Tibialis anterior electromyographic bursts during sleep in histamine-deficient mice.

Antihistamine medications have been suggested to elicit clinical features of restless legs syndrome. The available data are limited, particularly concerning periodic leg movements during sleep, which are common in restless legs syndrome and involve bursts of tibialis anterior electromyogram. Here, we tested whether the occurrence of tibialis anterior electromyogram bursts during non-rapid eye movement sleep is altered in histidine decarboxylase knockout mice with congenital histamine deficiency compared with that in wild-type control mice. We implanted six histidine decarboxylase knockout and nine wild-type mice to record neck muscle electromyogram, bilateral tibialis anterior electromyogram, and electroencephalogram during the rest (light) period. The histidine decarboxylase knockout and wild-type mice did not differ significantly in terms of sleep architecture. In both histidine decarboxylase knockout and wild-type mice, the distribution of intervals between tibialis anterior electromyogram bursts had a single peak for intervals < 10 s. The total occurrence rate of tibialis anterior electromyogram bursts during non-rapid eye movement sleep and the occurrence rate of the tibialis anterior electromyogram bursts separated by intervals < 10 s were significantly lower in histidine decarboxylase knockout than in wild-type mice. These data do not support the hypothesis that preventing brain histamine signalling may promote restless legs syndrome. Rather, the data suggest that limb movements during sleep, including those separated by short intervals, are a manifestation of subcortical arousal requiring the integrity of brain histamine signalling.

Histamine deficiency facilitates coronary microthrombosis after myocardial infarction by increasing neutrophil-platelet interactions.

Neutrophil-platelet interactions are responsible for thrombosis as well as inflammatory responses following acute myocardial infarction (AMI). While histamine has been shown to play a crucial role in many physiological and pathological processes, its effects on neutrophil-platelet interactions in thromboinflammatory complications of AMI remain elusive. In this study, we show a previously unknown mechanism by which neutrophil-derived histamine protects the infarcted heart from excessive neutrophil-platelet interactions and redundant arterial thrombosis. Using histamine-deficient (histidine decarboxylase knockout, HDC-/- ) and wild-type murine AMI models, we demonstrate that histamine deficiency increases the number of microthrombosis after AMI, in accordance with depressed cardiac function. Histamine-producing myeloid cells, mainly Ly6G+ neutrophils, directly participate in arteriole thrombosis. Histamine deficiency elevates platelet activation and aggregation by enhancing Akt phosphorylation and leads to dysfunctional characteristics in neutrophils which was confirmed by high levels of reactive oxygen species production and CD11b expression. Furthermore, HDC-/- platelets were shown to elicit neutrophil extracellular nucleosomes release, provoke neutrophil-platelet interactions and promote HDC-expressing neutrophils recruitment in arteriole thrombosis in vivo. In conclusion, we provide evidence that histamine deficiency promotes coronary microthrombosis and deteriorates cardiac function post-AMI, which is associated with the enhanced platelets/neutrophils function and neutrophil-platelet interactions.

Histamine deficiency delays ischaemic skeletal muscle regeneration via inducing aberrant inflammatory responses and repressing myoblast proliferation.

Histidine decarboxylase (HDC) catalyses the formation of histamine from L-histidine. Histamine is a biogenic amine involved in many physiological and pathological processes, but its role in the regeneration of skeletal muscles has not been thoroughly clarified. Here, using a murine model of hindlimb ischaemia, we show that histamine deficiency in Hdc knockout (Hdc-/- ) mice significantly reduces blood perfusion and impairs muscle regeneration. Using Hdc-EGFP transgenic mice, we demonstrate that HDC is expressed predominately in CD11b+ Gr-1+ myeloid cells but not in skeletal muscles and endothelial cells. Large amounts of HDC-expressing CD11b+ myeloid cells are rapidly recruited to injured and inflamed muscles. Hdc-/- enhances inflammatory responses and inhibits macrophage differentiation. Mechanically, we demonstrate that histamine deficiency decreases IGF-1 (insulin-like growth factor 1) levels and diminishes myoblast proliferation via H3R/PI3K/AKT-dependent signalling. These results indicate a novel role for HDC-expressing CD11b+ myeloid cells and histamine in myoblast proliferation and skeletal muscle regeneration.

Bacterial secretion of histamine within the gut influences immune responses within the lung.

BACKGROUND: Histamine is an important immunomodulator influencing both the innate and adaptive immune system. Certain host cells express the histidine decarboxylase enzyme (HDC), which is responsible for catalysing the decarboxylation of histidine to histamine. We and others have shown that bacterial strains can also express HDC and secrete histamine; however, the influence of bacterial-derived histamine on the host immune responses distant to the gut is unclear. METHODS: The Escherichia coli BL21 (E coli BL21) strain was genetically modified to express the Morganella morganii (M morganii)-derived HDC gene (E coli BL21_HTW). E coli BL21 and E coli BL21_HTW were gavaged to ovalbumin (OVA) sensitized and challenged mice to investigate the effect of bacterial-derived histamine on lung inflammatory responses. RESULTS: Oral administration of E coli BL21_HTW, which is able to secrete histamine, to wild-type mice reduced lung eosinophilia and suppressed ex vivo OVA-stimulated cytokine secretion from lung cells in the OVA respiratory inflammation mouse model. In histamine receptor 2 (H2R)-deficient mice, administration of histamine-secreting bacteria also reduced inflammatory cell numbers in bronchoalveolar lavage (BAL). However, the suppressive effect of bacterial-derived histamine on BAL inflammation was lost in HDC-deficient mice. This loss of activity was associated with increased expression of histamine degrading enzymes and reduced histamine receptor expression. CONCLUSION: Histamine secretion from bacteria within the gut can have immunological consequences at distant mucosal sites, such as within the lung. These effects are influenced by host histamine receptor expression and the expression of histamine degrading enzymes.

A critical time window for the analgesic effect of central histamine in the partial sciatic ligation model of neuropathic pain.

BACKGROUND: It is known that histamine participates in pain modulation. However, the effect of central histamine on neuropathic pain is not fully understood. Here, we report a critical time window for the analgesic effect of central histamine in the partial sciatic nerve ligation model of neuropathic pain. METHODS: Neuropathic pain was induced by partial sciatic nerve ligation (PSL) in rats, wild-type (C57BL/6J) mice and HDC(-/-) (histidine decarboxylase gene knockout) and IL-1R(-/-) (interleukin-1 receptor gene knockout) mice. Histidine, a precursor of histamine that can increase the central histamine levels, was administered intraperitoneally (i.p.). Histidine decarboxylase (HDC) enzyme inhibitor α-fluoromethylhistidine was administered intracerebroventricularly (i.c.v.). Histamine H1 receptor antagonist mepyramine and H2 receptor antagonist cimetidine were given intrathecally (i.t.) and intracisternally (i.c.). Withdrawal thresholds to tactile and heat stimuli were measured with a set of von Frey hairs and infrared laser, respectively. Immunohistochemistry and Western blot were carried out to evaluate the morphology of microglia and IL-1ß production, respectively. RESULTS: Histidine (100 mg/kg, i.p.) administered throughout days 0-3, 0-7, or 0-14 postoperatively (PO) alleviated mechanical allodynia and thermal hyperalgesia in the hindpaw following PSL in rats. Intrathecal histamine reversed PSL-induced thermal hyperalgesia in a dose-dependent manner and intracisternal histamine alleviated both mechanical allodynia and thermal hyperalgesia. Moreover, α-fluoromethylhistidine (i.c.v.) abrogated the analgesic effect of histidine. However, histidine treatment initiated later than the first postoperative day (treatment periods included days 2-3, 4-7, and 8-14 PO) did not show an analgesic effect. In addition, histidine treatment initiated immediately, but not 3 days after PSL, inhibited microglial activation and IL-1ß upregulation in the lumbar spinal cord, in parallel with its effects on behavioral hypersensitivity. Moreover, the inhibitory effects on pain hypersensitivity and spinal microglial activation were absent in HDC(-/-) mice and IL-1R(-/-) mice. H1 receptor antagonist mepyramine (200 ng/rat i.t. or i.c.), but not H2 receptor antagonist cimetidine (200, 500 ng/rat i.t. or 500 ng/rat i.c.), blocked the effects of histidine on pain behavior and spinal microglia. CONCLUSIONS: These results demonstrate that central histamine is analgesic within a critical time window in the PSL model of neuropathic pain via histamine H1 receptors. This effect may partly relate to the inhibition of microglial activation and IL-1ß production in the spinal cord following nerve injury.

High-amplitude theta wave bursts characterizing narcoleptic mice and patients are also produced by histamine deficiency in mice.

Histamine and orexins are wake promoters released by hypothalamic neurons. The activity of histamine neurons is increased by orexin neurons. Recently, it has been shown that orexin deficiency entails high-amplitude theta wave bursts during rapid eye movement sleep and cataplexy in narcoleptic mice. The primary aim of this study was to assess whether histamine system is involved in high-amplitude theta wave burst generation during rapid eye movement sleep. The secondary aim was to assess the effects of combined histamine and orexin deficiency on high-amplitude theta wave bursts during rapid eye movement sleep in mice. Twelve histidine-decarboxylase knockout mice with congenital histamine deficiency, seven double mutant mice with combined deficiency of orexin neurons and histamine, and 11 wild-type control mice were studied with electrodes for sleep recordings and a telemetric blood pressure transducer. High-amplitude theta wave bursts during rapid eye movement sleep were detected in each of the histidine-decarboxylase knockout and double mutant mice, whereas only one burst was found in a wild-type control mouse. High-amplitude theta wave bursts occurred significantly more often and were significantly longer in double mutant than in histidine-decarboxylase knockout mice. In conclusion, it was demonstrated that, similarly to orexin, the chronic impairment of histamine entailed high-amplitude theta wave bursts during rapid eye movement sleep. The current data also suggested a synergistic role of orexin and histamine signalling on high-amplitude theta wave bursts during rapid eye movement sleep in mice.

Histamine suppresses regulatory T cells mediated by TGF-ß in murine chronic allergic contact dermatitis.

Regulatory T cells (Tregs) suppress effector T cells and ameliorate contact hypersensitivity (CH); however, the role of Tregs in chronic allergic contact dermatitis (CACD) has not been assessed. Repeated elicitation of CH has been used to produce CACD models in mice. We previously showed that the presence of histamine facilitates the creation of eczematous lesions in this model using histidine decarboxylase (HDC) (-/-) mice. Therefore, the effects of histamine on Tregs in the CACD model were investigated in this study. CACD was developed by repeated epicutaneous application of 2, 4, 6-trinitro-1-chlorobenzene (TNCB) on HDC (+/+) and HDC (-/-) murine skin to assess the effects of histamine in CACD. Histamine aggravated CACD in the murine model and suppressed the number of Tregs in the skin. Histamine also suppressed the level of TGF-ß1 in this model. Recombinant TGF-ß1 or anti-TGF-ß1 antibody was injected into the dorsal dermis of HDC (+/+) mice daily just before TNCB challenge to determine the effects of histamine-regulated TGF-ß on the Treg population in CACD. Recombinant TGF-ß1 injection promoted the infiltration of Tregs in the skin and the production of IL-10; however, anti-TGF-ß1 antibody injection suppressed the number of Tregs in the skin and the production of IL-10. Histamine suppresses the number of Tregs in CACD, and this effect is mediated by TGF-ß.

Systemic lack of canonical histamine receptor signaling results in increased resistance to autoimmune encephalomyelitis.

Histamine (HA) is a key regulator of experimental allergic encephalomyelitis (EAE), the autoimmune model of multiple sclerosis. HA exerts its effects through four known G-protein-coupled receptors: H1, H2, H3, and H4 (histamine receptors; H(1-4)R). Using HR-deficient mice, our laboratory has demonstrated that H1R, H2R, H3R, and H4R play important roles in EAE pathogenesis, by regulating encephalitogenic T cell responses, cytokine production by APCs, blood-brain barrier permeability, and T regulatory cell activity, respectively. Histidine decarboxylase-deficient mice (HDCKO), which lack systemic HA, exhibit more severe EAE and increased Th1 effector cytokine production by splenocytes in response to myelin oligodendrocyte gp35-55. In an inverse approach, we tested the effect of depleting systemic canonical HA signaling on susceptibility to EAE by generating mice lacking all four known G-protein-coupled-HRs (H(1-4)RKO mice). In this article, we report that in contrast to HDCKO mice, H(1-4)RKO mice develop less severe EAE compared with wild-type animals. Furthermore, splenocytes from immunized H(1-4)RKO mice, compared with wild-type mice, produce a lower amount of Th1/Th17 effector cytokines. The opposing results seen between HDCKO and H1-4RKO mice suggest that HA may signal independently of H1-4R and support the existence of an alternative HAergic pathway in regulating EAE resistance. Understanding and exploiting this pathway has the potential to lead to new disease-modifying therapies in multiple sclerosis and other autoimmune and allergic diseases.

Pathophysiologic role of histamine: evidence clarified by histidine decarboxylase gene knockout mice.

The role of histamine in various murine disease models has been clarified using histidine decarboxylase gene knockout mice. The mice were generated using conventional gene-targeting methods. Studies, including ours, using knockout mice have shown that the activity of histamine is not limited to allergic, peptic and neurologic functions as in the old paradigm, but extends to other processes related to wound healing, circulatory disease, immunology, oncology and infectious disease. The recent observation of the activity of newly cloned histamine receptors and a pathophysiologic effect of histamine has dramatically expanded our understanding of the scope of histamine function.

Histamine deficiency decreases atherosclerosis and inflammatory response in apolipoprotein E knockout mice independently of serum cholesterol level.

OBJECTIVE: Histamine and histamine receptors are found in atherosclerotic lesions, and their signaling and subsequent proatherogenic or proinflammatory gene expression are involved in atherogenesis. In the present study, we generated apolipoprotein E (apoE) and histamine synthesizing histidine decarboxylase double knockout (DKO) mice on a C57BL/6J (wild-type mice) background to clarify the roles of histamine in atherosclerosis. METHODS AND RESULTS: Wild-type, apoE knockout (KO), and DKO mice were fed a high-cholesterol diet to analyze hyperlipidemia-induced atherosclerosis. Compared with wild-type mice, apoE-KO mice showed increased expression of histamine and its receptors, corresponding to increased atherosclerotic lesion areas and expression of inflammatory regulators, such as nuclear factor-κB, scavenger receptors, inflammatory cytokines, and matrix metalloproteinases. Histamine deficiency after deletion of histidine decarboxylase reduced atherosclerotic areas and expression of a range of the inflammation regulatory genes, but serum cholesterol levels of DKO mice were higher than those of apoE-KO mice. CONCLUSIONS: These results indicate that histamine is involved in the development of atherosclerosis in apoE-KO mice by regulating gene expression of inflammatory modulators, an action that appears to be independent of serum cholesterol levels. In addition to acute inflammatory response, histamine participates in chronic inflammation, such as hyperlipidemia-induced atherosclerosis, and might be a novel therapeutic target for the treatment of atherosclerosis.

Cutting edge: histamine receptor H4 activation positively regulates in vivo IL-4 and IFN-gamma production by invariant NKT cells.

Histamine (HA) is a biogenic amine with multiple activities in the immune system. In this study we demonstrate that histamine-free histidine decarboxylase-deficient (HDC(-/-)) mice present a numerical and functional deficit in invariant NK T (iNKT) cells as evidenced by a drastic decrease of IL-4 and IFN-gamma production. This deficiency was established both by measuring cytokine levels in the serum and intracellularly among gated iNKT cells. It resulted from the lack of HA, because a single injection of this amine into HDC(-/-) mice sufficed to restore normal IL-4 and IFN-gamma production. HA-induced functional recovery was mediated mainly through the H4 histamine receptor (H4R), as assessed by its abrogation after a single injection of a selective H4R antagonist and the demonstration of a similar iNKT cell deficit in H4R(-/-) mice. Our findings identify a novel function of HA through its H4R and suggest that it might become instrumental in modulating iNKT cell functions.

Histidine decarboxylase deficiency inhibits NBP-induced extramedullary hematopoiesis by modifying bone marrow and spleen microenvironments.

Histidine decarboxylase (HDC), a histamine synthase, is expressed in various hematopoietic cells and is induced by hematopoietic cytokines such as granulocyte colony-stimulating factor (G-CSF). We previously showed that nitrogen-containing bisphosphonate (NBP)-treatment induces extramedullary hematopoiesis via G-CSF stimulation. However, the function of HDC in NBP-induced medullary and extramedullary hematopoiesis remains unclear. Here, we investigated changes in hematopoiesis in wild-type and HDC-deficient (HDC-KO) mice. NBP treatment did not induce anemia in wild-type or HDC-KO mice, but did produce a gradual increase in serum G-CSF levels in wild-type mice. NBP treatment also enhanced Hdc mRNA expression and erythropoiesis in the spleen and reduced erythropoiesis in bone marrow and the number of vascular adhesion molecule 1 (VCAM-1)-positive macrophages in wild-type mice, as well as increased the levels of hematopoietic progenitor cells and proliferating cells in the spleen and enhanced expression of bone morphogenetic protein 4 (Bmp4), CXC chemokine ligand 12 (Cxcl12), and hypoxia inducible factor 1 (Hif1) in the spleen. However, such changes were not observed in HDC-KO mice. These results suggest that histamine may affect hematopoietic microenvironments of the bone marrow and spleen by changing hematopoiesis-related factors in NBP-induced extramedullary hematopoiesis.

Orexin/hypocretin and histamine: distinct roles in the control of wakefulness demonstrated using knock-out mouse models.

To determine the respective role played by orexin/hypocretin and histamine (HA) neurons in maintaining wakefulness (W), we characterized the behavioral and sleep-wake phenotypes of orexin (Ox) knock-out (-/-) mice and compared them with those of histidine-decarboxylase (HDC, HA-synthesizing enzyme)-/- mice. While both mouse strains displayed sleep fragmentation and increased paradoxical sleep (PS), they presented a number of marked differences: (1) the PS increase in HDC(-/-) mice was seen during lightness, whereas that in Ox(-/-) mice occurred during darkness; (2) contrary to HDC(-/-), Ox(-/-) mice had no W deficiency around lights-off, nor an abnormal EEG and responded to a new environment with increased W; (3) only Ox(-/-), but not HDC(-/-) mice, displayed narcolepsy and deficient W when faced with motor challenge. Thus, when placed on a wheel, wild-type (WT), but not littermate Ox(-/-) mice, voluntarily spent their time in turning it and as a result, remained highly awake; this was accompanied by dense c-fos expression in many areas of their brains, including Ox neurons in the dorsolateral hypothalamus. The W and motor deficiency of Ox(-/-) mice was due to the absence of Ox because intraventricular dosing of orexin-A restored their W amount and motor performance whereas SB-334867 (Ox1-receptor antagonist, i.p.) impaired W and locomotion of WT mice during the test. These data indicate that Ox, but not HA, promotes W through enhanced locomotion and suggest that HA and Ox neurons exert a distinct, but complementary and synergistic control of W: the neuropeptide being more involved in its behavioral aspects, whereas the amine is mainly responsible for its qualitative cognitive aspects and cortical EEG activation.

Ameliorating effect of histamine on impairment of cued fear extinction induced by morphine withdrawal in histidine decarboxylase gene knockout mice.

AIM: Histamine plays an important role in morphine addiction and memory-dependent behavior. However, little is known about the effect of histamine on the impairment of memory after morphine withdrawal. This study was designed to investigate the effect of histamine on memory impairment induced by morphine withdrawal in histidine decarboxylase knockout (HDC-KO) and wild-type (WT) mice. METHODS: WT and HDC-KO mice were given subcutaneous morphine or saline twice daily for 5 consecutive days. The mice received a cued or contextual fear conditioning session 7 days after the last injection. During subsequent days, mice received 4 cued or contextual extinction sessions (one session per day). Western blot was used to assess extracellular signal-regulated kinase (ERK) phosphorylation in the amygdala and hippocampus. RESULTS: Morphine withdrawal did not affect the acquisition of cued or contextual fear responses. It impaired cued but not contextual fear extinction. The acquisition of cued and contextual fear responses was accelerated in HDC-KO mice. Histamine deficiency aggravated the impairment of cued fear extinction induced by morphine withdrawal, whereas histamine (icv, 5 µg/mouse) reversed this effect. Morphine withdrawal decreased ERK phosphorylation in the amygdala after cued fear extinction, especially in HDC-KO mice. CONCLUSION: These results suggest that morphine withdrawal specifically impairs cued fear extinction and histamine ameliorates this impairment. Its action might be mediated by the modulation of ERK phosphorylation in the amygdala. Histamine should be explored for possible roles in the prevention or treatment of morphine abuse and relapse.

Histamine plays an essential regulatory role in lung inflammation and protective immunity in the acute phase of Mycobacterium tuberculosis infection.

The course and outcome of infection with mycobacteria are determined by a complex interplay between the immune system of the host and the survival mechanisms developed by the bacilli. Recent data suggest a regulatory role of histamine not only in the innate but also in the adaptive immune response. We used a model of pulmonary Mycobacterium tuberculosis infection in histamine-deficient mice lacking histidine decarboxylase (HDC(-/-)), the histamine-synthesizing enzyme. To confirm that mycobacterial infection induced histamine production, we exposed mice to M. tuberculosis and compared responses in C57BL/6 (wild-type) and HDC(-/-) mice. Histamine levels increased around fivefold above baseline in infected C57BL/6 mice at day 28 of infection, whereas only small amounts were detected in the lungs of infected HDC(-/-) mice. Blocking histamine production decreased both neutrophil influx into lung tissue and the release of proinflammatory mediators, such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha), in the acute phase of infection. However, the accumulation and activation of CD4(+) T cells were augmented in the lungs of infected HDC(-/-) mice and correlated with a distinct granuloma formation that contained abundant lymphocytic infiltration and reduced numbers of mycobacteria 28 days after infection. Furthermore, the production of IL-12, gamma interferon, and nitric oxide, as well as CD11c(+) cell influx into the lungs of infected HDC(-/-) mice, was increased. These findings indicate that histamine produced after M. tuberculosis infection may play a regulatory role not only by enhancing the pulmonary neutrophilia and production of IL-6 and TNF-alpha but also by impairing the protective Th1 response, which ultimately restricts mycobacterial growth.

Abnormal behavior, striatal dopamine turnover and opioid peptide gene expression in histamine-deficient mice.

Hypothalamic histaminergic neurons regulate a variety of homeostatic, metabolic and cognitive functions. Recent data have suggested a modulatory role of histamine and histamine receptors in shaping striatal activity and connected the histaminergic system to neuropsychiatric disorders. We characterized exploratory behavior and striatal neurotransmission in mice lacking the histamine producing enzyme histidine decarboxylase (Hdc). The mutant mice showed a distinct behavioral pattern during exploration of novel environment, specifically, increased frequency of rearing seated against the wall, jumping and head/body shakes. This behavioral phenotype was associated with decreased levels of striatal dopamine and serotonin and increased level of dopamine metabolite DOPAC. Gene expression levels of dynorphin and enkephalin, opioids released by medium spiny neurons of striatal direct and indirect pathways respectively, were lower in Hdc mutant mice than in control animals. A low dose of amphetamine led to similar behavioral and biochemical outcomes in both genotypes. Increased striatal dopamine turnover was observed in Hdc KO mice after treatment with dopamine precursor l-Dopa. Overall, our study suggests a role for striatal dopamine and opioid peptides in formation of distinct behavioral phenotype of Hdc KO mice.

Histamine-deficient mice do not respond to the antidepressant-like effects of oleoylethanolamide.

It has been suggested that the bioactive lipid mediator oleoylethanolamide (OEA), a potent agonist of the peroxisome proliferator-activated receptor-alpha (PPAR-α) possesses anti-depressant-like effects in several preclinical models. We recently demonstrated that several of OEA's behavioural actions require the integrity of the brain histaminergic system, and that an intact histaminergic neurotransmission is specifically required for selective serotonin re-uptake inhibitors to exert their anti-depressant-like effect. The purpose of our study was to test if OEA requires the integrity of the histaminergic neurotransmission to exert its antidepressant-like effects. Immobility time in the tail suspension test was measured to assess OEA's potential (10 mg/kg i.p.) as an antidepressant drug in histidine decarboxylase null (HDC-/-) mice and HDC+/+ littermates, as well as in PPAR-α+/+ and PPAR-α-/- mice. CREB phosphorylation was evaluated using Western blot analysis in hippocampal and cortical homogenates, as pCREB is considered partially responsible for the efficacy of antidepressants. Serotonin release from ventral hippocampi of HDC+/+ and HDC-/- mice was measured with in-vivo microdialysis, following OEA administration. OEA decreased immobility time and increased brain pCREB levels in HDC+/+ mice, whereas it was ineffective in HDC-/- mice. Comparable results were obtained in PPAR-α+/+ and PPAR-α-/- mice. Microdialysis revealed a dysregulation of serotonin release induced by OEA in HDC-/- mice. Our observations corroborate our hypothesis that brain histamine and signals transmitted by OEA interact to elaborate appropriate behaviours and may be the basis for the efficacy of OEA as an antidepressant-like compound.

Highly activated c-fos expression in specific brain regions (ependyma, circumventricular organs, choroid plexus) of histidine decarboxylase deficient mice in response to formalin-induced acute pain.

Activation of different brain regions for acute pain-related stress induced by a single subcutaneous injection of 4% formalin was investigated in histidine decarboxylase-deficient mice. Besides pain- and stress-related brain areas and the tuberomamillary neurons, strong Fos activation and c-fos mRNA expression were found in distinct brain regions and cell types, which have not been activated in wild type control mice. These structures include the circumventricular organs (organum vasculosum of the lamina terminalis, subfornical organ, area postrema), some of the ependymal cells along the wall of the ventricles, tanycytes in the third ventricle's ependyma and the median eminence, as well as in the epithelial cells of the choroid plexus in the lateral, third and fourth ventricles. All of these areas and cell types are known as compartments of the brain-blood-cerebrospinal fluid interface. The present observations provide strong evidence that an acute stressor, formalin-evoked painful stimulus elicits rapid alterations in the activity of neuroglial elements of histidine decarboxylase-deficient mice that are directly involved in the communication between the brain and the cerebrospinal fluid space.

Involvement of chemical mediators in nasal allergic responses of HDC-KO mice.

The present study was undertaken to investigate the involvement of chemical mediators in nasal allergic responses using histidine decarboxylase knockout (HDC-KO) mice. An allergic rhinitis model was developed in HDC-KO and wild-type mice by the intraperitoneal injection of ovalbumin, aluminum hydroxide gel and pertussis toxin. Five days later, they were boosted by a subcutaneous injection of ovalbumin into the back. From day 18 after the first immunization to day 39, intranasal sensitization with ovalbumin was performed every day and the severity of allergic rhinitis was observed by measuring nasal allergic responses and total IgE levels. It was found that the intranasal administration of antigen caused a significant increase of nasal sneezing and rubbing from day 25 to day 39 both in sensitized HDC-KO and wild-type mice. In addition, a significant elevation of total IgE levels in serum was also found both in sensitized HDC-KO and wild-type mice from day 18 to day 39 after the first immunization. L-733,060, a tachykinin NK(1) receptor antagonist at a dose of 10 mg/kg (s.c.), resulted in the dose-dependent inhibition of nasal allergic responses induced by antigen in both HDC-KO and wild-type mice. In addition, both chlorpheniramine at doses of 3 and 10 mg/kg (p.o.) and BW A868C at doses of 0.3 and 1 mg/kg (i.v.) also showed a dose-related reduction of the nasal allergic responses induced by antigen in sensitized wild-type mice. On the other hand, they had no effects on the nasal signs induced by antigen in HDC-KO mice. From these results, it was revealed that substance P induces nasal allergic responses in the mouse model of chronic allergic rhinitis through the activation of tachykinin NK(1) receptors. Therefore, it can be concluded that not only histamine, but also substance P and prostaglandin D(2), participated in the nasal allergic responses induced by antigen in mice.

Carnosine inhibits pentylenetetrazol-induced seizures by histaminergic mechanisms in histidine decarboxylase knock-out mice.

In the present study, we used both histidine decarboxylase-deficient (HDC-KO) mice and wild-type (WT) mice to elucidate the possible role of carnosine in pentylenetetrazol (PTZ)-induced seizures. In the acute PTZ challenge study, PTZ (75 mg/kg) was injected intraperitoneally (i.p.) to induce seizures. Carnosine (200, 500 or 1000 mg/kg, i.p.) significantly decreased seizure stage, and prolonged the latency for myoclonic jerks in WT mice in a dose-dependent manner. The effects of carnosine (500 mg/kg) were time-dependent and reached a peak at 1h. However, it had no significant effect on HDC-KO mice. Carnosine (500 mg/kg) also significantly elevated the thresholds in WT mice but not HDC-KO mice following intravenous (tail vein) administration of PTZ. We also found that alpha-fluoromethylhistidine substantially reversed the protective effects of carnosine in WT mice. In addition, carnosine pretreatment reduced the cortical EEG activity induced by PTZ (75 mg/kg, i.p.). These results indicate that carnosine can protect against PTZ-induced seizures and its action is mainly through the carnosine-histidine-histamine metabolic pathway. This suggests that carnosine may be an endogenous anticonvulsant factor in the brain and may be used as a new antiepileptic drug in the future.