Effects of thioperamide on seizure development and memory impairment induced by pentylenetetrazole-kindling epilepsy in rats / 中华医学杂志(英文版)

<p><b>BACKGROUND</b>Histamine H(3) receptor antagonists have been considered as potential drugs to treat central nervous system diseases. However, whether these drugs can inhibit epileptogenesis remains unclear. This study aimed to investigate the effects of thioperamide, a selective and potent histamine H(3) receptor antagonist, on the seizure development and memory impairment induced by pentylenetetrazole (PTZ)-kindling epilepsy in rats.</p><p><b>METHODS</b>Chemical kindling was elicited by repeated intraperitoneal (ip) injections of a subconvulsant dose of PTZ (35 mg/kg) once every 48 hours for 12 times, and seizure activity of kindling was recorded for 30 minutes. Control rats were ip injected with saline instead of PTZ. Morris water maze was used to evaluate the spatial memory. Phosphorylated cyclic adenosine monophosphate response element binding protein (p-CREB) was tested by Western blotting in hippocampus.</p><p><b>RESULTS</b>Intracerebroventricular (icv) injections with thioperamide (10 µg, 20 µg) 30 minutes before every PTZ injections, significantly prolonged the onset of PTZ-kindling and inhibited the seizure stages. PTZ-kindling seizures led to the impairment of spatial memory in rats, and thioperamide ameliorated the impairment of spatial learning and memory. Compared to non-kindling rats, there was a significant decrease in p-CREB level in hippocampus of the PTZ-kindling rats, which was reversed by thioperamide.</p><p><b>CONCLUSIONS</b>Thioperamide plays a protective role in seizure development and cognitive impairment of PTZ-induced kindling in rats. The protection of thioperamide in cognitive impairment is possibly associated with the enhancement of CREB-dependent transcription.</p>

Identification of a HEK-293 cell line containing stably-transfected H3R gene and screening for novel non-imidazole histamine H3 receptor antagonists / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To identify a HEK293 cell line containing stably-transfected H3R gene, and to screen the novel non-imidazole compounds with H3R antagonist activity.</p><p><b>METHODS</b>The expression of rat H3 receptor in cell line was detected by RT-PCR and Western blot. An elevation of intercellular cAMP concentration induced by forskolin was measured as the index for screening compounds with H3R antagonist activity.</p><p><b>RESULTS</b>The H3R-transfected HEK-293 cells stably expressed high level of rat H3 receptor mRNA and protein. Forskolin significantly increased intercellular cAMP concentration in the H3R-transfected HEK-293 cells. H3R agonist (R)-α-methylhistamine inhibited the forskolin-induced production of intercellular cAMP. H3R antagonist thioperamide and newly synthesized non-imidazole compounds XHA23 and XHA25 blocked (R)-α- methylhistamine reversal of forskolin-induced cAMP formation in a concentration-dependent manner, and the IC50 values were 3.62 μmol/L, 0.49 μmol/L, 0.14 μmol/L, respectively.</p><p><b>CONCLUSION</b>The H3R-transfected HEK293 cells stably express high level of rat H3 receptor, and can be used for screening compounds with H3R antagonist activity. The non-imidazole compounds XHA23 and XHA25 may have H3R antagonist activity.</p>

[Imidazole-containig drugs and inhibition of cytochrome P450]

Nowadays, multi-medicament use is increasing in clinical practice, especially, in the treatment of elder patients. Therefore, the pharmacokinetic drug-drug interaction of medicaments, which are expected to be co administrated in clinical practice, seems to be significant. The present review provides an update for the relationship between type of chemical substitution [aliphatic or aromatic] of imdazole-containig drugs and their tendency to affect hepatic metabolizing enzyme cytochrome [CYP450s]. In the present review, examples of different therapeutically used imidazole-containing drugs are highlighted to support the first evidence regarding the relationship between CYP-inhibition and chemistry of imidazole ring system. The informations provided throughout this article are intended to improve the medicinal chemist's knowledge of imidazole-containig drugs that are therapeutically widely applied as agents including histamine H1 receptor antagonists [antiallergics], histamine H2 receptor antagonists [antiulcers], histamine H3 receptor antagonists [management of cognitive disorders and attention-deficit-hyperactivity-disorder], antivirals, antiHIV, antibacterials, antifungals, anethelmintics, antiemetics, and antihypertensives

Reversing effect of histamine on neurotoxicity induced by beta-amyloid1-42 / 浙江大学学报·医学版

<p><b>OBJECTIVE</b>To investigate the effects of histamine on the neurotoxicity induced by beta-amyloid(1-42)(Abeta42) in rat phaeochromocytoma (PC12) cells.</p><p><b>METHODS</b>The in vitro model of Alzheimer's disease was constructed with A beta42-treated PC12 cells. Cell morphology and MTT assay were used to evaluate the cell toxicity and histamine effects. The different histamine antagonists were applied to investigate the involvement of receptor subtypes.</p><p><b>RESULT</b>The neurotoxicity was induced by A beta42 in a concentration-dependent manner, which was reversed by histamine at concentration of 10(-7), 10(-6) mol/L. The effect was reversed by H(2) antagonist zolantidine and H(3)antagonist clobenpropit, but not by H(1) antagonist diphenhydramine.</p><p><b>CONCLUSION</b>Histamine reduces neurotoxicity induced by beta-amyloid(1-42), which may be mediated by H(2) and H(3)receptors.</p>

The effect of central histamine H3 receptor on breathing activity of asthmatic guinea pigs / 中国应用生理学杂志

<p><b>AIM</b>To investigate the effect of selective H3 receptor agonist(R)-alpha-methylhistamine and antagonist thioperamide on the respiratory response in asthmatic guinea pigs respectively.</p><p><b>METHODS</b>Anesthesized guinea pigs were prepared with a implanted intracerebroventricular (icv) cannula and instrumented for the measurement of respiratory rate (RR) and diaphragmatic electric activity (DA). Substance P-like immunoreactive (SP-LI) substances in lower respiratory tract were detected by immunohistochemical method. Brain histamine contents were measured by fluorometric determination.</p><p><b>RESULTS</b>(1) Intravenous injection of ovalbumin caused tachypnea and significant decrease in DA magnitude. At the same time, SP-LI substances increased in trachea, bronchus and lung. (2) Administration of selective H3 receptor agonist (R)-alpha-methylhistamine (5 microg) icv immediately after i.v. ovalbumin could significantly ameliorate the changes in RR and DA induced by ovalbumin. In accordance, SP-LI substances in lower respiratory tract markedly decreased at 5 min and 10 min after (R)-alpha-methylhistamine microinjection. (3) Icv thioperamide (20 microg) caused a significant increase in RR and a decrease in DA. (4) Brain histamine contents increased in hypothalamus and cortex during asthma. After microinjection of thioperamide (20 microg) icv significant increase of histamine contents in hypothalamus and cortex was observed.</p><p><b>CONCLUSION</b>Brain histamine H3 receptors may be related to asthmatic respiratory responses.</p>