UNLABELLED Neurological complications after mild head injury can include vasogenic edema and/or subsequent development of epilepsy, conditions associated with elevated histamine. In the present study we assessed the potential of mast cells located in the dura mater to contribute to elevated cortical histamine and breakdown of the blood-brain barrier after minor head injury, modeled by either a parietal craniectomy or producing a groove in (scoring) the parietal bone surface to model a grazing head injury. We measured the following effects at 5-20 min after a unilateral parietal craniectomy (rats) or unilateral scoring of the parietal bone (mice): (1) mast cell integrity in subjacent dura mater; (2) subjacent vs. contralateral histamine in dura mater and cerebral cortex; (3) vascular permeability of cerebral cortical blood vessels subjacent to the injury, and; (4) the effects of an H(2)-receptor antagonist on cerebral cortical vascular permeability. RESULTS Dural mast cells subjacent to the craniectomy became activated (degranulated) concomitant with (1) decreased histamine in dura mater subjacent to the craniectomy; (2) increased histamine in the subjacent cerebral cortex; and (3) extravasation of Evans blue-albumin which stained the subjacent cerebral cortex, indicating a localized breakdown of the blood-brain barrier. Similar results were observed in mice after scoring the parietal bone surface and, additionally, pretreatment with the histamine H(2)-receptor antagonist zolantadine (1 h before injury) dose-dependently inhibited extravasation of Evans blue-albumin. We conclude that even a minor grazing injury of the skull, in the absence of penetrating brain injury or concussion, can activate dural mast cells and elevate cortical histamine, a novel mechanism with potential contributions to neurotraumatic complications arising from a relatively minor or grazing head wound.

Mast cells cultured from bone marrow of BALB/c and SJL/J inbred strains of mice using IL-3 showed distinct patterns of growth and marked differences in their content of TNF-alpha and histamine. Mast cells derived from SJL/J mice grew and matured at a faster rate than those from BALB/c bone marrow. SJL/J mast cells were found to contain more than twice the amount of histamine and TNF-alpha in their granules than BALB/c-derived cells. In addition, when triggered by anti-DNP IgE antibody and specific antigen (DNP-albumin), mast cells derived from SJL/J mice released more histamine and TNF-alpha than mast cells derived from BALB/c mice. These results confirm previous observations regarding a genetic basis for mouse strain differences in mast cell growth rates, and extend previous observations to document differences in mast cell mediator contents. These results are consistent with the concept that genetically controlled differences in the numbers of central nervous system (CNS)-associated mast cells and their vasogenic mediators may play an important role in modulating oedema and inflammation in CNS trauma and diseases in mice.

Mast cells and their potent chemical mediators are known to initiate and modulate a number of important inflammatory cascades. With respect to the central nervous system, the role of mast cells as participants in the promotion and resolution of inflammation has been widely underestimated. Mast cell-derived histamine, serotonin, kallikreins, and tumor necrosis factor-alpha (TNF-alpha) can enhance microvascular permeability, leukocyte rolling, adhesion, and extravasation of inflammatory cells into the brain and spinal cord. Mast cell mediators may play an important role in autoimmune encephalomyelitis and multiple sclerosis by promoting the entry of autoreactive T cells and the recruitment of nonspecific monocytes across the blood:brain barrier.

CNS Drug ReviewsVolume 1, Issue 1 p. 27-49 CI-1002: A Combined Acetylcholinesterase Inhibitor and Muscarinic Antagonist 1 Mark R. Emmerling, Corresponding Author Mark R. Emmerling Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USAAddress correspondence and reprint requests to: Dr. M.R. Emmerling, at Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., 2800 Plymouth Road, Ann Arbor, MI 48106, USA. Fax: (313)996–1193.Search for more papers by this authorVlad E. Gregor, Vlad E. Gregor Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorMichael J. Callahan, Michael J. Callahan Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorRoy D. Schwarz, Roy D. Schwarz Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorJeff D. Scholten, Jeff D. Scholten Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorEdward L. Orr, Edward L. Orr Department of Anatomy, University of Texas Health Science Center, Fort Worth, TX, USA.Search for more papers by this authorThomas Pugsley, Thomas Pugsley Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorCatherine J. Moore, Catherine J. Moore Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorCharlotte Raby, Charlotte Raby Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorSharie L. Myers, Sharie L. Myers Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorRobert E. Davis, Robert E. Davis Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorJuan Jaen, Juan Jaen Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this author Mark R. Emmerling, Corresponding Author Mark R. Emmerling Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USAAddress correspondence and reprint requests to: Dr. M.R. Emmerling, at Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., 2800 Plymouth Road, Ann Arbor, MI 48106, USA. Fax: (313)996–1193.Search for more papers by this authorVlad E. Gregor, Vlad E. Gregor Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorMichael J. Callahan, Michael J. Callahan Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorRoy D. Schwarz, Roy D. Schwarz Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorJeff D. Scholten, Jeff D. Scholten Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorEdward L. Orr, Edward L. Orr Department of Anatomy, University of Texas Health Science Center, Fort Worth, TX, USA.Search for more papers by this authorThomas Pugsley, Thomas Pugsley Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorCatherine J. Moore, Catherine J. Moore Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorCharlotte Raby, Charlotte Raby Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorSharie L. Myers, Sharie L. Myers Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorRobert E. Davis, Robert E. Davis Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this authorJuan Jaen, Juan Jaen Parke-Davis Pharmaceutical Research Division, Division of Warner Lambert Co., Ann Arbor, MI USASearch for more papers by this author First published: March 1995 https://doi.org/10.1111/j.1527-3458.1995.tb00275.xCitations: 2 1 Portions of this manuscript appeared in an earlier publication (see ref. 19) and are reprinted with permission from the publisher. AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume1, Issue1March 1995Pages 27-49 RelatedInformation

Regional changes in percent water content, a measure of regional levels of edema, were determined in female Lewis rats during key stages of recurrent experimental autoimmune encephalomyelitis (rEAE). The changes in percent water content of the spinal cord and brainstem closely paralleled the clinical and, to a lesser extent, histological course of rEAE (increasing during exacerbations and decreasing during remissions), whereas the percent water content of the forebrain, thalamus/midbrain, hypothalamus, and cerebellum remained constant and equal to control levels at all stages of the disease process. These results suggest that edema formation and resolution in the brainstem and spinal cord may be significant determinants of the transient and recurrent course of neurological dysfunction exhibited by rats with rEAE.

The actions of histamine on pial venule leaky site formation were measured intravitally in two inbred strains of mice (BALB/c and SJL/J). Pial venules were visualized using a cranial window microscopy technique, and microvascular leaky site formation was assessed visually using a fluorescein-dextran indicator. SJL/J mice were found to be sensitive to histamine-induced leakage, whereas the BALB/c strain was refractory. Exposure to pertussis toxin enhanced the sensitivity to histamine in the SJL/J strain, but little effect was observed for BALB/c mice. However, the employment of a polymerase chain reaction (PCR) technique for the detection of mRNA for histamine H1 receptor identified receptor-specific message in isolated cerebrovascular endothelium from both strains of mice. The lack of pial responsiveness in the BALB/c mice remains unexplained. Mast cells in the dura mater were found to be more numerous in SJL/J mice than in BALB/c mice. This observation supports previous observations of strain-specific differences in CNS inflammation. The results support the concept that genetically controlled differences in vascular sensitivity and localization of CNS-associated mast cells may play important roles in the generation of vasogenic edema and inflammation in CNS trauma and disease.

Choroidal mast cells have been implicated in experimental autoimmune uveitis (EAU), an ocular inflammatory disease induced by S-antigen. Our data confirm that choroidal mast cell numbers decrease with clinical onset of S-antigen-induced EAU in Lewis rats, and establish that the decrease is statistically significant. In addition, we find that the numbers of limbal mast cells also decrease during S-antigen-induced EAU, and that this decrease occurs earlier in the course of the disease than that observed for choroidal mast cells. Activation and degranulation of mast cells, as evidenced by decreases in mast cell number, result in the synthesis and/or release of large quantities of mast cell mediators, such as histamine. Histamine levels in EAU were found to change significantly, decreasing in the anterior portion of the eye and increasing in the choroid and retina, in concert with changes in mast cell number over the course of EAU. Mast cell mediators may actively contribute to the pathogenesis of EAU through direct enhancement of the inflammation, by stimulation of other elements of the immune system, and/or through facilitation of the blood-retinal barrier breakdown that occurs in EAU. Overall, these results add to the evidence for a mast cell role in EAU, and, in addition, show that the mast cell involvement in EAU includes the mast cells of the limbus.

Experimental autoimmune enchephalomyelltis (EAE) is a disease which can be induced in Lewis rats by exposure of the animal to a source of myelin in the presence of adjuvant. Similar symptoms and histopathology are observed In people with multiple sclerosis (MS) leading to the widespread use ofEAEas an animal model forMS (1). Induction ofEAEin the male Lewis rat results In a monophasic disease characterized by a single severe occurrence of symptoms followed by spontaneous recovery. Female Lewis rats when exposed to identical stimuli will develop a recurrent form of the disease (rEAE) characterized by a temporally consistent, spontaneous secondary occurrence of clinical symptoms(2), which more closely mimics humanMS.The goal of this preliminary study was to characterize the disease process in female Lewis rats (rEAE) using both light and transmission electron microscopy (TEM). Samples of lumbrosacral spinal cord were chosen for Initial examination. This tissue was sampled at four stages of the disease process, namely: in the primary occurrence phase (Peak 1, Day 12), the first recovery phase (Day 18), the secondary occurrence (Peak 2, Day 24) and the second recovery phase (Day 31) (seeFigure 1). Lumbrosacral spinal cord tissue from non-sensitized female Lewis rats, were used as control tissue.

The appearance of increased levels of histamine in the central nervous system (CNS) concomitant with the development of clinically significant acute experimental autoimmune encephalomyelitis (EAE) in male Lewis rats suggests that CNS-associated mast cells may mediate acute EAE in Lewis rats. We now report that, compared to controls, rats with acute EAE exhibit fewer detectable mast cells in their dura mater and velum interpositum. In addition, intracisternal, but not intraperitoneal administration of Compound 48/80 just prior to the appearance of clinical signs of acute or recurrent EAE in male and female rats, respectively, significantly attenuates the clinical severity of both forms of EAE. These results further support the hypothesis that CNS-associated, but not peripheral mast cells are mediators or modulators of acute and recurrent EAE in Lewis rats.

Abstract: Acute experimental autoimmune encephalomyelitis (EAE) was induced in Lewis rats by inoculation with guinea pig spinal cord homogenate emulsified with Mycobacterium tuberculosis‐enriched complete Freund's adjuvant (CFA). Control rats were inoculated with CFA alone. Control and EAE rats were killed on days 7,9, 11, and 13 postinoculation, and regional brain and spinal cord levels of histamine were determined. No regional differences in histamine content between control and EAE rats were seen on day 7 or 9 post‐inoculation. However, depending on the region, EAE rats exhibited significantly higher levels of histamine in their CNS on day 11 or 13 postinoculation or on both. Thus, regionally and temporally specific increases in brain and spinal cord levels of histamine develop concomitant with or just after the appearance (on day 10 postinoculation) of clinical signs of acute EAE, a finding suggesting that histamine may be involved in the development or expression of acute EAE in Lewis rats.

Although mast cells have been described in or near certain areas of the central and peripheral nervous systems, the present investigation demonstrates that nervous‐system‐associated mast cells in the mouse are strategically located along the vasculature that supply or drain these tissues. Of particular interest are the mast cells present in the velum interpositum of the transverse fissure. These mast cells are distributed along blood vessels that perfuse or drain the thalmus, hippocampal formation, corpus striatum, corpora quadrigemini, and the choroid plexi of the lateral ventricles. Such a distribution suggests that mast cells and their vasoactive products (e.g., histamine, serotonin, leucotrienes) may be involved in regulating the regional permeability of the vessels supplying or draining these important brain regions. In addition, numerous periganglionic mast cells were found to be distributed in and around vessels of the dorsal root ganglia and spinal roots. Consequently, periganglionic mast cells may control the permeability of the blood vessels perfusing or draining the dorsal root ganglia and spinal roots and thereby control the ability of immune components to access these tissues, the spinal cord, and the adjacent subarachnoid space. Thus, nervous‐system‐associated mast cells may serve as cellular gatekeepers of interactions between the immune and nervous systems.

Unilateral cryogenic lesions of the brain were produced in mice by applying the face of the brass rod cooled in liquid nitrogen to the exposed parietal bone. As a result of the cryogenic lesion, the mast cells in the dura mater underlying the parietal bone were disrupted. This disruption of dural mast cells was accompanied by a significant increase in the histamine content within the cryogenically injured cerebral cortex. However, when similar lesions were produced in mice which are deficient or lacking in mast cells, this increase in cerebral cortical histamine did not occur. Thus, the cryolesion-induced elevation of cerebral cortical histamine apparently depends on the release of histamine from mast cells located near the injured cerebral cortex. The significance and role(s) of the lesion-induced elevation of this potent biogenic amine and putative neurotransmitter is presently unknown, but may involve alteration of the blood-brain barrier, vasomotor activity of the cerebrovasculature and/or other sequelae to brain injury.

This study examines the changes in uterine histamine content in mast-cell normal and deficient mice during deciduoma formation. Surgical trauma (e.g., sutures) and intraluminal injection of oil produce deciduoma formation in ovariectomized mast-cell normal (+/+) and mast-cell deficient (W/WV) pseudopregnant mice that had previously received a single control ovary transplanted under the kidney capsule. Mast-cell normal (+/+) mice exhibit significant elevation of total uterine histamine content during both trauma and oil induced deciduoma formation. Mast-cell deficient (W/WV) mice under conditions of similar deciduoma formation did not show any change in total uterine histamine content. These results indicate that the change in histamine observed in mast-cell normal mice during deciduoma formation is most likely of mast cell origin. The lack of any measurable change in uterine histamine in mast-cell deficient mice indicates that an increase of non-mast cell histamine is not a prerequisite for deciduoma formation.

Annals of the New York Academy of SciencesVolume 540, Issue 1 p. 723-726 Presence and Distribution of Nervous System-Associated Mast Cells That May Modulate Experimental Autoimmune Encephalomyelitis EDWARD L. ORR, EDWARD L. ORR Department of Anatomy, Texas College of Osteopathic Medicine, Fort Worth, Texas 76107Search for more papers by this author EDWARD L. ORR, EDWARD L. ORR Department of Anatomy, Texas College of Osteopathic Medicine, Fort Worth, Texas 76107Search for more papers by this author First published: November 1988 https://doi.org/10.1111/j.1749-6632.1988.tb27226.xCitations: 25AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Citing Literature Volume540, Issue1Advances in NeuroimmunologyNovember 1988Pages 723-726 RelatedInformation

The ovaries from mast cell-normal (+/+) and mast cell-deficient (W/Wv) mice were examined with light and electron microscopy. In addition the effect of ovariectomy and subsequent steroid treatment on total uterine histamine content, total mast cell numbers and surface and glandular epithelial cell heights was measured. The ovaries of +/+ mice were normal, displaying various stages of follicular growth and atresia and numerous corpora lutea; the ovaries of W/Wv mice lacked follicles and corpora lutea but contained numerous hyperplastic interstitial cells which contained numerous lipid droplets, vesiculated mitochondria and abundant endoplasmic reticulum suggestive of steroid synthesis. Steroid treatment of ovariectomized +/+ and W/Wv mice caused a significant increase in uterine wet weight and endometrial surface and glandular epithelial cell heights. In +/+ mice, steroid treatment caused a concomitant increase in total mast cells per uterine horn while mast cells were totally absent in W/Wv mice. The increase in uterine histamine in +/+ mice is consistent with the increase in mast cell numbers. Measurable amounts of uterine histamine, which increases slightly after steroid treatment, were demonstrated in W/Wv mice. Since the uteri of +/+ and W/Wv mice respond to steroids in a similar manner with the sole exception being histamine content and mast cell numbers, our results demonstrate the potential of using these animals to investigate the role(s) of uterine mast cells and non-mast cell uterine histamine in the process of implantation and the formation of a decidual cell response.

Abstract: Knowledge of the relative contributions of mast cells and neurons to the overall pool of histamine in the brain is a prerequisite to determining the significance and role of this amine in brain function. Consequently, we analyzed the levels of brain histamine in four genotypes (+/+, W/+, Wv/+, and WIWv) of WBB6F1 mice, whose numbers of brain‐associated mast cells vary in a genotypically specific manner. Although mast cell numbers ranged from a total absence of mast cells (W/Wv) to an average of about 500 mast cells/brain (W/+), no significant differences between genotypes were found in the quantities of histamine in whole brains, brain regions, or crude subcellular fractions. Thus, in this strain of mice, mast cells are not a significant source of histamine in the brain. This suggests that most of the histamine is of neuronal origin. Since neuronal histamine levels are maintained only by continued histidine decarboxylase activity, complete inhibition of this enzyme by α‐fluoromethylhistidine, a “suicide” inhibitor of histidine decarboxylase, would totally deplete W/Wv mice of brain histamine. This was not found to occur in the W/Wv mice, suggesting that neuronal stores of histamine can be maintained in the absence of histidine decarboxylase, or that an additional nonneuronal, non‐mast cell source of histamine exists in the W/Wv mouse brain.

Abstract: Histamine levels were determined in mouse brains from WBB6F1‐ +/+ (mast cell normal) and WBB6F1‐W/Wv (mast cell‐deficient) mice whose brains were dissected immediately after decapitation or after freezing the severed heads in liquid nitrogen for 10 s. In WBB6F1‐+/+ mice, brains obtained from frozen heads contained significantly higher levels of histamine than those obtained from unfrozen heads. The converse was found in brains obtained from the WBB6F1‐W/Wv mice. When CF‐1 mice (which also contain brain‐associated mast cells) were treated as described above, results very similar to those found with the WBB6F1‐ +/+ mice were obtained. Further, the high levels of histamine found in CF‐1 mice whose brains had been frozen in situ were accompanied by an extensive degranulation of mast cells in the dura mater of these mice. Because of this degranulation of mast cells, and the fact that increased levels of brain histamine were not found in mast cell‐deficient mice, it is concluded that dural mast cells are the likely source of the artifactually higher levels of histamine seen in brains frozen in situ.