Effects of histamine H(3) antagonists and donepezil on learning and mnemonic deficits induced by pentylenetetrazol kindling in weanling mice

Childhood epilepsy is one of the main risk factors for a variety of problems involving cognition and behavior. Pentylenetetrazol (PTZ) kindling is currently an acceptable model for epilepsy research. The objectives of this study are to clarify the learning and mnemonic characteristics of PTZ kindling in developing mice, and to examine the effects of thioperamide and JNJ-5207852, two histamine H(3) receptor antagonists and donepezil, an acetylcholinesterase (AChE) inhibitor, on learning and memory deficits induced by PTZ kindling in the brains of developing mice. PTZ kindling led to learning and mnemonic deficits as assessed by social discrimination, acoustic fear conditioning, water maze and passive avoidance tests. Thioperamide and JNJ-5207852, ameliorated PTZ kindling-induced learning and mnemonic deficits in all tests except for the water maze test. In addition, the learning and mnemonic impairments induced by PTZ kindling were significantly improved by donepezil in all tests. These findings suggest that histamine and acetylcholine are involved in the different processes of learning and memory in the brain and that histamine H(3) receptor antagonists might be useful in the treatment of cognitive impairment in epilepsy.     

H3 receptor blockade by thioperamide enhances cognition in rats without inducing locomotor sensitization

Rationale. Attention deficit hyperactivity disorder (ADHD) is currently treated with psychomotor stimulants, including methylphenidate and amphetamine. Several adverse effects are associated with these drugs, however, such as agitation and abuse. H₃ receptor antagonists are under clinical investigation for ADHD. Objectives. To investigate the potential of thioperamide, a prototypical H₃ receptor antagonist, to enhance learning and attention while inducing no effects on locomotor stimulation and sensitization, or alterations in ACTH levels. Methods. Thioperamide (1, 3, 10, 30 mg/kg) was administered prior to testing in a multi-trial, inhibitory avoidance response in rat pups (five trials separated by 1 min) to evaluate attention/cognition. Locomotor sensitization and cross-sensitization was assessed following administration of methylphenidate (3 mg/kg), cocaine (10 mg/kg), or thioperamide (1, 3, 10 mg/kg). Results. Thioperamide significantly enhanced performance of the five-trial inhibitory avoidance response with efficacy similar to that previously reported for methylphenidate. Administration of amphetamine, methylphenidate and cocaine produced significant locomotor sensitization, however. In contrast, thioperamide did not induce locomotor stimulation or sensitization, nor did it cross-sensitize to the stimulant effects of amphetamine or cocaine. The repeated administration of methylphenidate significantly elevated ACTH levels, while thioperamide did not affect this neuroendocrine endpoint. Conclusions. H₃ receptor blockade may offer a safer alternative to psychomotor stimulants for the treatment of ADHD. Electronic Publication     

Microinjection of histamine into the dentate gyrus produces antinociception in the formalin test in rats

The present study was aimed to investigate the effects of microinjection of histamine, chlorpheniramine (a histamine H₁ receptor antagonist), ranitidine (a histamine H₂ receptor antagonist) and thioperamide (a histamine H₃ receptor antagonist) into the dentate gyrus on the formalin-induced pain. A biphasic pattern (first phase: 0-5 min and second phase: 15-60 min) in nociceptive responses was induced after subcutaneous injection of formalin (50 μl, 2.5%) into the ventral surface of the right hind paw. Microinjection of histamine (1 and 2 μg) into the dentate gyrus decreased the intensity of nociceptive responses. Intra-dentate gyrus microinjection of chlorpheniramine and ranitidine at the same doses of 1 and 4 μg had no effects, whereas thioperamide at a dose of 4 μg suppressed both phases of formalin-induced pain. Pretreatments with chlorpheniramine and ranitidine at the same dose of 4 μg prevented histamine (2 μg)-induced antinociception, while thioperamide (4 μg) increased histamine (2 μg)-induced antinociception. These results indicated that activation of brain neuronal histamine at the levels of dentate gyrus produced antinociception. The post-synaptic H₁, H₂ receptors and pre-synaptic H₃ receptors of histamine may be involved in the histamine-induced antinociception at the level of the dentate gyrus.     

Histamine 3 receptor activation mediates inhibition of acid secretion during Helicobacter-induced gastritis

AIM: To test the hypothesis that histamine 3 receptor (H3R) activation during Helicobacter infection inhibits gastric acid secretion in vivo and in vitro.METHODS: Helicobacter felis (H. felis) infected and uninfected C57Bl/6 mice were infused with either PBS or the H3 receptor antagonist thioperamide (THIO) for 12 wk. After treatment, mice were analyzed for morphological changes and gastric acid content. Total RNA was prepared from the stomachs of each group and analyzed for changes in somatostatin and gastrin mRNA abundance by real time-polymerase chain reaction (RT-PCR). Location of H3 receptors in the stomach was analyzed by co-localization using antibodies specific for the H3 receptor and parietal cell marker H⁺, K⁺-ATPase β subunit.RESULTS: Inflammation and parietal cell atrophy was observed after 12 wk of H. felis infection. Interestingly, treatment with the H3R antagonist thioperamide (THIO) prior to and during infection prevented H. felis-induced inflammation and atrophy. Compared to the uninfected controls, infected mice also had significantly decreased gastric acid. After eradication of H. felis with THIO treatment, gastric acidity was restored. Compared to the control mice, somatostatin mRNA abundance was decreased while gastrin gene expression was elevated during infection. Despite elevated gastric acid levels, after eradication of H. felis with THIO, somatostatin mRNA was elevated whereas gastrin mRNA was suppressed. Immunofluorescence revealed the presence of H3 receptors on the parietal cells, somatostatin-secreting D-cells as well as the inflammatory cells.CONCLUSION: This study shows that during H. felis infection, gastric acidity is suppressed as a consequence of an inhibitory effect on the parietal cell by H3R activation. The stimulation of gastric mucosal H3Rs increases gastrin expression and release by inhibiting release of somatostatin.     

Inhibitory effect of iodophenpropit, a selective histamine H3 antagonist, on amygdaloid kindled seizures

The effect of histamine H₃ antagonist, iodophenpropit on amygdaloid kindled seizures in rats was studied in comparison with those of other H₃ antagonists. Under pentobarbital anesthesia, the rats were fixed to a stereotaxic apparatus and bipolar electrodes were implanted into the amygdala. Electrodes were connected to a miniature receptacle, which was embedded in the skull with dental cement. To cause kindled seizures, electrical stimulation was applied to the amygdala bipolarly every day by a constant current stimulator, and electroencephalogram and convulsive behavior were observed. Drug effects were estimated in rats showing generalized kindled seizures. Intraperitoneal injection of H₃ antagonists, iodophenpropit, thioperamide, AQ0145 and clobenpropit, resulted in a dose-related inhibition of amygdaloid kindled seizures. The effect of iodophenpropit on amygdaloid kindled seizures was more potent than those of thioperamide, AQ0145 and clobenpropit. In conclusion, iodophenpropit may be useful for the treatment of partial epilepsy and/or secondary generalized seizures in humans.     

Evaluation of Thioperamide Effects Using Rat's Trachea Model

Objectives

Thioperamide is used as an antagonist to the histamine H₃ receptor. During administration of the drug, the trachea may be affected via nasal or oral inhalation. This study was to determine the effects of thioperamide on the trachea of rats in vitro.

Methods

We tested the effectiveness of thioperamide on isolated rat trachea submersed in Kreb''s solution in a muscle bath. Changes in tracheal contractility in response to the application of parasympathetic mimetic agents were measured. The following assessments of thioperamide were performed: 1) effect on tracheal smooth muscle resting tension; 2) effect on contraction caused by 10^-6 M methacholine as a parasympathetic mimetic; 3) effect of the drug on electrically-induced tracheal smooth muscle contractions.

Results

Thioperamide induced a significant relaxation response at a preparation concentration up to 10^-4 M. The drug also inhibited the electrical field stimulation induced spike contraction. However, thioperamide alone had a minimal effect on the basal tension of the trachea at increasing concentrations.

Conclusion

The study indicated that high concentrations of thioperamide might actually antagonize cholinergic receptors and block parasympathetic function of the trachea.     

CSF histamine levels in rats reflect the central histamine neurotransmission

Reduced cerebrospinal fluid (CSF) histamine levels were found in human hypersomnia. To evaluate the functional significance of changes in CSF histamine levels, we measured the levels in rats across 24 h, after the administration of wake-promoting compounds modafinil, amphetamine, and thioperamide, and after sleep deprivation and food deprivation. Thioperamide significantly increased CSF histamine levels with little effects on locomotor activation. Both modafinil and amphetamine markedly increased the locomotor activity, but had no effects on histamine. The levels are high during active period and are markedly elevated by sleep deprivation, but not by food deprivation. Our study suggests that CSF histamine levels in rats reflect the central histamine neurotransmission and vigilance state changes, providing deeper insight into the human data.     

Role of histamine receptors in the regulation of edema and circulation postburn

Despite histamine being a potent endogenous vasoactive agent released in increasing amounts postburn, its role in postburn oedema formation has been controversial and its effect on burn circulation poorly investigated. The present study investigated the involvement of H₁, H₂ and H₃ receptors in postburn edema in rats exposed to skin and muscle burns and their influence on skin circulation postburn. We used the selective antagonists clemastine (H₁), ranitidine (H₂), thioperamide (H₃) and the selective H₃ receptor agonist, imetit. Results showed that none of the antagonists or the H₃ agonist had significant effect on postburn edema measured by quantitative spectrophotometric analysis of extravasated Evans blue-albumin in the full-thickness burned skin or muscle. Clemastine and thioperamide failed to induce significant effect on blood flow in the partial- or full-thickness skin burn injury as measured by laser Doppler flowmetry, while ranitidine significantly (P<0.01) reduced blood flow in the full-thickness burn. In contrast, the H₃ receptor agonist, imetit, significantly increased blood flow, both in the partial-thickness burn injury (P<0.05) and in the full-thickness burn (P<0.01). Moreover, imetit significantly (P<0.01) increased mean arterial pressure while thioperamide significantly (P<0.01) reduced systemic pressure. In conclusion, H₁, H₂ and H₃ receptors are not important actors in the regulation of vascular patency permeability, whereas H₃ receptors play an important role by increasing skin circulation postburn, presumably by relaxation of vascular smooth muscle and/or by interacting with other inflammatory neurotransmitters. Data also suggest that H₂ receptor blockers may not be best choice for stress ulcer prophylaxis in burn patients.     

Histaminergic modulation of neocortical spindling and slow-wave activity in freely behaving rats

Summary Histaminergic H3 receptor antagonists stimulate neuronal histamine release and could consequently have a number of physiological effects in the brain. The effects of H3 receptor blockade, induced by systemically administered thioperamide, were assessed on the frontal cortex electroencephalographic (EEG) properties in freely behaving rats. The relationship of EEG activity variables to endogenous brain histaminergic markers was also examined, both in controls and in portocaval anastomosis (PCA)-operated rats (which show increased levels of brain histamine and t-methylhistamine). Thioperamide reduced the incidence of thalamusregulated EEG spindles, while it slightly increased their amplitude. It furthermore reduced the spectral power of low-frequency (1.5–5 Hz) EEG, which effect was equally distributed over the spindle and non-spindle EEG states. These EEG effects were accompanied by increased motor activity of the animals. Both the low-frequency EEG activity and spindle incidence correlated inversely with the histamine level of the brain (hypothalamus and cerebellum excluded) while t-methylhistamine level correlated with the degree of thioperamide-induced reduction of slow-wave EEG activity. The present results provide evidence for the involvement of endogenous brain histamine level, histamine release (as assessed by t-methylhistamine level) and H3 receptors in the histaminergic regulation of neocortical synchronization patterns assumed to be linked to arousal control.     

Evidence that histamine H3 receptors are involved in the control of gastric acid secretion in the conscious cat

Summary In an attempt to assess the role of histamine H₃ receptors in the control of gastric acid secretion, the effects of the selective histamine H3 receptor agonist, (R)-methylhistamine and antagonist, thioperamide were evaluated in the conscious gastric fistula cat under basal conditions and against different stimuli. (R)-methylhistamine (0.05–0.2 mol/kg/h) was ineffective against spontaneous and dimaprit-induced acid secretion; it also did not reduce significantly pentagastr-ininduced acid output, but caused a dose-dependent (0.05–0.1 mol/kg/h) and significant inhibition of the acid response to 2-deoxy-d-glucose. Thioperamide (0.02–0.04 mol/kg/h) did not modify spontaneous acid secretion, whereas it evoked a significant enhancement of the acid response to submaximal doses (50 mg/kg i. v.) of 2-deoxy-d-glucose. Thioperamide completely reversed the inhibitory effect of (R)-methylhistamine against 2-deoxy-d-glucose-induced secretion, while leaving unaffected the inhibition induced by somatostatin. These data suggest that histamine H3 receptors may be involved in the control of acid secretion stimulated by indirectly acting secretagogues. Send offprint requests to G. Bertaccini at the above address