J.J. Rozniecki

Morphological and functional demonstration of rat dura mater mast cell-neuron interactions in vitro and in vivo.

Mast cells derive from a distinct bone marrow precursor and mature in tissues under the influence of stem cell factor, nerve growth factor (NGF) and certain interleukins. Intracranial mast cells first appear in the meninges and are located perivascularly close to neurons. They can be activated by antidromic stimulation of the trigeminal nerve, as well as by acute immobilization stress. Substance P (SP) and corticotropin-releasing hormone (CRH) are particularly potent in stimulating mast cell release of vasoactive, inflammatory and nociceptive molecules. These findings have suggested that mast cells may be involved in neuroinflammatory conditions, such as migraines. In this study, dura mast cells were shown to have characteristics of connective tissue mast cells (CTMC) as they contained histamine, heparin and rat mast cell protease I (RMCP-I). Mast cells were localized close to SP-positive neurons immunocytochemically and mast cell-neuron contacts were also documented using scanning electron microscopy. Dura stimulated by SP and carbachol in situ released histamine. Preincubation of dura with estradiol slightly augmented histamine release by SP, an effect possibly mediated through estrogen receptors identified on dura mast cells. Acute stress by immobilization led to dura mast cell degranulation which was prevented by pretreatment with a neutralizing antibody to CRH or a CRH receptor antagonist. The present results further clarify the biology of intracranial mast cells and support their involvement in the pathophysiology of migraines which are precipitated or worsened by stress.

Estradiol Augments while Tamoxifen Inhibits Rat Mast Cell Secretion

Mast cells have been studied extensively for their involvement in allergic reactions, where they secrete numerous powerful mediators in response to immunoglobulin E and specific antigens. However, they are also triggered by neuropeptides, they have been found in close contact with neurons, and they are activated in diseases such as angioedema, interstitial cystitis and irritable bowel disease, the prevalence of which is much higher in women. When tested on purified rat peritoneal mast cells, 17 beta-estradiol augmented secretion of histamine and serotonin, starting at 1 microM and in a dose-dependent manner, whether stimulated by the mast cell secretagogue compound 48/80 or the neuropeptide substance P. However, 17 beta-estradiol did not augment mast cell secretion stimulated by immunoglobulin E and specific antiserum indicating that immunologic stimulation is under different regulation. Testosterone inhibited secretion induced by compound 48/80. Tamoxifen, an estrogen receptor antagonist used in the treatment of breast cancer, inhibited serotonin and histamine release from purified rat peritoneal mast cells triggered by compound 48/80 or substance P. Tamoxifen also inhibited the increase in intracellular free Ca2+ originating from an influx of extracellular Ca2+ in response to compound 48/80. Moreover, tamoxifen antagonized the synergistic effect of phorbol myristate and the cation ionophore A23187 on mast cell secretion, suggesting that tamoxifens inhibition may be due to regulation of protein kinase C activity. Tamoxifen may, therefore, have a beneficial effect in other neuroimmunoendocrine disorders both through estrogen receptor blockade and inhibition of mast cell secretion.

Synergistic action of estradiol and myelin basic protein on mast cell secretion and brain myelin changes resembling early stages of demyelination

Mast cells are known for their participation in immediate and, more recently, delayed hypersensitivity reactions. They have been found in the meninges and certain brain areas where they are strictly perivascular, in close apposition to neurons, and they are activated by direct nerve stimulation or by neuropeptides. Intracranial mast cells contain many vasoactive substances which can increase the permeability of the blood-brain barrier, proteolytic enzymes which can degrade myelin in vitro, as well as chemotactic molecules which can attract inflammatory molecules in vivo. Connective tissue mast cells, with which intracranial mast cells share many characteristics, contain cytokines which can cause inflammation directly. Multiple sclerosis is a human demyelinating disease of unknown etiology, with a high prevalence in women which results in penetration of blood-borne immune cells within the brain parenchyma and subsequent destruction of myelin. Here, we report that 17 beta-estradiol and myelin basic protein, a major suspected immunogen in multiple sclerosis, had a synergistic action on inducing mast cell secretion. This effect was more pronounced in Lewis rats, which are susceptible to the development of experimental allergic encephalomyelitis, an animal model for multiple sclerosis, than in Sprague-Dawley rats, which are fairly resistant. Moreover, 18 h incubation of purified peritoneal mast cells with homogeneic slices of brain white matter in the presence of 17 beta-estradiol and myelin basic protein resulted in myelin changes resembling early stages of brain demyelination, which were also more evident in Lewis rats than in Sprague-Dawley rats. These results support the notion that mast cells could participate in the pathophysiology of demyelinating diseases.

Definitive characterization of rat hypothalamic mast cells

Mast cells have previously been identified in mammalian brain by histochemistry and histamine fluorescence, particularly in the rat thalamus and hypothalamus. However, the nature of brain mast cells has continued to be questioned, especially because the electron microscopic appearance often shows secretory granule morphology distinct from that of typical connective tissue mast cells. Here we report that mast cells in the rat hypothalamus, identified based on metachromatic staining with Toluidine Blue, fluoresced after staining with berberine sulfate, indicating the presence of heparin. These cells were also positive immunohistochemically for histamine, as well as for rat mast cell protease I, an enzyme characteristically present in rat connective tissue mast cells. In addition, these same cells showed a very strong signal with in situ hybridization for immunoglobulin E binding protein messenger RNA. However, use of antibodies directed towards immunoglobulin E or its binding protein did not label any cells, which may mean either the binding protein is below the level of detection of the techniques used or that it is not expressed except in pathological conditions when the blood-brain barrier becomes permeable. At the ultrastructural level, perivascular mast cells contained numerous, intact, electron-dense granules which were labeled by gold-labeled anti-rat mast cell protease I. These results clearly demonstrate the presence of perivascular mast cells in the rat hypothalamus, where they may participate in homeostatic processes.

Impact of stress and mast cells on brain metastases

Metastases continue to be the chief cause of morbidity and mortality for many tumors, including brain metastases of lung and mammary adenocarcinoma. Stress appears to increase metastases, but the mechanism is not understood. Recent evidence suggests that local inflammation is conducive for cancer growth and a unique immune cell, the mast cell, accumulates in the stroma surrounding tumors and is critically located at the blood-brain-barrier (BBB). Mast cells express receptors for and can be stimulated by corticotropin-releasing hormone (CRH), secreted under stress, to release mediators such as histamine, IL-8, tryptase and vascular endothelial growth factor (VEGF), which disrupt the BBB permitting metastases. Stress and mast cells could serve as new targets for drug development to prevent brain metastases, especially since CRH receptor antagonists and brain mast cell inhibitors have recently been developed.

Mast Cell Activation in Children With Migraine Before and After Training in Self-regulation

Migraine may affect as many as 9% of all schoolchildren and often presents with abdominal symptoms of pain, nausea, and vomiting. Even though the pathophysiology of migraine remains unknown, self‐regulation techniques appear to be more effective in prevention of childhood migraine than conventional pharmacotherapy which is often associated with adverse effects. Mast cells have been implicated in the pathogenesis of migraine in adults, but have not been previously studied in children with migraine.

Hypoglycemia as a trigger for the syndrome of acute bilateral basal ganglia lesions in uremia

The syndrome of acute bilateral basal ganglia lesions is a rarely described complication of uremia occurring typically in the setting of concurrent long-standing diabetes mellitus. Reversible symmetrical lesions located in basal ganglia found on brain magnetic resonance imaging are hallmarks of this syndrome. Clinical presentation includes parkinsonism and/or involuntary movements. The cause of this syndrome is largely unknown. Among the factors that are believed to contribute to its pathogenesis are uremic toxins, metabolic acidosis and diabetic microangiopathy. Here we report a patient with uremia and newly diagnosed diabetes, who developed the syndrome of acute bilateral basal ganglia lesions after an incidence of severe hypoglycemia induced by oral hypoglycemic agents. We consider hypoglycemia as a candidate trigger factor for the syndrome of acute bilateral basal ganglia lesions and highlight the importance of strict glucose control in uremic patients.

Brain metastases of mouse mammary adenocarcinoma is increased by acute stress.

Brain metastases from mammary adenocarcinoma constitute the chief cause of morbidity and mortality. Some evidence suggests that stress may contribute to disease progression and metastases. Here we show that acute restraint stress (30 min) induces statistically significant increase in brain metastases of systemically administered luciferase-tagged 4T1-BR-3P mouse mammary adenocarcinoma cells as evidenced by the total brain-associated photons from 5.6 × 10(7) photons in unstressed controls to 1.7 × 10(8) photons in C57BL/6 (p = 0.0018) and from 7.6 × 10(7) to 2.1 × 10(7) photons in BALB/c (p = 0.004) mice. Acute stress may increase metastases by disrupting the blood-brain-barrier (BBB), through release of corticotropin-releasing-hormone (CRH) activating perivascular brain mast cells.

Anatomical variations of the insular gyri: A morphological study and proposal of unified classification: Anatomical Variations of the Insular Gyri

The locations of gyral landmarks vary among individuals. This can be crucial during local landmark‐based mapping of the human cortex, so the aim of the present study was to establish criteria for classifying the morphological variability of the human insula. The study was conducted on 50 isolated, randomly‐selected adult cadaveric hemispheres, fixed in 10% formalin, and preserved in 70% ethanol (24 right and 26 left hemispheres). A thorough rating system, including bifid form (i.e., divided on top), branching or hypoplasia, was used to analyze the insular gyri. The number of all insular gyri ranged from four to six (mean = 5.16, SD = 0.65). Within the anterior lobule, the number of short gyri ranged from two to four (mean = 3.3, SD = 0.54). The middle short gyrus was the most variable. It was well‐developed in 25 of the 50 cases (50%). Within the posterior lobule there were one or two long insular gyri (mean = 1.88, SD = 0.32). In 48 cases (96%), the anterior long gyrus was well‐developed. A complete lack of the posterior long gyrus was noted in six of the 50 cases (12%). In conclusions, the accessory, the middle short, and the posterior long gyri of the insula were the most variable. The middle short gyrus was well‐developed in only half of the cases. The number of insular gyri found in horizontal sections of the brain does not necessarily indicate their true number. Clin. Anat. 31:347–356, 2018.