Inhibitory Effect of Imiquimod-Induced Psoriasis-Like Skin Inflammation in Mice by Histamine H4 Receptor Agonist 4-Methylhistamine.

Psoriasis is a chronic inflammatory immune-mediated autoimmune skin disorder. The histamine H4 receptor (H4R) agonist 4-methylhistamine (4-MH) plays an important role in immunomodulation of inflammatory responses associated with allergic inflammatory diseases. In this study, we investigated the effects of H4R agonist 4-MH on the development of imiquimod (IMQ)-induced psoriasis-like skin inflammation in mice and explored the immunoregulatory mechanism involved. The total clinical severity scores were significantly ameliorated by treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Histological analysis of the skin revealed that 4-MH (20 mg/kg) and 4-MH (40 mg/kg) significantly attenuated the psoriatic phenotypes, including epidermal hyperplasis, hyperkeratosis and lymphocytes infiltration. Treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg) led to reductions in the levels of Th1 cytokines (TNF-α, IFN-α, and IL-27) in the serum and dorsal skin, whereas Th17 cytokines levels (IL-17A and IL-23) did not change in response to treatment with 4-MH (20 mg/kg) and 4-MH (40 mg/kg). Furthermore, the number of CD4(+) CD25(+) FoxP3(+) regulatory T (Treg) cells was significantly increased by treatment with 4-MH (40 mg/kg). Taken together, these results imply that H4R agonist 4-MH might be an effective immunomodulatory approach for treatment of patients with psoriasis and the effects may be related to inhibited epidermal alteration, selectively reduced Th1 pro-inflammatory cytokines, and recruited CD4(+) CD25(+) FoxP3(+) Treg cells.

(R)-alpha-methylhistamine suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons counteracting propofol-induced amnesia in rats.

BACKGROUND: Propofol is a short-acting, intravenous general anesthetic that is widely used in clinical practice for short procedures; however, it causes depressed cognitive function for several hours thereafter. (R)-alpha-methylhistamine (RAMH), a selective histamine H3 receptor agonist, can enhance memory retention and attenuates memory impairment in rats. In this study, we investigated whether RAMH could rescue propofol-induced memory deficits and the underlying mechanisms partaking in this process. METHODS: In the modified Morris water maze (MWM) test, rats were randomized into the following groups: control, propofol (25 mg/kg, i.p., 30 min before training), RAMH (10 mg/kg, i.p., 60 min before training), and propofol plus RAMH. All randomized rats were subjected to 2 days of training, and a probe test was conducted on day 3. Field excitatory postsynaptic potentials were recorded from CA1 neurons in rat hippocampal slices, and long-term potentiation (LTP) was induced by either theta-burst stimulation (TBS) or high-frequency tetanic stimulation (HFS). Spontaneous and miniature inhibitory (sIPSCs, mIPSCs) or excitatory (sEPSCs, mEPSCs) postsynaptic currents were recorded from CA1 pyramidal neurons by whole-cell patch clamp. RESULTS: In the MWM task, propofol injection significantly impaired spatial memory retention. Pretreatment with RAMH reversed propofol-induced memory retention. In hippocampal CA1 slices, propofol perfusion markedly inhibited TBS- but not HFS-induced LTP. Co-perfusion of RAMH reversed the inhibitory effect of propofol on TBS-induced LTP reduction. Furthermore, in hippocampal CA1 pyramidal neurons, RAMH significantly suppressed the frequency but not the amplitude of sIPSCs and mIPSCs and had little effects on both the frequency and amplitude of sEPSCs and mEPSCs. CONCLUSIONS: Our results suggest that RAMH, by inhibiting presynaptic GABAergic neurotransmission, suppresses inhibitory neurotransmission in hippocampal CA1 pyramidal neurons, which in turn reverses inhibition of CA1 LTP and the spatial memory deficits induced by propofol in rats.

N alpha methyl histamine versus propranolol in migraine prophylaxis.

OBJECTIVES: To compare the efficacy and tolerability of the subcutaneous administration of N alpha methyl histamine versus oral propranolol in the treatment of migraine prophylaxis. BACKGROUND: N alpha methyl histamine has a selective affinity for H3 receptors and could constitute a new therapeutic drug in migraine prophylaxis. METHODS: Sixty patients with migraine were selected and enrolled in a 12-week double-blind controlled clinical trial to evaluate the efficacy of subcutaneous administration of N-alpha methyl histamine (1 to 3 ug twice a week ) n=30, compared to administration of 120 mg/day of oral propranolol n=30. the variables were: headache intensity, frequency of attacks, duration of migraine attacks and analgesic intake. RESULTS: fifty five patients completed the study. the data collected during the 4th week of treatment revealed that N alpha methyl histamine and propranolol caused a significantly (p<0.01) greater reduction between the basal values and final values of every variable studied. CONCLUSIONS: Both N alpha methyl histamine and propranolol are similarly effective in reducing or eliminating the headache in migraine prophylaxis. low doses of N-alpha methyl histamine injected subcutaneously may represent a novel and effective therapeutic alternative in migraine patients and may lay the clinical and pharmacological groundwork for the use of H3 receptor agonist in migraine prophylaxis.

Role of a histamine 4 receptor as an anti-inflammatory target in carrageenan-induced pleurisy in mice.

The histamine 4 receptor (H4R) is expressed primarily on cells involved in inflammation and immune responses. Despite much research into inflammatory diseases, no drugs with favourable safety profiles are yet available for their treatment. The aim of the present study was to determine the potential anti-inflammatory effect of 4-methylhistamine (4-MeH) or JNJ77777120 (JNJ) and to explore the role of H4R in a mouse model of carrageenan (Cg) -induced pleurisy. A single dose of 4-MeH or JNJ (30 mg/kg) was administered intraperitoneally 1 hr before Cg administration. The results illustrate that both the numbers of CD4(+) , CD25(+) , CD4(+)  CD25(+) , GITR(+) , GITR(+)  IL-17A(+) -expressing T cells and the levels of T helper type 1 (Th1)/Th17 cytokines were markedly increased in both the Cg-treated and 4-MeH-treated groups, whereas the cytokines produced by Th2 cells were significantly decreased in the same groups. However, JNJ treatment significantly decreased both the number of T-cell subsets and GITR(+) , GITR(+)  IL-17A(+) -expressing T cells, and the production of Th1/Th17 cytokines. Further, JNJ up-regulated the expression of the Th2 cytokines. RT-PCR analysis revealed an increased expression of interleukin-1ß, tumour necrosis factor-α, monocyte chemoattractant protein-1 and intercellular adhesion molecule-1 in the Cg-treated and 4-MeH-treated groups, which was reduced by treatment with JNJ in lung tissues. Moreover, histological examinations revealed anti-inflammatory effects of JNJ, whereas 4-MeH worsened Cg-induced inflammation. In conclusion, the results of the present work clearly indicate that JNJ possesses important anti-inflammatory properties that are increased in 4-MeH-treated mice, suggesting that H4R are involved in pleurisy and that JNJ has an anti-inflammatory effect in associated disease conditions.

Nalpha-methylhistamine safety and efficacy in migraine prophylaxis: phase I and phase II studies.

OBJECTIVE: To study the therapeutic potential of the subcutaneous administration of Nalpha-methylhistamine in migraine prophylaxis. BACKGROUND: The histamine catabolite, Nalpha-methylhistamine, possesses a selective affinity for H3 receptors. We consequently considered it viable to conduct a clinical pharmacological study to evaluate the safety and efficacy of this histaminergic H3 agonist in migraine prophylactic treatment, which specifically may inhibit the neurogenic edema response involved in migraine pathophysiology. METHODS: Phase I.-In a clinical trial of 30 healthy volunteers, the effects of the subcutaneous administration of Nalpha-methylhistamine and placebo were studied to assess undesirable symptomatic effects. Phase II.-In a clinical open study, we evaluated the efficacy of Nalpha-methylhistamine in reducing headache intensity, frequency, and duration; and in decreasing analgesic intake in 18 patients with migraine. RESULTS: Phase I.-None of the variables studied showed significant differences (P>.05), and no secondary effects were observed at doses below 10 ng. Phase II.-Nalpha-methylhistamine, at doses of 1 to 3 ng, significantly reduced (P<.0001) the frequency, intensity, and duration of migraine attacks, as well as the need for rescue analgesics. However, at doses greater than 3 ng, patients experienced intense headache. CONCLUSIONS: The present study provides evidence of the safety and efficacy of Nalpha-methylhistamine applied subcutaneously at doses of 1 to 3 ng twice a week.

Histamine and selective H3-receptor ligands: a possible role in the mechanism and management of epilepsy.

The interaction of selective histamine H3-receptor agonist R(alpha)-methyl-histamine (RAMH) and antagonist thioperamide (THP) with some antiepileptic drugs [AED; phenytoin (PHT), carbamazepine (CBZ), sodium valproate (SVP), and gabapentin (GBP)] was studied on seizures induced by maximal electroshock (MES) and pentylenetetrazole (PTZ) in mice. It was found that subeffective dose of THP in combination with the subeffective doses of PHT and GBP provided protection against MES and/or PTZ-induced seizures. Further, RAMH reversed the protection afforded by either PHT or GBP on MES and/or PTZ seizures. In another set of experiments, the histamine content was measured in the whole brain and in different brain regions including cerebral cortex, hypothalamus, brain stem and cerebellum following convulsant (MES and PTZ) and AED treatment. It was seen that while MES exhibited a tendency to enhance brain histamine levels, PTZ showed the opposite effect. AEDs either increased (PHT and GBP) or decreased (SVP) brain histamine content in different regions to varying degrees. The results indicate a role for histamine in seizures and in the action of AEDs and suggest that selective H3-receptor antagonists may prove to be of value as adjuncts to conventional AEDs.

Effects of histamine H3 receptor ligands in experimental models of anxiety and depression.

Histamine H3 receptor ligands have been proposed to be of potential therapeutic interest for the treatment of different central nervous system disorders; however, the psychopharmacological properties of these drugs have not been studied extensively. In this work, we investigated the possible involvement of histamine H3 receptor function in experimental models of anxiety (elevated plus-maze) and depression (forced swimming test). Male Sprague-Dawley rats were treated i.p. with the histamine H3 receptor agonist R-alpha-methylhistamine (10 mg/kg) or the histamine H3 receptor antagonist thioperamide (0.2, 2 and 10 mg/kg) and 30 min afterwards the time spent in the open arms of an elevated plus-maze was registered for 5 min. The immobility time of male OF1 mice in the forced swimming test was recorded for 6 min, 1 h after the i.p. administration of R-alpha-methylhistamine (10 and 20 mg/kg), thioperamide (0.2, 2, 10 and 20 mg/kg) or another histamine H3 receptor antagonist, clobenpropit (5 mg/kg). The locomotor activity of mice was checked in parallel by means of an activity meter. Both saline controls and active drug controls were used in all the paradigms. Neither thioperamide nor R-alpha-methylhistamine significantly changed animal behaviour in the elevated plus-maze. R-alpha-methylhistamine and the higher dose of thioperamide assayed (20 mg/kg) were also inactive in the forced swimming test. By contrast, thioperamide (0.2-10 mg/kg) dose-dependently decreased immobility, the effect being significant at 10 mg/kg (33% reduction of immobility); clobenpropit produced an effect qualitatively similar (24% reduction of immobility). None of these histamine H3 receptor antagonists affected locomotor activity. These preliminary results suggest that the histamine H3 receptor blockade could be devoid of anxiolytic potential but have antidepressant effects. Besides, the stimulation of these receptors does not seem to be followed by changes in the behavioural parameters studied.

Comparison of the protective effect of (R)-alpha-methylhistamine and its prodrugs on gastric mucosal damage induced by ethanol in the rat.

1. The gastroprotective activity of two azomethine prodrugs of (R)-alpha-methylhistamine was examined in lesions induced by absolute ethanol (1 ml/rat intragastrically for 1 h). 2. Pretreatment with (R)-alpha-methylhistamine as well as with the prodrugs (30 and 100 mg/kg intragastrically [IG]) significantly reduced macroscopically visible lesions caused by ethanol, with protection being almost complete at 100 mg/kg. 3. Histologically, in rats pretreated with the three compounds at a dose of 100 mg/kg, the evidence of damage was rare, with the appearance of gastric mucosa being similar in the different groups. 4. Present results are suggestive of a local component in the protective activity of (R)-alpha-methylhistamine.

Drugs for peptic ulcer.

Conservative management of peptic ulcer relies on the use of drugs as an adjuvant to the time-honored measures of avoiding stress, reducing gastric secretion, and regulating the diet. Alkalies neutralize acid and anticholinergic drugs partly inhibit secretion.. Both are widely used but are often inadequate to control symptoms. Carbenoxolone appears to have a more specific effect in promoting healing of gastric ulcers and has now been used for 15 years. Its role in the treatment of gastric ulcer can be critrically examined, particularly in relation to how this influences surgical management. Recently introduced compounds know as histamine H2-receptor antagonists have a profound effect in inhibiting gastric secretion. Early experience in patients with duodenal ulcer indicated the efficacy of these compounds in promoting healing. These potent new drugs are likely to influence strongly the management of patients with duodenal ulcer, and this may affect the indications for surgery.