases and the level of malondialdehyde was higher in rats with maternal hHcy. Concentrations of H₂S and the activity and expression of the H₂S generating enzyme—cystathionine-beta synthase—were lower compared to the control group. Administration of the H₂S donor to females with hHcy during pregnancy prevented behavioral alterations and oxidative stress of their offspring. The acquisition of behavioral together with biochemical studies will add to our knowledge about homocysteine neurotoxicity and proposes H₂S as a potential agent for therapy of hHcy associated disorders.

Homocysteine is a sulfur-containing endogenous amino acid leading to neurotoxic effects at high concentrations. Population studies suggest an association between plasma homocysteine levels and the risk of migraine headaches. The aim of this study was to analyze the sensitivity of rats with prenatal hyperhomocysteinemia (hHCY) in respect of the development of behavioral correlates of headache and spreading cortical depolarization (CSD) in a migraine model induced by the administration of the nitric oxide (NO) donor nitroglycerin. Animals with hHCY were characterized by migraine-related symptoms such as mechanical hyperalgesia, high-level anxiety, photophobia, as well as an enhanced level of neuronal activity in the somatosensory cortex along with a lower threshold of CSD generation. Likewise, acute or chronic intermittent administration of nitroglycerin also induced the development of mechanical allodynia, photophobia and anxiety in control groups. However, these symptoms were more pronounced in rats with hHCY. Unlike hHCY, nitroglycerin administration did not affect the threshold of CSD generation, but like hHCY, increased the background neuronal activity in layers 2/3 and 4 of the cerebral cortex. The latter was more pronounced in animals with hHCY. Thus, the migraine profile associated with hHCY can be further exaggerated in conditions with enhanced levels of migraine triggering the gaseous transmitter NO. Our data are consistent with the view that high levels of plasma homocysteine can act as a risk factor for the development of migraine.

Nitric oxide is one of the endogenous molecules that play a key role in migraine. However, the interaction between NO and the main players in the nociceptive activity of the meningeal trigeminal afferents—TRPV1 and P2X3 receptors—remains unstudied. In the current project, the effects of acute and chronic NO administration on the activity of TRPV1 and P2X3 receptors in the peripheral afferents were studied using electrophysiological recording of action potentials of the trigeminal nerve in the rat hemiskull preparations. The data obtained indicate that exogenous and endogenous NO increased the activity of the trigeminal nerve independent on the inhibition of the TRPV1 and P2X3 receptors. The activity of the trigeminal nerve triggered by ATP changed neither in acute incubation in the NO donor—sodium nitroprusside (SNP) nor in the chronic nitroglycerine (NG)-induced migraine model. Moreover, the chronic NG administration did not increase in the number of degranulated mast cells in the rat meninges. At the same time, the capsaicin-induced activity of the trigeminal nerve was higher with chronic NO administration or after acute NO application, and these effects were prevented by N-ethylmaleimide. In conclusion, we suggested that NO positively modulates the activity of TRPV1 receptors by S-nitrosylation, which may contribute to the pro-nociceptive action of NO and underlie the sensitization of meningeal afferents in chronic migraine.

Migraine is characterized by severe pain and somatic symptoms like allodynia and photophobia, driven by neuroinflammation that sensitizes the trigeminal vascular system (TVS). This study investigated how neuroinflammation induced by systemic lipopolysaccharide (LPS) affects migraine-related nociceptive signaling. Using a chronic migraine model in rats with nitroglycerin (NTG), we compared prenatal and acute postnatal LPS administration. Rats with prenatal LPS exhibited lower mechanical thresholds and enhanced allodynia and photophobia after NTG. Acute LPS also increased allodynia, but not photophobia. Both LPS groups showed increased mast cell degranulation in the dura mater. Plasma CGRP after NTG administration was elevated in the acute LPS group. Electrophysiology revealed enhanced trigeminal afferent responses to serotonin in both acutely and prenatally LPS-treated rats. Calcium imaging demonstrated increased neuronal responses to serotonin and capsaicin, suggesting an upregulation of serotonin and TRPV1 receptors. Our findings show that LPS-induced neuroinflammation, whether prenatal or acute, promotes sensitization of peripheral and central nociceptive pathways, involving serotoninergic mechanisms.

Migraine is a common chronic neurovascular disease accompanied by unilateral headache, photophobia, allodynia, and autonomic disturbances. About 1/3 of migraine patients have a transient neurological deficit that precedes or overlaps the headache phase, called aura. The main physiological mechanism underlying aura is thought to be cortical spreading depression (CSD), a wave of massive depolarization passing through neurons and glial cells of the cortex. The aim of the present study was to develop the model of chronic migraine with aura in rats and analyze the main behavioral and biochemical correlates of migraine. Male rats were subjected to surgery with the installation of a mini bath providing access to the dura mater above the somatosensory cortex. KCl was applied on the dura mater to induce CSD every other day for 9 days. Sham rats obtained NaCl application according to the same protocol. Behavioral tests were performed before and after application of KCl or NaCl. Repeated KCl application decreased locomotor and exploratory activity, as well as cognitive ability, increased anxiety and induced photophobia and allodynia in rats. Besides, rats with a model of chronic migraine with aura showed increased plasma calcitonin gene-related peptide (CGRP) concentration and decreased glutathione peroxidase activity in brain tissue. In conclusion, the proposed model can be used to study the behavioral correlates of chronic migraine with aura in experimental animals, which will allow us to investigate the underlying mechanisms and develop treatment approaches.

В нашей работе исследовали влияние умеренного непредсказуемого хронического стресса у самок крыс в течение двух недель до наступления и двух недель во время беременности на развитие потомства в период от рождения до 3 месяцев жизни. Воздействие прегестационного стресса приводило к повышению тревожности самок уже к началу беременности, которая сохранялась и в первую неделю лактации. Пренатальный стресс приводил к уменьшению размера помета, снижению массы тела детенышей, отставанию в физическом развитии и созревании некоторых сенсомоторных рефлексов в первые две недели после рождения. Сниженная в первые две недели двигательная активность восстанавливалась к 26-му дню жизни (Р), изменений мышечной силы и двигательной координации у крыс не выявили. Во всех анализируемых возрастах (Р16, 26, 80) наблюдали снижение исследовательской активности и повышение уровня тревожности. Нарушение процессов обучения, пространственной и непространственной памяти было показано в тесте водный лабиринт Морриса (Р21–22) и тесте на распознавание нового объекта (Р72–90). Таким образом, полученные нами результаты свидетельствуют о том, что умеренный стресс самок до и во время беременности приводит не только к нарушениям физического и неврологического развития в раннем онтогенезе, но также и повышению уровня тревожности и когнитивным дисфункциям, сохраняющимся во взрослом периоде жизни потомства.