Morphological signs of neurogenic inflammation in the heart of rats during aging

С помощью гистологических методов окраски толуидиновым синим, гематоксилином и эозином и иммуногистохимических реакций на белок PGP 9.5, тирозингидроксилазу (ТГ), белок Iba-1, изучены клеточные изменения в разных отделах сердца крыс линии Wistar в возрасте 18- 23 мес. В соединительной ткани основания сердца обнаружены очаговые воспалительные инфильтраты, внутри которых выявлены PGP 9.5 и ТГ сплетения, состоящие из парасимпатических и симпатических нервных волокон. В области клапанного аппарата, на границе фиброзного кольца и миокарда правого предсердия, обнаружены патологические изменения нервных структур - дегенерация нервных пучков и зернистый распад варикозных аксонов терминального сплетения. Установлены тесные взаимоотношения аксонов терминальной нервной сети с клетками воспалительных инфильтратов и кровеносными сосудами. Определены закономерности встречаемости в различных отделах миокарда у старых животных нейроклеточных воспалительных комплексов, состоящих из нервных волокон, кровеносных капилляров и клеток-участников местного воспалительного процесса (тучных клеток, макрофагов, фибробластов, плазмоцитов). Установлен хронический характер нейрогенного воспаления в сердце при старении. Using histological methods of staining with toluidine blue, hematoxylin-eosin and immunohistochemical reactions for the PGP 9,5 protein, tyrosine hydroxylase (TH), Iba-1 protein, cellular changes in different parts of the heart of Wistar rats at the age of 18-23 months were studied. In the connective tissue of the heart base, focal inflammatory infiltrates were found, near which PGP 9.5 and TH plexuses, consisting of parasympathetic and sympathetic nerve fibers, were detected. In the area of the valvular heart apparatus, at the border of the anneau fibreux and the myocardium of the right atrium, pathological changes in nerve structures were found: degeneration of nerve fibers and granular destruction varicose axons of the terminal plexus. A close relationship has been established between axons of the terminal nervous network and cells of inflammatory infiltrates and blood capillaries. The features of the localization of neurocellular inflammatory complexes consisting of nerve fibers, blood capillaries and cells participating in the local inflammatory process (mast cells, histiocytes, monocytes, fibroblasts, plasma cells) in various parts of the myocardium in old animals are described. The chronic nature of neurogenic inflammation in the heart during aging has been established.

Topical Treatment of Colquhounia Root Relieves Skin Inflammation and Itch in Imiquimod-Induced Psoriasiform Dermatitis in Mice

Itch is one of the major clinical manifestations of psoriasis, which is closely related with neurogenic inflammation and difficult to control. Colquhounia Root (CR) is a Chinese herb exhibiting broad bioactivities on anti-inflammation. This study was designed to explore the antipsoriatic and anti-itch potential of CR and its underlying mechanisms. Mice in a model of imiquimod-induced psoriasiform dermatitis were treated topically with CR for 7 days, and the severity of skin lesions and itch was significantly ameliorated. CR reduced the inflammatory cell infiltration, as well as mast cells in skins. Particularly, the expression of inflammatory cytokines and chemokine including Il17a, Il22, and Ccl20 and itch-related molecules such as SP, CGRP, and NGF in lesions were decreased in diseased mice upon application with CR. The normal human epidermal keratinocytes were stimulated with the M5 cytokine cocktail, the mixture of IL-17A, IL-22, Oncostatin M, IL-1α, and TNF-α, and cell viability and mRNA expression levels of inflammatory factors and itch-related molecules were measured after being treated with CR. We found that CR inhibited both cell hyperproliferation and overexpression of inflammatory cytokines and itch-related molecules in vitro. Altogether, we conclude that CR relieves psoriatic lesions and itch via controlling immunological and neurogenic inflammation.

Neuroimmune mechanisms of pruritus in atopic dermatitis

Atopic dermatitis is a chronic hereditary recurrent skin disease. One of the most pronounced symptoms of this dermatosis is itchy skin. Pruritus accompanies atopic dermatitis in more than 80% of cases. This review presents modern data on the mechanisms of pruritus formation in atopic dermatitis. The issues of etiological factors, neuroimmune interactions, peculiarities of skin dysfunction, as well as the role of stress are considered. The relevance of studying the topic is due to the high prevalence of atopic dermatitis among the population, a decrease in the quality of life and the lack of effective therapy. Analysis of the literature indicates the need for a comprehensive assessment of the pathogenetic mechanisms of the development of pruritus in atopic dermatitis. A more in-depth study of the mechanisms of neurogenic inflammation in atopic dermatitis will contribute to the development of new methods of diagnosis and treatment.

Neurogenic Inflammation: The Participant in Migraine and Recent Advancements in Translational Research

Migraine is a primary headache disorder characterized by a unilateral, throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors, and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses, including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This narrative review discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

Polymorphism of methylenetetrahydrofolate reductase (MTHFR) folate metabolism gene and hyperhomocysteinemia in migraine

В обзоре обсуждается роль полиморфизма гена фолатного обмена метилентетрагидрофолат-редуктазы (MTHFR), ответственного за развитие гипергомоцистеинемии в патогенезе мигрени. Изложены общие данные о полиморфизме С677 гена фолатного цикла и метаболизме гомоцистеина. Представлен патогенетический механизм развития мигрени, связанный с провоспалительными, прокоагулянтными свойствами гомоцистеина, активацией процессов окислительного стресса, эндотелиальной дисфункцией и нейрогенным воспалением при повышении концентрации этой аминокислоты. Отражены перспективы и социальная значимость имплементации данных генетических исследований в клиническую практику, их роль в прогнозировании течения мигрени и оценке риска развития осложнений, а также коррекции фармакотерапевтических подходов. Методика. Для поиска данных в базах MEDLINE, SCOPUS и Web of Science использованы поисковые запросы: МТHFR, мигрень, патофизиология, гипергомоцистеинемия, таргетная терапия. The review discusses the role of polymorphism of the methylenetetrahydrofolate reductase (MTHFR) folate metabolism gene responsible for hyperhomocysteinemia in the pathogenesis of migraine. Data on the polymorphism of the folate cycle gene C677 and homocysteine metabolism are presented. The pathogenetic mechanism of migraine associated with proinflammatory, procoagulant properties of homocysteine and with the activation of oxidative stress, endothelial dysfunction, and neurogenic inflammation related with increased concentrations of homocysteine is described. Prospects and social significance of implementing data of genetic research into clinical practice are discussed. Included is the role of genetic research in predicting the course and complications of migraine, in assessment of risk for complications, and in pharmacotherapeutic approaches to migraine treatment. Methods. MEDLINE, SCOPUS and Web of Science databases were used to search for data: MTHFR, migraine, pathophysiology, hyperhomocysteinemia, targeted therapy

Neurogenic Inflammation in the Context of Endometriosis—What Do We Know?

Endometriosis (EM) is an estrogen-dependent disease characterized by the presence of epithelial, stromal, and smooth muscle cells outside the uterine cavity. It is a chronic and debilitating condition affecting ~10% of women. EM is characterized by infertility and pain, such as dysmenorrhea, chronic pelvic pain, dyspareunia, dysuria, and dyschezia. Although EM was first described in 1860, its aetiology and pathogenesis remain uncertain. Recent evidence demonstrates that the peripheral nervous system plays an important role in the pathophysiology of this disease. Sensory nerves, which surround and innervate endometriotic lesions, not only drive the chronic and debilitating pain associated with EM but also contribute to a growth phenotype by secreting neurotrophic factors and interacting with surrounding immune cells. Here we review the role that peripheral nerves play in driving and maintaining endometriotic lesions. A better understanding of the role of this system, as well as its interactions with immune cells, will unearth novel disease-relevant pathways and targets, providing new therapeutics and better-tailored treatment options.

Neurogenic Inflammation: One of the Participants of Migraine and the Contribution of Translational Research

Migraine is a primary headache disorder characterized by unilateral throbbing, pulsing headache, which lasts for hours to days, and the pain can interfere with daily activities. It exhibits various symptoms, such as nausea, vomiting, sensitivity to light, sound, and odors and physical activity consistently contributes to worsening pain. Despite the intensive research, little is still known about the pathomechanism of migraine. It is widely accepted that migraine involves activation and sensitization of the trigeminovascular system. It leads to the release of several pro-inflammatory neuropeptides and neurotransmitters and causes a cascade of inflammatory tissue responses including vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Convincing evidence obtained in rodent models suggests that neurogenic inflammation is assumed to contribute to the development of a migraine attack. Chemical stimulation of the dura mater triggers activation and sensitization of the trigeminal system and causes numerous molecular and behavioral changes; therefore, this is a relevant animal model of acute migraine. This review article discusses the emerging evidence supporting the involvement of neurogenic inflammation and neuropeptides in the pathophysiology of migraine, presenting the most recent advances in preclinical research and the novel therapeutic approaches to the disease.

ROLE OF SUBSTANCE P IN PANCREATITIS AND ASSOCIATED DISEASES

Substance P (SP) is a neuropeptide that has its place in the tachykinin family and helps in the transmission of neurogenic signals. SP is also a neuromodulator that plays a crucial part in pain during inflammatory processes. It is produced by the capsaicin-sensitive unmyelinated C fibers sensory neurons by the central and peripheral nervous systems. Substance P is known as a critical primary responder to most of the extreme stimuli, i.e., specifically those with the ability to destabilize the biological integrity. Hence, SP can be considered as an instantaneous system for defense, stress, healing, etc. SP is known to perform a vital role in neurogenic inflammation and the pathophysiology of acute pancreatitis. Out of these, neurogenic inflammation is responsible for acute interstitial pancreatitis as a result of oedema. SP binds itself to the G-protein coupled neurokinin-1 receptor and causes plasma leakage, cell proliferation, and invasion resulting in pancreatic cancer. SP along with comparable neuropeptides seems to be crucial targets with the capability of satisfying several unfulfilled medical requisites. This review article mainly focuses on compiling the available evidence to show that SP could be a novel therapeutic target for pancreatic diseases, and more exploration into the SP signaling pathways is the call of the hour.