IL-17 crosses the blood–brain barrier to trigger neuroinflammation: a novel mechanism in nitroglycerin-induced chronic migraine

Background Chronic migraine places a disabling burden on patients, which is extensively modeled by the nitroglycerin (NTG)-treated animal model. Although the NF-κB pathway is involved in an increase in CGRP levels and activation of the trigeminal system in the NTG model, the relationship between NTG and neuroinflammation remains unclear. This study aimed to optimize a chronic NTG rat model with hyperalgesia and the ethological capacity for estimating migraine therapies and to further explore the underlying mechanism of NTG-induced migraine. Methods Rats were administered different doses of NTG s.c. daily or every 2 d; 30 min and 2 h later, the mechanical threshold was tested. After 9 d, the rats were injected with EB or Cy5.5 for the permeability assay. The other animals were sacrificed, and then, brainstem and caudal trigeminal ganglion were removed to test CGRP, c-Fos and NOS activity; Cytokines levels in the tissue and serum were measured by ELISA; and NF-κB pathway and blood–brain barrier (BBB)-related indicators were analyzed using western blotting. Immunohistochemistry was performed to observe microglial polarization and IL-17A+ T cell migration in the medulla oblongata. Results NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition, resulting in progressive hyperalgesia and migraine behavior. TNC neuroinflammation with increases in cytokines, CGRP and c-Fos and activation of the NF-κB pathway was observed, and these changes were alleviated by ibuprofen. Furthermore, NTG administration increased BBB permeability by altering the levels functional proteins (RAGE, LRP1, AQP4 and MFSD2A) and structural proteins (ZO-1, Occludin and VE-cadherin-2) to increase peripheral IL-17A permeation into the medulla oblongata, activating microglia and neuroinflammation, and eventually causing hyperalgesia and migraine attack. Conclusions This study confirmed that NTG (10 mg/kg, s.c., every 2 d for a total of 5 injections) was the optimal condition to provoke migraine, resulting in mechanical hyperalgesia and observable migraine-like behavior. Furthermore, IL-17A crossed the blood–brain barrier into the medulla oblongata, triggering TNC activation through microglia-mediated neuroinflammation. This process was a novel mechanism in NTG-induced chronic migraine, suggesting that IL-17A might be a novel target in the treatment of migraine.

Lateral Medullary Infarction with Contralateral Segmental Dysesthesia and Ipsilateral Headache: A Case Report

Introduction: The medulla oblongata is the lowest segment of the brain stem, located adjacent to the spinal cord, with a complex anatomical structure. Thus, a small injury to the medulla oblongata can show complex clinical manifestations. Case Presentation: A patient experienced dysesthesia, which manifested as numbness in her right lower limb and decreased temperature sense, and dizziness 20 days before admission. The numbness worsened 1 week before admission, reaching the right thoracic (T) 12 dermatomes. Her thermoception below the T12 dermatomes decreased, and the degree of dizziness increased, accompanied by nausea and vomiting. Magnetic resonance imaging (MRI) of the neck, chest, and abdomen performed at a local hospital showed no abnormalities. MRI of the brain was performed after admission. One week after admission, she experienced a severe headache in the upper left periorbital area. The numbness extended to T4, and thermoception decreased below T4. Diagnosis: Lateral medullary infarction. Interventions: Anti-platelet aggregation and mitochondrial nutritional therapies were performed along with treatments for improving circulation and establishing collateral circulation. Outcomes: The intensity of limb numbness decreased, and the symptoms of headache and dizziness resolved. Conclusion: Lesions leading to segmental sensory disorders can occur in the medulla oblongata. Ipsilateral headaches with contralateral segmental paresthesia can be a specific sign of lateral medullary infarction.

Prof. G. Guillain. Neurologes neurolog'iques. 3-я серия. Стр. 453, рис. 119 Masson etemp-edema. Ц. фр. 70.

In this volume, prof. Guillain collected the last works of his supervisor. Salpetriera clinics; he divided them into 7 sections: cerebral tumors, pathology of the brain, pathology of the legs of the pons, the medulla oblongata, the cerebellum, pathology of the spinal cord, pathology of the cranial and spinal nerves, muscle atrophy and other, and then a chapter on the history of neurology, dedicated to the works of the famous Boulogne neuropathologist Duchenne.

Neurophysiological justification of the G. F. Lang hypothesis about the occurrence of essential hypertension

This article is an analysis of modern data on the morphological, functional and neurochemical organization of the central mechanisms of blood circulation regulation, the violation of which can cause the development of essential hypertension. The data indicating the validity of the hypothesis of G.F. Lang that prolonged emotional stress leads to a violation of the neuronal activity of the hypothalamus structures are presented. The article describes the morphological connections of the hypothalamus with the neurons of the ventrolateral region of the medulla oblongata and the structures of the spinal cord that provide neurogenic vascular tone. The evidence of convergence of axons of neurons of the paraventricular nucleus of the hypothalamus on the preganglionic neurons of the spinal cord is presented. Neurochemical processes in the vasomotor center of the medulla oblongata are considered, morphological changes of preganglionic sympathetic neurons in experimental arterial hypertension are indicated.

Role of indole derivative SS-68 in increasing the frequency range of cardiac rhythm control (reflex stimulation of the sinoatrial node)

Introduction: Cardiac pacing is indicated for sick sinus syndrome. It is performed with a pacemaker via electrodes implanted in the heart. This technique has several disadvantages. The search for alternative methods of cardiac pacing is underway. One of them is control of heart rhythm through stimulation of the tragus. Objective: To perform the reflex stimulation of the sinoatrial node and to study the influence of the SS-68 substance on it. Materials and methods: Two electrodes were fixed in the reflexogenic zone of rabbits’ auricles, volleys of electrical impulses from an electrical stimulator were applied to the electrodes, and the synchronization range of volley frequency and cardiac contractions was recorded. This range was re-recorded again after injecting the SS-68 substance (2-phenyl-1-(3-pyrrolidine-1-cyclopropyl)-1H-indole hydrochloride) intravenously at a dose of 50 µg/kg. In other experiments on frogs in a high-frequency electromagnetic field, the process of excitation of the area of the medulla oblongata associated with the heart rhythm was visualized. After the application of SS-68 (50 μM) to the surface of this zone, the process of its excitation was recorded. Results and discussion: Stimulation of the auricular reflexogenic zone of rabbits produced a synchronization of volley frequency and heart rate in the range from 173.5 ± 2.0 to 214.0 ± 1.8 per minute. SS-68 extended this range from 168.2 ± 1.9 to 219.4 ± 1.5 per minute. In the frog’s medulla oblongata, an area synchronous to the heart rhythm glowed in the high-frequency electromagnetic field. SS-68 increased the area of glow by 131.0%. Conclusion: The substance SS-68 increases the frequency range of heart rhythm control by activating reflex stimulation of the sinoatrial node. The main point of application of SS-68 is the medulla oblongata. Glow in the high-frequency electromagnetic field reflects the process of neuron excitation. The increase in the glow zone under the influence of SS-68 indicates synchronously excited neurons, which leads to the assimilation of the central heart rhythm generation by the sinoatrial node.