Histamine receptors in the central nervous system

The role of histamine in brain function is discussed. A brief review is presented on the three types of histamine receptors with regard to their biochemistry and functions, as well as on specific ligands, both agonists and antagonists. It is concluded that several aspects of the pharmacology of histamine in the central nervous system are still a matter of empirism and speculations. The recent publications on the brain-penetrating H₂ antagonist zolantidine and the selective H₃ agonists and antagonists are expected to contribute to the knowledge of the histaminergic pathways in the brain. Therapeutical areas within the central nervous system are related to behaviour (including wake-sleep), neuroendocrinal processes, the control of muscle activity and cerebral circulation.     

Accumulation of nodularin-like compounds from the cyanobacterium Nodularia spumigena and changes in acetylcholinesterase activity in the clam Macoma balthica during short-term laboratory exposure

In this laboratory study the effects of the cyanobacterium Nodularia spumigena (strain AV1) that produces hepatotoxic nodularin (NODLN), non-toxic Nodularia sphaerocarpa (strain UP16f) and purified NODLN on the infaunal clam Macoma balthica from the Baltic Sea were examined. N. sphaerocarpa (2.4 and 12.5 mg dw l(-1)), N. spumigena (4 and 20 mg dw l(-1), intracellular NODLN content ca. 4 and 20 microg l(-1)) and purified NODLN (10 and 50 microg l(-1)) were applied in experimental tanks at 24 h intervals for 96 h. Water samples were taken during the experiment for the measurement of soluble NODLN concentrations. The concentrations of total hepatotoxins in the soft tissues were analysed with enzyme-linked immunosorbent assay (ELISA) and NODLN with high-performance liquid chromatography/diode array detection (HPLC/DAD). Acetylcholinesterase (AChE) activity was measured from the foot tissue samples taken at 0, 24 and 96 h. In the water phase, 60-100% of NODLN in the pure-toxin treatments and all the NODLN in N. spumigena treatments appeared as a yet unidentified form with NODLN-like spectral characteristics. The compound was present in similar quantities also in the non-toxic N. sphaerocarpa treatments. In the toxic N. spumigena treatments the tissue concentration of hepatotoxic NODLN-like compounds (measured with ELISA) increased from the control levels of 0.16 to 16.6 microg g(-1) dw (24 h), reaching 30.3 microg g(-1) dw at 96 h. However, <5% of the toxin detected by ELISA could be shown to be NODLN in HPLC/DAD analysis. Matrix-assisted laser desorption/ionisation-time of flight mass spectrometry (MALDI-TOF/MS) analyses revealed no NODLN-glutathione (GSH) conjugates in the tissues of M. balthica. Combining the responses in the AChE activity recorded after 24 and 96 h exposure, increases by 46% (N. spumigena) and 36% (soluble NODLN) compared with the control activity were observed in the low-level toxic exposures. Oppositely, decreases by 19% (N. spumigena) and 27% (soluble NODLN) of control activity were observed in the high-level exposures. Only the differences between the increased and decreased AChE activities were statistically significant, with individuals exposed to high levels expressing approximately 55% of the activity of those exposed to low concentrations. The results show that M. balthica readily ingests toxic N. spumigena and that accumulation of peptides takes place rapidly, which has potential food chain effects through toxin enrichment. However, it appears that M. balthica is at least partly able to metabolise NODLN. In addition to hepatotoxicity, NODLN seems to induce concentration-dependent neurotoxic effects; this must be taken into consideration when applying AChE activity as a biomarker of specific anthropogenic contamination (e.g. organophosphate and carbamate pesticides).     

Histamine H3 receptor: a potential drug target for the treatment of central nervous system disorders

Histamine H(3) receptors were first described in the eighties but finally cloned four years ago. They are G-protein coupled, mostly presynaptic, and are involved in the control of the synthesis and/or release of different neurotransmitters both in the central nervous system and the periphery. The availabiliy of specific ligands has permitted the study of potential therapeutic applications of either stimulating or blocking the function of these receptors. There is experimental evidence that drugs targeted at histamine H(3) receptors could be beneficial for neurodegenerative diseases such as Alzheimer and Parkinson's disease, epilepsy, drug abuse and several affective, appetite and sleeping disorders, among others. This review presents recent advances in this field.     

Histamine dihydrochloride (subcutaneous) Maxim

Maxim is developing a subcutaneous formulation of histamine dihydrochloride (Ceplene, formerly known as Maxamine) for use as an adjuvant with interleukin (IL)-2 therapy for the potential treatment of metastatic melanoma, hepatitis C virus infection, acute myelogenous leukemia and renal cell carcinoma. In October 2002, the compound was in phase III trials for metastatic melanoma in Europe, Australia, Canada, Israel and the US. In November 2003, Maxim submitted an MAA to the EMEA for malignant melanoma in combination with IL-2.     

Histamine in the developing sympathoadrenal system.

The ontogenetic distribution of histamine in correlation with catecholamines in the developing rat sympathoadrenal system was analyzed by using an indirect immunohistochemical method and a specific rabbit anti-histamine antiserum. Tyrosine hydroxylase (TH) immunoreactivity was used as a marker of catecholamine synthesis. TH immunoreactivity appeared in retroperitoneal sympathetic tissues on embryonic day 12.5 (E 12.5) when it was found in cells of lumbar chain ganglia. In preaortic sympathetic tissue. TH immunoreactivity was observed on day E 13.5 and in adrenal medullae on day E 14.5. Histamine immunoreactivity was expressed in all of these tissues beginning from day E 14.5. First it was found mainly in nerve fibers, but also in some cells. During the embryonic development the number of histamine-immunoreactive cells increased in all sympathetic tissues studied. In newborn rats, histamine immunoreactivity was restricted to a subpopulation of sympathetic cells, i.e. small intensely fluorescent (SIF) cells of sympathetic ganglia, paraganglion-type cells and some adrenaline-synthesizing cells of the adrenal medulla.     

Autonomic (sympathetic) nervous system involvement in rheumatoid arthiritis patients

Fifty Rheumatoid arthritis (RA) patients between the age group of 20 to 60 years were investigated for sympathetic autonomic functions using standard tests. All the patients liable to develop dysautonomia or having a treatment interfering with autonomic nervous system were excluded. Previous studies to evalute sympathetic nervous system involvement used only a single test like sweating response, orthostatic test. In the present study 3 tests of sympathetic nervous system evaluation have been used. The evaluation was done by cardiovascular tests like orthostatic test, sustained hand grip and cold pressor test. A control series of 50 healthy subjects was tested to determine abnormal threshold for each one of the 3 tests. The reference value of Ewing and Clark were used to interpret the results of the tests. Sympathetic dysfuction was found in 26% of rheumatoid arthritis patients.     

Physiological significance of pituitary adenylate cyclase-activating polypeptide (PACAP) in the nervous system

Pituitary adenylate cyclase-activating polypeptide (PACAP) has been conserved remarkably during evolution and is widely expressed in the nervous system across phyla. PACAP has an amino acid sequence homology of 68% with that of vasoactive intestinal polypeptide (VIP) and of 37% with that of secretin, indicating that PACAP is a member of the VIP/glucagon/secretin superfamily. PACAP exerts its actions via three heptahelical G-protein-linked receptors: one PACAP-specific (PAC1) receptor and two receptors (VPAC1 and VPAC2) shared with VIP. PACAP stimulates several different signaling cascades in neurons, leading to the activation of adenylate cyclase, phospholipase C, and mitogen-activated protein kinase and mobilization of calcium. Although PACAP and VIP have no apparent homology with calcitonin and parathyroid hormone (PTH), PAC1, VPAC, secretin, glucagon, glucagon-like peptide 1, growth hormone-releasing hormone, calcitonin, and PTH/PTH-related peptide receptors are related to each other and constitute a subfamily of the G-protein-coupled receptors. Distribution analysis of PACAP and its receptors and pharmacological studies have elucidated its pleiotropic effects in the central and peripheral nervous systems. However, the relevance of the pharmacological PACAP effects to the actual physiological activities of endogenous PACAP has not been addressed, because potent and selective low-molecular-weight PACAP antagonists have not yet been developed. To assess the function of PACAP in vivo, we have recently generated PAC1 receptor- and PACAP-targeted mice, and provided evidence that PACAP plays a previously uncharacterized role in the regulation of psychomotor behaviors. In this review, we focus on the physiological and or pathophysiological roles mediated by PACAP in the nervous system.     

Delivery of radioligands for positron emission tomography (PET) in the central nervous system

Positron emission tomography (PET) is an imaging technique to monitor the delivery of tracers labeled with positron emitters ((11)C, (13)N, (15)O and (18)F). A wide variety of probes have been labeled to measure biochemical and physiological parameters in the central nervous system (CNS), such as glucose and oxygen metabolism, protein synthesis, blood flow, and neurotransmitter receptor functions. The delivery of labeled compounds to the target tissue, which directly reflect the distribution and kinetics patterns, especially to the neurotransmitter receptors is modulated by several factors, such as regional cerebral blood flow (rCBF), peripheral metabolism, and neurotransmitter concentration in the synaptic cleft. These factors provide misunderstanding of the apparent results, which do not reflect the true state of the CNS. The present paper will summarize several factors that affect the delivery of labeled compounds related to the neurotransmitter receptors in the CNS.     

注射用左旋奥硝唑磷酸酯二钠对小鼠神经系统的影响

目的 探讨注射用左旋奥硝唑磷酸酯二钠静脉注射对ICR小鼠神经系统的影响.方法 将小鼠分为空白组、左旋奥硝唑(S-O)组、右旋奥硝唑磷酸酯二钠(R-ODP)组和左旋奥硝唑磷酸酯二钠(S-ODP)低、中、高剂量组(50、100、200 mg·kg-1);观察药物延长戊巴比妥钠致小鼠睡眠的时间、对运动及平衡能力的影响和对自发活动的影响.结果 S-ODP、S-O、R-ODP均可明显缩短小鼠的入睡潜伏期,延长睡眠时间;对小鼠的自发活动次数有一定的抑制作用;可降低小鼠转棒掉落时的转速、缩短掉落时间及经过路程.相同剂量R-ODP的以上作用明显强于S-ODP.结论 较高浓度S-ODP与巴比妥类镇静催眠药物有明显的协同作用,对小鼠自发活动及运动平衡能力也有轻微的影响,但效果弱于相同剂量的R-ODP.     

药源性神经中枢损害1例的用药分析

1例88岁的女性患者在住院治疗过程中出现谵妄、神志不清、嗜睡状态,脑电图等诊断不支持中枢感染。临床医生认为是头孢吡肟所致,但从临床病情变化与用药过程的分析看,最大可能是阿奇霉素引发的中枢神经异常反应。     

Effects of oxilofrine on the activity of the sympathetic nervous system (author's transl)

The effects of 1-(4-hydroxyphenyl)-2-methylamin-propanol- (1) (oxilofrine, 4-HMP) on the catecholamine metabolism were investigated in vitro in isolated rat hearts and spleen sections. Investigations were conducted in vivo to determine the influence exerted by the sympathomimetic agent on the noradrenaline biosynthesis in the heart and on the oxygen-dependent enzymes tyrosine hy droxylase and dopamine-beta-hydroxylase. Oxilofrine is an excellent inhibitor of the noradrenaline storage in the heart (DI = 1.5 X 10(-6) mol/l). At the same time, the sympathomimetic agent releases noradrenaline from the storage compartments. In this process, preferably newly synthetised noradrenaline is released both from the heart and from the spleen. This double mechanism of action is associated with an acceleration of the noradrenaline biosynthesis and an increase in enzymal activity of tyrosine hydroxylase and dopamine-beta-hydroxylase. The transmitter concentrations in the region of the postsynaptic receptors are enhanced by oxilofrine.     

Morphological alterations of central nervous system (CNS) myelin in vanadium (V)-exposed adult rats

In the present work we show morphological data of the in vivo susceptibility of CNS myelin to sodium metavanadate [V(+5)] in adult rats. The possible role of vanadium in behavioral alterations and in brain lipid peroxidation was also investigated. Animals were injected intraperitoneally (i.p.) with 3 mg/kg body weight (bw) of sodium metavanadate [1.25 V/kg bw/day] for 5 consecutive days. Open field and rotarod tests were performed the day after the last dose had been administered and then animals were sacrificed by different methods for histological and lipid peroxidation studies. The present results show that intraperitoneal administration of V(+5) to adult rats resulted in changes in locomotor activity, specific myelin stainings and lipid peroxidation in some brain areas. They support the notion that CNS myelin could be a preferential target of V(+5)-mediated lipid peroxidation in adult rats. The mechanisms underlying this action could affect the myelin sheath leading to behavioral perturbations.     

114例神经系统不良反应报告分析

目的分析药品不良反应(ADR)发生的规律及特点,为临床合理用药及药物安全性评价提供依据。方法对我院2007年收集的114例神经系统ADR报告进行分析。结果114例神经系统不良反应涉及13类药物,52个品种,抗感染药居首位(18例,占15.78%),其次是眼用药物(16例,占14.04%)和消化系统药物(13例,占11.41%)。静脉用药引发神经系统ADR最多(93例,占81.58%)。ADR均较轻,无严重不良反应发生,临床主要表现为手脚麻木、头痛、精神异常。结论临床应重视ADR的报告和监测工作,指导临床合理用药,以减少或避免ADR的发生。