Hypolipemic effects of histamine is due to inhibition of VLDL secretion from the liver: involvement of both H1 and H2-receptors.

The research was performed to study the mechanism whereby histamine affects the profile of plasma lipids. Six groups of ten male rats were received two injections with histamine or its H1- and H2-agonists and antagonists. Histamine caused a significant decrease in the concentrations of triglyceride, total cholesterol, and LDLc, while HDLc had no significant change. The rate of VLDL secretion was 263.6 ± 25.8 mg/h dL in control rats and was inhibited by about 68% in histamine injected rats. These changes have been mimicked by either histamine H1- or H2-agonists. The effects of H1- and H2-agonists were abolished in the presence of cetirizine and famotidine respectively. Histamine causes a significant decrease in serum triglyceride, total, and LDL-cholesterol by both H1 and H2-receptors. The decrease in serum lipids is due to the inhibitory effect of histamine or its agonists on VLDL secretion from the liver.

Histaminergic Control of Corticostriatal Synaptic Plasticity during Early Postnatal Development.

A reduction in the synthesis of the neuromodulator histamine has been associated with Tourette's syndrome and obsessive-compulsive disorder. Symptoms of these disorders are thought to arise from a dysfunction or aberrant development ofcorticostriatal circuits. Here, we investigated how histamine affects developing corticostriatal circuits, both acutely and longer-term, during the first postnatal weeks, using patch-clamp and field recordings in mouse brain slices (C57Bl/6, male and female). Immunohistochemistry for histamine-containing axons reveals striatal histaminergic innervation by the second postnatal week, and qRT-PCR shows transcripts for H1, H2, and H3 histamine receptors in striatum from the first postnatal week onwards, with pronounced developmental increases in H3 receptor expression. Whole-cell patch-clamp recordings of striatal spiny projection neurons and histamine superfusion demonstrates expression of functional histamine receptors from the first postnatal week onwards, with histamine having diverse effects on their electrical properties, including depolarization of the membrane potential while simultaneously decreasing action potential output. Striatal field recordings and electrical stimulation of corticostriatal afferents revealed that histamine, acting at H3 receptors, negatively modulates corticostriatal synaptic transmission from the first postnatal week onwards. Last, we investigated effects of histamine on longer-term changes at developing corticostriatal synapses and show that histamine facilitates NMDA receptor-dependent LTP via H3 receptors during the second postnatal week, but inhibits synaptic plasticity at later developmental stages. Together, these results show that histamine acutely modulates developing striatal neurons and synapses and controls longer-term changes in developing corticostriatal circuits, thus providing insight into the possible etiology underlying neurodevelopmental disorders resulting from histamine dysregulation.SIGNIFICANCE STATEMENT Monogenic causes of neurologic disorders, although rare, can provide opportunities to both study and understand the brain. For example, a nonsense mutation in the coding gene for the histamine-synthesizing enzyme has been associated with Tourette's syndrome and obsessive-compulsive disorder, and dysfunction of corticostriatal circuits. Nevertheless, the etiology of these neurodevelopmental disorders and histamine's role in the development of corticostriatal circuits have remained understudied. Here we show that histamine is an active neuromodulator during the earliest periods of postnatal life and acts at developing striatal neurons and synapses. Crucially, we show that histamine permits NMDA receptor-dependent corticostriatal synaptic plasticity during an early critical period of postnatal development, which suggests that genetic or environmental perturbations of histamine levels can impact striatal development.

[Mechanisms of histamine ameliorating memory impairment induced by pentylenetetrazole-kindling epilepsy in rats].

Objective: To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms. Methods: A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed. Results: Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all P<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all P<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all P<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine. Conclusion: Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.

Syrian hamster neuroplasticity mechanisms fail as temperature declines to 15 °C, but histaminergic neuromodulation persists.

Previous research suggests that hippocampal neurons in mammalian hibernators shift their major function from memory formation at euthermic brain temperatures (T b = ~37 °C) to modulation of hibernation bout duration as T b decreases. This role of hippocampal neurons during torpor is based in part on in vivo studies showing that histamine (HA) infused into ground squirrel hippocampi lengthened torpor bouts by ~50%. However, it was unclear if HA acted directly on hippocampal neurons or on downstream brain regions via HA spillover into lateral ventricles. To clarify this, we used hippocampal slices to determine if HA would modulate pyramidal neurons at low levels of synaptic activity (as occurs in torpor). We tested the hypotheses that although LTP (a neuroplasticity mechanism) could not be generated at low temperatures, HA (via H2 receptors) would increase population spike amplitudes (PSAs) of Syrian hamster CA1 pyramidal neurons at low stimulation voltages and low temperatures. PSAs were recorded following Schaffer collateral stimulation from subthreshold levels to a maximum response plateau. We found that tetanus evoked LTP at 35 °C but not 15 °C; and at temperatures from 30 to 15 °C, HA significantly enhanced PSA at near threshold levels in slices from non-hibernating hamsters housed in "summer-like" or "winter-like" conditions and from hibernating hamsters. Cimetidine (H2 antagonist) blocked HA-mediated PSA increases in 8 of 8 slices; pyrilamine (H1 antagonist) had no effect in 7 of 8 slices. These results support our hypotheses and show that HA can directly enhance pyramidal neuron excitability via H2 receptors and thus may prolong torpor bouts.

Histaminergic H1 and H2 Receptors Mediate the Effects of Propofol on the Noradrenalin-Inhibited Neurons in Rat Ventrolateral Preoptic Nucleus.

The ventrolateral preoptic nucleus is a sleep-promoting nucleus located in the basal forebrain. A commonly used intravenous anesthetic, propofol, had been reported to induce sleep spindles and augment the firing rate of neurons in ventrolateral preoptic nucleus, but the underlining mechanism is yet to be known. By using patch clamp recording on neuron in acute brain slice, present study tested if histaminergic H1 and H2 receptors play a role in the effect of propofol on the noradrenalin-inhibited neurons in ventrolateral preoptic nucleus. We found that the firing rate of noradrenalin-inhibited neurons were significantly augmented by propofol; the frequency of inhibitory postsynaptic currents of noradrenalin-inhibited neuron were evidently attenuated by propofol; such inhibition effect was suppressed by histamine; and both triprolidine (antagonist for H1 histamine receptor) and ranitidine (antagonist for H2 histamine receptor) were able to increase the inhibition rate of propofol in presence of histamine. Present study demonstrated that propofol-induced inhibition of inhibitory postsynaptic currents on noradrenalin-inhibited neurons were mediated by histaminergic H1 and H2 receptors.

Major neurotransmitter systems in dorsal hippocampus and basolateral amygdala control social recognition memory.

Social recognition memory (SRM) is crucial for reproduction, forming social groups, and species survival. Despite its importance, SRM is still relatively little studied. Here we examine the participation of the CA1 region of the dorsal hippocampus (CA1) and the basolateral amygdala (BLA) and that of dopaminergic, noradrenergic, and histaminergic systems in both structures in the consolidation of SRM. Male Wistar rats received intra-CA1 or intra-BLA infusions of different drugs immediately after the sample phase of a social discrimination task and 24-h later were subjected to a 5-min retention test. Animals treated with the protein synthesis inhibitor, anisomycin, into either the CA1 or BLA were unable to recognize the previously exposed juvenile (familiar) during the retention test. When infused into the CA1, the ß-adrenoreceptor agonist, isoproterenol, the D1/D5 dopaminergic receptor antagonist, SCH23390, and the H2 histaminergic receptor antagonist, ranitidine, also hindered the recognition of the familiar juvenile 24-h later. The latter drug effects were more intense in the CA1 than in the BLA. When infused into the BLA, the ß-adrenoreceptor antagonist, timolol, the D1/D5 dopamine receptor agonist, SKF38393, and the H2 histaminergic receptor agonist, ranitidine, also hindered recognition of the familiar juvenile 24-h later. In all cases, the impairment to recognize the familiar juvenile was abolished by the coinfusion of agonist plus antagonist. Clearly, both the CA1 and BLA, probably in that order, play major roles in the consolidation of SRM, but these roles are different in each structure vis-à-vis the involvement of the ß-noradrenergic, D1/D5-dopaminergic, and H2-histaminergic receptors therein.

Evidence of a broad histamine footprint on the human exercise transcriptome.

KEY POINTS: Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors, in a variety of pathways that probably predate its more recent role in innate and adaptive immunity. Although histamine is normally associated with pathological conditions or allergic and anaphylactic reactions, it may contribute beneficially to the normal changes that occur within skeletal muscle during the recovery from exercise. We show that the human response to exercise includes an altered expression of thousands of protein-coding genes, and much of this response appears to be driven by histamine. Histamine may be an important molecular transducer contributing to many of the adaptations that accompany chronic exercise training. ABSTRACT: Histamine is a primordial signalling molecule, capable of activating cells in an autocrine or paracrine fashion via specific cell surface receptors. In humans, aerobic exercise is followed by a post-exercise activation of histamine H1 and H2 receptors localized to the previously exercised muscle. This could trigger a broad range of cellular adaptations in response to exercise. Thus, we exploited RNA sequencing to explore the effects of H1 and H2 receptor blockade on the exercise transcriptome in human skeletal muscle tissue harvested from the vastus lateralis. We found that exercise exerts a profound influence on the human transcriptome, causing the differential expression of more than 3000 protein-coding genes. The influence of histamine blockade post-exercise was notable for 795 genes that were differentially expressed between the control and blockade condition, which represents >25% of the number responding to exercise. The broad histamine footprint on the human exercise transcriptome crosses many cellular functions, including inflammation, vascular function, metabolism, and cellular maintenance.

CCL22/Macrophage-derived Chemokine Expression in Apolipoprotein E-deficient Mice and Effects of Histamine in the Setting of Atherosclerosis.

AIM: Macrophage-derived chemokine (CCL22) is a member of the CC-family of chemokines synthesized by monocyte-derived macrophages. Previous studies have reported a relationship between CCL22 and atherosclerosis and the role of histamine in this pathway. Histamine ncreases the CCL22 expression in human monocytes via the H2 receptor. In this study, we investigated the effects of CCL22 and the role of histamine in mouse monocytes with respect to atherosclerosis. METHODS AND RESULTS: The expression of CCL22 was investigated in apolipoprotein E (apoE)-deficient mice. The mice had high serum concentrations of CCL22 and their atherosclerotic lesions contained abundant levels of CCL22. In addition, when the mouse monocyte cell line (J774A.1 cells) differentiated into macrophage-like cells, the cells showed a similar expression of CCL22 and reduced expression of H2 receptors. Histamine is synthesized from l-histidine by histidine decarboxylase (HDC) in a single enzymatic step. HDC knockout mice were compared with apoE/HDC double knockout mice. The findings indicated that the expression of CCL22 in atherosclerosis models is under the influence of histamine. In addition, in vitro studies using J774A.1 cells and an in vivo study using histamine receptor knockout mice showed that histamine stimulates the CCL22 expression via the histamine H2 receptor. CONCLUSIONS: The current results support our previous CCL22 studies in the setting of human atherosclerosis and suggest that this molecule is involved in the atherogenic processes in a mouse model of atherosclerosis.

The role of the central histaminergic receptors in the exercise-induced improvements of the spatial learning and memory in rats.

While it is well known that exercise can improve cognitive performance, the underlying mechanisms are not fully understood. There is now evidence that histamine can modulate learning and memory in different types of behavioral tasks. The present study was designed to examine the possible role of central histamine H1 and H2 receptors in forced treadmill running-induced enhancement of learning and memory in rats. For this purpose the animals received intracerebroventricularly chlorpheniramine (H1 receptor blocker) and cimetidine (H2 receptor blocker) before each day of fifteen consecutive days of exercise. Then their learning and memory were tested on the water maze task using a four-trial-per-day for 4 consecutive days. A probe trial was performed after the last training day. Our data showed that cimetidine reversed the exercise-induced improvement in learning and memory in rats; however, this was not the case regarding chlorpheniramine. Our findings indicate that central histamine H2 receptors play an important role in mediating the beneficial effects of forced exercise on learning and memory.

Itching for answers: how histamine relaxes lymphatic vessels.

In the current issue of Microcirculation, studies by Kurtz et al. and Nizamutdinova et al. together provide new evidence supporting a role for histamine as an endothelial-derived molecule that inhibits lymphatic muscle contraction. In particular, Nizamutdinova et al. show that the effects of flow-induced shear stress on lymphatic endothelium are mediated by both nitric oxide and histamine, since only blockade of both prevents contraction strength and frequency from being altered by flow. Separately, Kurtz et al. used confocal microscopy to determine a preferential expression of histamine receptors on the lymphatic endothelium and demonstrated that histamine applied to spontaneously contracting collecting lymphatics inhibits contractions. Previous studies disagreed on whether histamine stimulates or inhibits lymphatic contractions, but also used differing concentrations, species, and preparations. Together these new reports shed light on how histamine acts within the lymphatic vasculature, but also raise important questions about the cell type on which histamine exerts its effects and the signaling pathways involved. This editorial briefly discusses the contribution of each study and its relevance to lymphatic biology.

Involvement of H1 and H2 receptors and soluble guanylate cyclase in histamine-induced relaxation of rat mesenteric collecting lymphatics.

OBJECTIVE: This study investigated the roles of the H1 and H2 histamine receptors, NO synthase, and sGC cyclase in histamine-induced modulation of rat mesenteric collecting lymphatic pumping. METHODS: Isolated rat mesenteric collecting lymphatics were treated with 1- to 100-µM histamine. Histamine receptors were blocked with either the H1 antagonist mepyramine or the H2 antagonist cimetidine. The role of NO/sGC signaling was tested using the arginine analog L-NAME, the sGC inhibitor ODQ, and SNP as a positive control. RESULTS: Histamine applied at 100 µM decreased tone and CF of isolated rat mesenteric collecting lymphatics. Pharmacologic blockade of either H1 or H2 histamine receptors significantly inhibited the response to histamine. Pretreatment with ODQ, but not L-NAME, completely inhibited the histamine-induced decrease in tone. ODQ pretreatment also significantly inhibited SNP-induced lymphatic relaxation. CONCLUSIONS: H1 and H2 histamine receptors are both involved in histamine-induced relaxation of rat mesenteric collecting lymphatics. NO synthesis does not appear to contribute to the histamine-induced response. However, sGC is critical for the histamine-induced decrease in tone and contributes to the drop in CF.

Mechanisms of allergen-specific immunotherapy: multiple suppressor factors at work in immune tolerance to allergens.

Allergen-specific immunotherapy (AIT) has been used for more than 100 years as a desensitizing therapy for IgE-mediated allergic diseases and represents a potentially curative way of treatment. The mechanisms of action of AIT include the induction of very early desensitization of mast cells and basophils; generation of regulatory T and regulatory B (Breg) cell responses; regulation of IgE and IgG4; decreases in numbers and activity of eosinophils and mast cells in mucosal allergic tissues; and decreases in the activity of basophils in circulation. Skewing of allergen-specific effector T and effector B cells to a regulatory phenotype appears as a key event in the course of AIT and normal immune response to allergens. Recently, inducible IL-10-secreting Breg cells were also demonstrated to contribute to allergen tolerance through suppression of effector T cells and selective induction of IgG4 isotype antibodies. Allergen-specific regulatory T and Breg cells orchestrate a general immunoregulatory activity, which can be summarized as suppression of cytokines from inflammatory dendritic cells; suppression of effector TH1, TH2, and TH17 cells; suppression of allergen-specific IgE and induction of IgG4; and suppression of migration of mast cells, basophils, eosinophils, and effector T cells to tissues. A detailed knowledge of the mechanisms of AIT is not only important in designing the prevention and treatment of allergic diseases but might also find applications in the treatment of autoimmune diseases, organ transplantation, chronic infection, and cancer.

Disruption of histamine H2 receptor slows heart failure progression through reducing myocardial apoptosis and fibrosis.

Histamine H2 receptor (H2R) blockade has been reported to be beneficial for patients with chronic heart failure (CHF), but the mechanisms involved are not entirely clear. In the present study, we assessed the influences of H2R disruption on left ventricular (LV) dysfunction and the mechanisms involved in mitochondrial dysfunction and calcineurin-mediated myocardial fibrosis. H2R-knockout mice and their wild-type littermates were subjected to transverse aortic constriction (TAC) or sham surgery. The influences of H2R activation or inactivation on mitochondrial function, apoptosis and fibrosis were evaluated in cultured neonatal rat cardiomyocytes and fibroblasts as well as in murine hearts. After 4 weeks, H2R-knockout mice had higher echocardiographic LV fractional shortening, a larger contractility index, a significantly lower LV end-diastolic pressure, and more importantly, markedly lower pulmonary congestion compared with the wild-type mice. Similar results were obtained in wild-type TAC mice treated with H2R blocker famotidine. Histological examinations showed a lower degree of cardiac fibrosis and apoptosis in H2R-knockout mice. H2R activation increased mitochondrial permeability and induced cell apoptosis in cultured cardiomyocytes, and also enhanced the protein expression of calcineurin, nuclear factor of activated T-cell and fibronectin in fibroblasts rather than in cardiomyocytes. These findings indicate that a lack of H2R generates resistance towards heart failure and the process is associated with the inhibition of cardiac fibrosis and apoptosis, adding to the rationale for using H2R blockers to treat patients with CHF.

Histamine receptor 2 modifies dendritic cell responses to microbial ligands.

BACKGROUND: The induction of tolerance and protective immunity to microbes is significantly influenced by host- and microbiota-derived metabolites, such as histamine. OBJECTIVE: We sought to identify the molecular mechanisms for histamine-mediated modulation of pattern recognition receptor signaling. METHODS: Human monocyte-derived dendritic cells (MDDCs), myeloid dendritic cells, and plasmacytoid dendritic cells were examined. Cytokine secretion, gene expression, and transcription factor activation were measured after stimulation with microbial ligands and histamine. Histamine receptor 2 (H2R)-deficient mice, histamine receptors, and their signaling pathways were investigated. RESULTS: Histamine suppressed MDDC chemokine and proinflammatory cytokine secretion, nuclear factor κB and activator protein 1 activation, mitogen-activated protein kinase phosphorylation, and T(H)1 polarization of naive lymphocytes, whereas IL-10 secretion was enhanced in response to LPS and Pam3Cys. Histamine also suppressed LPS-induced myeloid dendritic cell TNF-α secretion and suppressed CpG-induced plasmacytoid dendritic cell IFN-α gene expression. H2R signaling through cyclic AMP and exchange protein directly activated by cyclic AMP was required for the histamine effect on LPS-induced MDDC responses. Lactobacillus rhamnosus, which secretes histamine, significantly suppressed Peyer patch IL-2, IL-4, IL-5, IL-12, TNF-α, and GM-CSF secretion in wild-type but not H2R-deficient animals. CONCLUSION: Both host- and microbiota-derived histamine significantly alter the innate immune response to microbes through H2R.

Postexercise hypotension and sustained postexercise vasodilatation: what happens after we exercise?

A single bout of aerobic exercise produces a postexercise hypotension associated with a sustained postexercise vasodilatation of the previously exercised muscle. Work over the last few years has determined key pathways for the obligatory components of postexercise hypotension and sustained postexercise vasodilatation and points the way to possible benefits that may result from these robust responses. During the exercise recovery period, the combination of centrally mediated decreases in sympathetic nerve activity with a reduced signal transduction from sympathetic nerve activation into vasoconstriction, as well as local vasodilator mechanisms, contributes to the fall in arterial blood pressure seen after exercise. Important findings from recent studies include the recognition that skeletal muscle afferents may play a primary role in postexercise resetting of the baroreflex via discrete receptor changes within the nucleus tractus solitarii and that sustained postexercise vasodilatation of the previously active skeletal muscle is primarily the result of histamine H(1) and H(2) receptor activation. Future research directions include further exploration of the potential benefits of these changes in the longer term adaptations associated with exercise training, as well as investigation of how the recovery from exercise may provide windows of opportunity for targeted interventions in patients with hypertension and diabetes.

Emotional memory consolidation impairment induced by histamine is mediated by H1 but not H2 receptors.

Histaminergic fibers are present in the molecular and granular layers of the cerebellum and have high density in the vermis and flocculus. Evidence indicates that the cerebellar vermis is involved in memory consolidation. Recently, we demonstrated that when histamine is microinjected into the cerebellar vermis it results in impaired emotional memory consolidation in mice that are submitted to the elevated plus maze (EPM). This study investigated whether histamine impairment was mediated by the H(1) or H(2) receptors. The cerebellar vermis of male mice (Swiss Albino) were implanted using a guide cannula. Three days after recovery, behavioral tests were performed in the EPM on two consecutive days (Trial 1 and Trial 2). Immediately after exposure to the EPM (Trial 1), animals received a microinjection of histaminergic drugs. In Experiment 1, saline (SAL) or histamine (HA, 4.07 nmol/0.1 µl) was microinjected 5 min after pretreatment with the H(1) antagonist chlorpheniramine (CPA, 0.16 nmol/0.1µl) or SAL. In Experiment 2, SAL or HA was microinjected into the mice 5 min after pretreatment with the H(2) antagonist ranitidine (RA, 2.85 nmol/0.1 µl) or SAL. Twenty-four hours later, the mice were re-exposed to the EPM (Trial 2) under the same experimental conditions but did not receive an injection. On both days, the test sessions were recorded to enable analysis of the behavioral measures. The decrease in open arm exploration (% entries and % time spent in the open arms) in Trial 2 relative to Trial 1 was used as a measure of learning and memory. The data were analyzed using the two-way analysis of variance (ANOVA) and Duncan's tests. In Experiment 1, the Duncan's test indicated that the mice entered the open arms less often (%OAE) and spent less time in the open arms (%OAT) in Trial 2 after being microinjected with SAL+SAL, SAL+CPA and CPA+HA. However, the animals that received SAL+HA did not enter the open arms less frequently or spend less time in them, which was significantly different from the CPA+HA group. The results of Experiment 2 demonstrated that the %OAE and %OAT in Trial 2 were different from Trial 1 for the groups that were microinjected with SAL+SAL and SAL+RA. The animals that were microinjected with RA+HA or with SAL+HA did not show a reduction in %OAE. These results demonstrate that the animals treated with HA did not avoid the open arms less on retesting and indicated that CPA did not alter the behavior parameters but did revert the histamine-induced impairment of memory consolidation. Furthermore, the H(2) antagonist RA, at the dose used in this study, did not affect memory consolidation and failed to revert histamine-induced impairment.

Role of histamine and its receptors in cerebral ischemia.

Histamine is recognized as a neurotransmitter or neuromodulator in the brain, and it plays a major role in the pathogenic progression after cerebral ischemia. Extracellular histamine increases gradually after ischemia, and this may come from histaminergic neurons or mast cells. Histamine alleviates neuronal damage and infarct volume, and it promotes recovery of neurological function after ischemia; the H1, H2, and H3 receptors are all involved. Further studies suggest that histamine alleviates excitotoxicity, suppresses the release of glutamate and dopamine, and inhibits inflammation and glial scar formation. Histamine may also affect cerebral blood flow by targeting to vascular smooth muscle cells, and promote neurogenesis. Moreover, endogenous histamine is an essential mediator in the cerebral ischemic tolerance. Due to its multiple actions, affecting neurons, glia, vascular cells, and inflammatory cells, histamine is likely to be an important target in cerebral ischemia. But due to its low penetration of the blood-brain barrier and its wide actions in the periphery, histamine-related agents, like H3 antagonists and carnosine, show potential for cerebral ischemia therapy. However, important questions about the molecular aspects and pathophysiology of histamine and related agents in cerebral ischemia remain to be answered to form a solid scientific basis for therapeutic application.

Combinatorial roles for histamine H1-H2 and H3-H4 receptors in autoimmune inflammatory disease of the central nervous system.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system in which histamine (HA) and its receptors have been implicated in disease pathogenesis. HA exerts its effects through four different G protein-coupled receptors designated H(1)-H(4). We previously examined the effects of traditional single HA receptor (HR) knockouts (KOs) in experimental allergic encephalomyelitis (EAE), the autoimmune model of MS. Our results revealed that H(1) R and H(2) R are propathogenic, while H(3) R and H(4) R are antipathogenic. This suggests that combinatorial targeting of HRs may be an effective disease-modifying therapy (DMT) in MS. To test this hypothesis, we generated H(1) H(2) RKO and H(3) H(4) RKO mice and studied them for susceptibility to EAE. Compared with wild-type (WT) mice, H(1) H(2) RKO mice developed a less severe clinical disease course, whereas the disease course of H(3) H(4) RKO mice was more severe. H(1) H(2) RKO mice also developed less neuropathology and disrupted blood brain barrier permeability compared with WT and H(3) H(4) RKO mice. Additionally, splenocytes from immunized H(1) H(2) RKO mice produced less interferon(IFN)-γ and interleukin(IL)-17. These findings support the concept that combined pharmacological targeting of HRs may be an appropriate ancillary DMT in MS and other immunopathologic diseases.

Histamine promotes rat motor performances by activation of H(2) receptors in the cerebellar fastigial nucleus.

The cerebellar fastigial nucleus (FN), together with the interpositus nucleus (IN), constitutes the two final output nuclei of the spinocerebellum and plays an important role in body and limb movements. Previous studies have revealed a direct histaminergic projection from the hypothalamus to the cerebellar nuclei and an excitatory effect of histamine on the IN neurons. However, role of hypothalamic histaminergic projection in the FN has been still little known. Here we show that histamine elicited the FN neurons of rats a concentration-dependent excitatory response in vitro. The histamine-induced excitation on FN neurons was mediated by postsynaptic histamine H2 rather than H1 receptors. In behavioral tests, microinjection of histamine into bilateral FNs remarkably improved motor performances of rats on both accelerating rota-rod and balance beam. Selective H2 receptor antagonist ranitidine considerably declined those motor performances and selective H2 receptor agonist dimaprit mimicked the facilitation effect of histamine on the movements. But selective H1 receptor antagonist triprolidine and agonist 2-pyridylethylamine had no effect. Furthermore, microinjection of histamine into bilateral FNs narrowed stride width of footprint but did not influence wire suspension, whereas microinjection of histamine into bilateral INs increased stride length and promoted suspension. These results demonstrate that histamine enhances rat motor balance and coordination through modulation of both proximal and distal muscles by activation of histamine H2 receptors in the cerebellar FN and IN, and suggest that the hypothalamocerebellar histaminergic projections may modulate the final outputs of the spinocerebellum and participate in the cerebellum-mediated motor control.

[Effects of histamine on contractile activity of lymphatic node capsules. The NO role].

Effects of histamine (10(-9)--5 x 10(-5) M) on the phase and tonic contractile activity of capsular smooth muscles of isolated bovine mesentery lymph node were investigated. Dual dose-depended effect of histamine was found. Low concentrations of histamine less than 10(-7) M caused a decrease of contractile activity, whereas higher concentrations of histamine (more than 5 x 10(-7) M) resulted in increase of the phase and tonic contractions. Both H1- and H2-receptors of smooth muscle cells are involved in the response. Much of the relaxing histamine-induced response is produced by the stimulation of the endothelial cells. We believe that activating effect of histamine is due to the excitation of H1-receptors located on the membrane of myocytes, whereas its inhibitory effect occurs in two ways: 1) via excitation of H2-receptors located on the membrane of myocytes; 2) via stimulation of the NO production by the endothelial cells of lymph node sinus.