Changes in the feeding behavior of rats elicited by histamine infusion

In this study, we examined the effect of a putative neurotransmitter or a neuromodulator histamine (HA) on the feeding behavior to elucidate its physiological function in the central nervous system. Rats were implanted with a cannula into the suprachiasmatic nucleus through which HA was continuously infused for 200 hours with an Alzet osmotic minipump. The food intake was recorded automatically. This infusion resulted in decrease in food intake during the dark period and increase in it during the light period which contributed to the decrease in total food intake and increase in the percentage of food intake during the light period. Percentage of food intake during the light period is a good index of the amplitude of the circadian rhythm. Presumably, HA is concerned not only in the meal size, but also in the chronological aspect of the feeding behavior. The administration of H1-antagonist, pyrilamine, antagonized the HA induced increase in food intake during the light period. These findings suggest that continuous infusion of HA affected the feeding behavior which is possibly mediated through the H1-receptors in rat brain.     

Involvement of the histaminergic system in leptin-induced suppression of food intake

The ob gene product leptin is secreted from white adipose tissue, and may regulate food intake by acting on the hypothalamus in the central nervous system. But the mechanism of this effect is still unclear. The central histaminergic system has been suggested to participate in the control of various physiological functions, particularly in feeding behavior, as it mediates anorectic signals like leptin. Thus, we hypothesized that the central histaminergic system is a target for leptin in its control of feeding. To prove this, we first examined the effect of i.p. administration of alpha-fluoromethylhistidine (FMH), a specific and irreversible inhibitor of histidine decarboxylase, on leptin-induced suppression of food intake in normal C57BL strain mice. Leptin treatment (1.3 mg/kg, i.p.) significantly reduced food intake by 60% of that of control at 6 h and by 84% at 24 h compared with control. When mice were injected with FMH (100 mg/kg, i.p.) before being given leptin, leptin-induced suppression of food intake was abolished and there was no significant difference compared with that of control. Additionally, we further examined the effects of leptin on food intake in mutant mice lacking histamine H, receptors (H1R-KO mice). Leptin injection significantly reduced food intake by 56% of that of control at 6 h and by 79% at 24 h in wild-type mice (WT mice), but not in H1R-KO mice. This finding suggests that leptin affects the feeding behavior through activation of the central histaminergic system via histamine H1 receptors.     

Anti-obesity and anti-diabetic actions of histamine neurons

Anti-obesity and anti-diabetic actions of histamine neurons     

A role of the histaminergic system for the control of feeding by orexigenic peptides

A considerable number of neuropeptides are involved in the hypothalamic regulation of feeding behavior. We previously reported that leptin, the ob gene product, expressed its anorectic effect though the histaminergic system via histamine H(1) receptors. However, the interactions among the orexigenic neuropeptides, such as orexin-A, neuropeptide Y (NPY), and ghrelin, and the histaminergic system have not yet been clarified. In this study, we investigated the effect of the neuropeptides on the hypothalamic histamine release in rats, and on food intake and locomotor activity in H(1)-receptor knockout (H1R-KO) mice. Orexin-A increased the histamine release and locomotor activity, but not food intake, suggesting that the histaminergic system participates in arousal rather than feeding by orexin-A. NPY also increased histamine release, but its effect was not immediate. NPY-injected H1R-KO mice consumed more food than the wild-type mice; thus, the histaminergic system may act as a feedback factor downstream of NPY. Ghrelin did not affect histamine release, and it increased food intake, even in H1R-KO mice. Thus, ghrelin expresses its action in a histamine-independent manner.     

Histamine-induced excitatory responses in mouse ventromedial hypothalamic neurons: ionic mechanisms and estrogenic regulation

Histamine is capable of modulating CNS arousal states by regulating neuronal excitability. In the current study, histamine action in the ventromedial hypothalamus (VMH), its related ionic mechanisms, and its possible facilitation by estrogen were investigated using whole cell patch-clamp recording in brain slices from ovariectomized female mice. Under current clamp, a bath application of histamine (20 microM) caused membrane depolarization, associated with an increased membrane resistance. In some cells, the depolarization was accompanied by action potentials. Histamine application also significantly reduced the latency of action potential evoked by current steps. Histamine-induced depolarization was not affected by either tetrodotoxin or Cd(2+). However, after blocking K(+) channels with tetraethylammonium, 4-aminopyridine, and Cs(+), depolarization was significantly decreased. Under voltage clamp, histamine-induced depolarization was associated with an inward current. The current-voltage relationship revealed that this inward current reversed near E(K). The histamine effect was mimicked by a histamine receptor 1 (H(1)) agonist, but not a histamine receptor 2 (H(2)) agonist. An H(1) antagonist, but not H(2) antagonist, abolished histamine responses. When ovariectomized mice were treated with estradiol benzoate (E2), histamine-induced depolarization was significantly enhanced with an increased percentage of cells showing action potential firing. These results suggest that histamine depolarized VMH neurons by attenuating a K(+) leakage current and this effect was mediated by H(1) receptor. E2 facilitated histamine-induced excitation of VMH neurons. This histamine effect may present a potential mechanism by which estrogens modulate the impact of generalized CNS arousal on a sexual arousal-related neuronal group.     

Fasting duration influences the inhibition of food intake by histamine in chickens

This work was performed to investigate the effect of duration of fasting in the responses of chickens peripherally injected with histamine on the regulation of food intake. The animals were 16-week-old male chickens from layer-strain and the doses of histamine used were 500 and 1000 microg/kg of body weight. The non fasted chickens showed no effect of histamine on the food intake. When the animals were fasted during 4 h, injected with the histamine and immediately refed, the results showed a reduction of food intake only the first 15 min of the experiments with the dose of 1000 mug. In chickens fasted during 16 h or 26 h and refed, the histamine inhibited significantly the food intake at all time with the two doses. When the animals were fasted 16 h and refed during 60 min before the administration of the histamine, there is no inhibition of food intake. No effect on water intake has been registered in all the experiments. The blockade of the action of histamine injected in chickens fasted during 16 h by cimetidine and promethazine, show that the inhibition of food intake occurs through the H1 but not through H2 receptors. The fasting used in paradigm to investigate the effect of drugs such as histamine on the appetite, can affect differently the responses according to its duration, as observed here in chickens.     

Effect of histamine H1- and H2-receptor agonists on gamma-aminobutyric acid (GABA) content in hypothalamus and striatum of the rat brain

The intraventricular administration of histamine in a dose of 500 microgram, and two histamine H2-receptor agonists i.e. 50-250 microgram of dimaprit and 100 microgram of 4-methylhistamine decreased GABA level after 30 min (by approximately 20%) in the hypothalamus, but not in the striatum of the rat brain. The level of GABA was significantly reduced by 100 microgram of dimaprit after 2 h. Drugs selectively stimulating histamine H1-receptor (100 microgram) did not significantly change GABA concentration of the rat hypothalamus. The results suggest the existence of an H2-receptor--mediated histamine--GABA interaction in the rat hypothalamus.     

Anabolic neuropeptides

The hypothalamus and other brain regions that control energy homeostasis contain neuronal populations that produce specific neuropeptides which have experimental effects on feeding behavior and body weight. Here, we describe examples of neuropeptides that exert 'anabolic' effects, notably stimulation of feeding and increased body weight. Neuropeptide Y (NPY) neurons in the hypothalamic arcuate nucleus (ARC) are inhibited by leptin and insulin, and thus are stimulated in states of energy deficit and fat loss, e.g., underfeeding. NPY neuronal overactivity contributes to enhanced hunger and food-seeking activity under these conditions. The lateral hypothalamic area (LHA) contains specific neuronal populations that affect feeding in different ways. Neurons expressing the appetite-stimulating peptide orexin A are stimulated by starvation (but not food restriction) and by hypoglycemia, but only if food is withheld. Orexin neurons are apparently activated by low glucose but are promptly inhibited by visceral feeding signals, probably mediated via vagal sensory pathway and the nucleus of the solitary tract (NTS); a short-term role in initiating feeding seems most likely. Other LHA neurons express melanin-concentrating hormone (MCH), which transiently increases food intake when injected centrally. MCH neurons may be regulated by leptin, insulin and glucose. Glucose-sensing neurons in the hypothalamus and elsewhere are sensitive to other cues of nutritional state, including visceral satiety signals (transmitted via the vagus) and orexin A. Thus, long- and short-term humoral and neural signals interact with each other to meet diverse nutritional needs, and anabolic neuropeptides are important in the overall integration of energy homeostasis. Clarifying the underlying mechanisms will be essential to understanding normal energy balance and the pathogenesis and treatment of disorders, such as obesity and cachexia.     

Regulation of feeding behavior in the prepubertal female rat.

Responses to challenges of long-term regulation of feeding behavior were compared between adult and weanling female rats. Adulteration of a high fat diet with NaCl caused both adult and weanling rats to reduce their food intake, but neither group refused to eat. Food deprivation for 24 hr was followed by an increase in feeding for both adult and weanling animals during a period when food intake is normally very low. Continued limited food access to 2 hr during the light period was compensated for by an increase in the normal food intake for this period for both adult and young female rats. It was observed that both adult and weanling rats showed a marked preference for the more dilute glucose solution when given a choice. In addition, both groups maintained a constant caloric intake during presentation of the glucose solutions by adjusting their intake of a solid food source. In each challenge of long-term regulation of feeding behavior, the response of weanling animals was as good or superior to that shown by adults. It is concluded that weanling female rats regulate their feeding just as adults to maintain long-term energy balance. It was also observed that bilateral lesions placed in the ventromedial hypothalamus (VMH) at 21 days of age resulted in reduced daily food intake and retarded body weight gain. Furthermore, young rats with VMH lesions failed to respond to 24 hr of food deprivation or limited food access. These data suggest an important role for the VMH in the long-term regulation of feeding in young rats.     

Increased neuronal histamine in thiamine-deficient rats

Previous studies have indicated that thiamine deficiency is associated with clearly elevated histamine concentrations in the rat hypothalamus, whereas other brain regions contain normal amounts of the amine. The purpose of this study was to find out if the increased hypothalamic histamine concentrations are due to increased numbers of mast cells or changes in neuronal histamine stores.Thiamine-deficiency was induced by daily injections of pyrithiamine until the animals lost the righting reflex. Control animals were pair-fed with either thiamine-deficient or normal thiamine-supplemented food. A significant increase in histamine concentration was observed in the hypothalamus and pons-medulla of the pyrithiamine-treated rats, but not in the cerebellum, thalamus, cerebral cortex or pituitary gland. Immunohistochemically, no histamine-containing mast cells were found in the hypothalami of the pyrithiamine-treated rats or control animals. The histaminergic tuberomammillary neurons were very intensely immunofluorescent, and the density of histamine-immunoreactive nerve fibers in the hypothalamus was also increased in the pyrithiamine-treated animals.     

Histamine and the hypothalamus

The chemical tools that could be used to examine the function of histamine in the brain are considered together with the evidence linking histamine specifically with the hypothalamus. The distribution of histamine and the enzymes responsible for its synthesis and metabolism is consistent with there being both mast cells and histaminergic nerve terminals within the hypothalamus. Iontophoresis, mepyramine binding and histamine-stimulated adenylate cyclase studies suggest that both histamine H1- and H2- receptors are present in the hypothalamus. In addition, intracerebroventricularly injected histamine receptor agonists and antagonists affect many functions associated with the hypothalamus such as cardiovascular control, food intake, body temperature control, and pituitary hormones whose release is mediated via the hypothalamus, such as corticotropin, growth hormone, thyroid stimulating hormone, prolactin, gonadotropins and vasopressin. However, only in the case of thyroliberin release, prolactin release, body fluid control and blood pressure control is there evidence yet that such effects are mediated via histamine receptors actually in the hypothalamus. The effects of enzyme inhibitors suggest endogenous histamine may be involved in the physiological control of thyroid stimulating hormone, growth hormone and blood pressure, and the effects of receptor antagonists support a role for endogenous histamine in prolactin control. Otherwise, there is little evidence for a physiological role for endogenous, as against exogenous, histamine whether it be from histaminergic terminals or mast cells. In addition, few studies have tried to distinguish possible effects on presynaptic receptors, postsynaptic receptors, hypothalamic blood vessels or the hypophyseal portal blood vessels. It is concluded that although there is good evidence now linking histamine and the hypothalamus more specific studies are required, for instance using microinjection or in vitro techniques and the more specific chemical tools now available, to enable a clearer understanding of the physiological role of histamine in the hypothalamus.     

Food intake and neuronal activation after acute 2DG treatment are attenuated during lactation

In the present study, we compared the ability of acute peripheral 2-deoxy--glucose (2DG) treatment to induce food intake and increase immediate early gene expression in lactating versus virgin female rats. In Experiment 1, virgin and lactating rats were treated intraperitoneally with either saline or 2DG (400 mg/kg) and their food intake was compared across the next 6 h. In Experiment 2, lactating and virgin rats were given saline or 2DG, sacrificed 1 h later, and their brains were processed for Fos-like immunocytochemistry (FLI). The average number of cells expressing Fos protein within different brain regions was compared among the different groups. Statistical analyses of the data from Experiment 1 show that 2DG produces an increase in food intake in virgin rats, but not in lactating rats. These data correlate with the results from Experiment 2, where 2DG treatment resulted in an increase in FLI within the caudal ventrolateral medulla (cVLM), the paraventricular nucleus of the hypothalamus (PVN), and the supraoptic nucleus of the hypothalamus (SON) of cycling females. In lactating rats, however, 2DG failed to increase FLI in these regions. Together, these results show that the 2DG-induced food intake response is attenuated during lactation and this attenuation is reflected in the activation of neuronal groups that are thought to participate specifically in the food intake response to glucoprivation. Processes mediating this differential response are discussed in terms of the hormonal and metabolic changes that are characteristic of lactation.     

Effect of the H1-histamine receptor agonist betahistine on drinking and eating behavior in pygmy goats.

The effect of different doses of the H1-receptor agonist betahistine (0.9 and 2, 4 and 8 mg/kg b.wt.(0.75)) on water and food intake was investigated in 12 pygmy goats. Intraperitoneal (i.p.) injection of betahistine (2, 4, and 8 mg/kg b.wt.(0.75)) stimulated drinking in a dose-dependent manner. Food intake was decreased after the injection of 4 or 8 mg/kg b.wt.(0.75) betahistine, respectively. The increase in water intake was characterized by an increased draft size and decreased latency to drink. The decrease in food intake at the highest dose tested was characterized by an increased latency to eat and by a decreased meal frequency, and food intake associated to drinking was decreased. In line with previous studies, these results support the hypothesis that food-associated drinking is mediated by stimulation of H1-receptors of histamine in pygmy goats.     

Sleep, brain energy levels, and food intake

Background

The feeling of hunger and feeding, a wake–state-dependent behavior, is regulated by specific centers within the hypothalamus. While paraventricular nucleus (PVN), arcuate nucleus (ARC), and dorso- and ventromedial hypothalamus (DMH/VMH) regulate feeding, the lateral hypothalamus (LH) is associated both with feeding and wake/REM sleep regulation. In order to examine the effects of sleep and wakefulness on food intake and body weight, we also measured hypothalamic ATP concentrations, which are known to be involved in feeding behavior and sleep–wake regulation.

Methods

In rats, food intake and body weight was measured during a 24-h light–dark cycle and during 6 h of sleep deprivation (SD) performed by gentle handling. Tissue samples from the PVN, ARC/DMH/VMH, and LH were collected after 6 h of SD and from time-matched diurnal controls. ATP was measured by luciferin-luciferase bioluminescence assay.

Results

Across the 24-h light–dark period, rats consumed approximately 28.13±4.48 g of food and gained 5.22±1.65 g with a positive correlation between food intake and body weight. During SD, while food intake increased significantly +147.31±6.13%, they lost weight significantly (–93.29±13.64%) when compared to undisturbed controls. SD resulted in a significant decrease in ATP levels only in LH (–44.60±21.13%) with no change in PVN, ARC/DMH/VMH region when compared with undisturbed controls.

Conclusion

The results indicate a strong overall correlation between ATP concentrations in the LH and individual food intake and suggest a sleep–wake dependent neuronal control of food intake and body weight.     

Inhibition of effects of endogenously synthesized histamine disturbs in vitro human dendritic cell differentiation

Histamine, a principal mediator in various physiological and pathological cell functions is synthesized from L-histidine exclusively by histidine decarboxylase, an enzyme, which is expressed in many tissues of mammalian organism. Histamine plays a role in various cellular functions, including cell differentiation. The aim of this study was to determine the presence and to characterize the role of the endogenously produced histamine during in vitro dendritic cell (DC) differentiation induced by interleukin-4 (IL-4) and granulocyte-monocyte colony stimulating factor (GM-CSF). The changes in intracellular histamine content, biosynthesis and gene expression of histidine decarboxylase were investigated during this process. One also studied how histamine receptor antagonists and a histamine synthesis blocker influence the expression of differentiation antigens on the DC during in vitro maturation. During in vitro differentiation parallel culture incubations were performed by adding H1 receptor antagonist triprolidine, H2 receptor antagonist tiotidine, the tamoxifene derivate DPPE which blocks the intracellular binding of histamine, and an irreversible blocker of histidine decarboxylase, alpha-fluoromethyl histamine (alpha-FMH). The results show simultaneous increase in both histidine decarboxylase level and histamine content during differentiation of elutriated monocytes toward DC. Both blockade of de novo histamine production (by alpha-FMH) and inhibition of histamine binding (by H1 and H2 receptor antagonists, triprolidine and tiotidine, respectively) markedly decreased CD40 expression and that of CD45 from the 3rd day of treatment. DPPE by disturbing intracellular interaction of histamine with cytochrome P-450 moieties was able to decrease the expression of CD45, CD86, HLA-DR, CD33, CD40 and CD11c. Based on the data it is suggested that endogenous histamine is actively synthesized during cytokine-induced in vitro DC differentiation. The functional relevance and autocrine and paracrine action of endogenously produced histamine is supported by the data showing that inhibition of histamine synthesis by HDC, blocking of histamine binding by both 'extracellular' histamine receptors (by specific antagonists, triprolidine and tiotidine) and 'intracellular' antagonists (DPPE) disturb the differentiation of DC. This conclusion is supported by the fact, that by the inhibition of histamine acting in an autocrine/paracrine way, the expression pattern of differentiation markers on DC is markedly changed.     

The role of GABAergic system on the inhibitory effect of ghrelin on food intake in neonatal chicks

Ghrelin is a gut-brain peptide that has a stimulatory effect on food intake in mammals. In contrast, this peptide decreases food intake in neonatal chicks when injected intracerebroventricularly (ICV). In mammals, neuropeptide Y (NPY) mediates the orexigenic effect of ghrelin whereas in chicks it appears that corticotrophin releasing factor (CRF) is partially involved in the inhibitory effect of ghrelin on food intake. Gamma aminobutyric acid (GABA) has a stimulatory effect on food intake in mammals and birds. In this study we investigated whether the anorectic effect of ghrelin is mediated by the GABAergic system. In Experiment 1, 3 h-fasted chicks were given an ICV injection of chicken ghrelin and picrotoxin, a GABA_A receptors antagonist. Picrotoxin decreased food intake compared to the control chicks indicating a stimulatory effect of GABA_A receptors on food intake. However, picrotoxin did not alter the inhibitory effect of ghrelin on food intake. In Experiment 2, THIP hydrochloride, a GABA_A receptor agonist, was used in place of picrotoxin. THIP hydrochloride appeared to partially attenuate the decrease in food intake induced by ghrelin at 30 min postinjection. In Experiment 3, the effect of ICV injection of chicken ghrelin on gene expression of glutamate decarboxylase (GAD)₁ and GAD₂, GABA synthesis enzymes in the brain stem including hypothalamus, was investigated. The ICV injection of chicken ghrelin significantly reduced GAD₂ gene expression. These findings suggest that ghrelin may decrease food intake in neonatal chicks by reducing GABA synthesis and thereby GABA release within brain feeding centers.     

Calcitonin as a feeding suppressant: localization of central action to the cerebral III ventricle

Calcitonin suppresses food and water intake. To further study this effect of calcitonin, rats were subjected to various intra-cerebroventricular (ICV) applications of calcitonin. The results show: (1) Intra-third ventricular (III-ICV) infusion of calcitonin dose-dependently decreased food intake with short- and long-term effects; (2) Potency was decreased by using non-siliconized materials; (3) Potency decreased with age of rats; (4) Infusion into the aqueduct and cisterna magna decreased short- and long-term food intake less than III-ICV administration; (5) Aqueduct obstruction did not affect feeding suppression by III-ICV calcitonin. Aqueduct obstruction did not affect dipsogenic response to III-ICV infusion of angiotensin II; (6) Results of water intake and food to water intake ratios suggest a greater calcitonin effect on food intake than on water intake. The evidence suggests that the hypothalamus is a main locus for suppression of food intake by ICV administered calcitonin.     

Uptake and utilization of metabolites in specific brain sites relative to feeding status

Two experiments were conducted to assess potential alterations in fatty acid and glucose metabolism within specific brain sites in relation to the feeding status of the rat. An in vivo serial analysis of brain palmitate and glucose uptake demonstrated that hypothalamic uptake of these substrates was reciprocally altered with respect to satiety. Hypothalamic uptake of palmitate was increased by 300% and uptake of glucose was decreased by 30% in fasted compared with fed rats. Other regional differences were observed and discussed in the text. An in vitro analysis showed that hypothalamic fatty acid oxidation was affected by feeding status. The ventrolateral hypothalamus (VLH) of fasted rats had 45% greater rates of fatty acid oxidation than VLH of fed rats. No alterations were observed for VLH glucose oxidation and ventromedial hypothalamic glucose and fatty acid oxidation when comparing fed and fasted rats. Other brain sites did not show variance for glucose and fatty acid metabolism relative to feeding status. Fatty acid uptake and subsequent metabolism in the hypothalamus and other brain sites may be one component of food intake control and energy balance regulation.     

低氧运动干预肥胖模型大鼠下丘脑Nesfatin-1和Ghrelin水平

文题释义：Ghrelin：是一种含有28个氨基酸残基的短肽，于1999年被发现，主要由胃底分泌，在下丘脑中也有表达，其可促进摄食、减少能量消耗和增加体质量，是目前发现的唯一促食欲激素。 Nesfatin-1：是一种由82个氨基酸组成的神经肽，于2006年被发现，具有减少摄食、调节能量平衡和减轻体质量的作用。 背景：均衡饮食和科学运动是公认的安全、有效且经济的体质量管理干预方式，但运动本身有时却提升了减肥者食欲，如果将低氧环境刺激和有氧运动干预结合，可能会收到最好的减质量效果。下丘脑作为机体调控摄食和能量平衡的中枢，其调控因子与肥胖症发病机制之间的关系备受关注。 目的：观察低氧或/和运动后肥胖大鼠下丘脑nesfatin-1和ghrelin水平变化，探讨低氧或/和运动影响机体摄食和体质量的神经内分泌机制。 方法：60只营养性肥胖SD大鼠均分为常氧安静组、常氧运动组、16.3%低氧安静组、16.3%低氧运动组、13.3%低氧安静组和13.3%低氧运动组，进行8周的低氧或/和运动干预。低氧环境采用低氧发生器分别营造体积分数为16.3%氧气和13.3%氧气环境，低氧干预组大鼠每天12 h在低氧环境中生活和运动；运动干预采用跑台运动方案(跑速20 m/min、坡度0°)，持续时间40 min，5 d/周。记录干预期大鼠体质量、摄食量，计算干预前后Lee’s指数，用ELISA试剂盒检测干预后大鼠下丘脑nesfatin-1和ghrelin水平。 结果与结论：①干预后大鼠体质量与Lee’s指数：单纯低氧环境刺激对大鼠体质量、Lee’s指数的影响没有单纯有氧运动刺激明显，而当低氧和运动结合时，其效果优于单一刺激；②干预期间大鼠日均摄食量：常氧安静组保持平稳，其余各组均减少，尤以16.3%低氧运动组、13.3%低氧运动组明显；③下丘脑nesfatin-1和ghrelin水平：低氧结合运动可影响大鼠下丘脑nesfatin-1水平，其中13.3%低氧运动组的nesfatin-1水平最高；单纯的运动或低氧均可影响大鼠下丘脑ghrelin水平，而单一运动刺激效果强于单一低氧刺激，当二者结合时降低效果更明显；④双因素方差分析：体质量和ghrelin水平受运动的影响，体质量、Lee’s指数和摄食量受氧气体积分数的影响，体质量、nesfatin-1和ghrelin水平受运动×氧气体积分数的影响；⑤结果表明，8周低氧运动可能通过影响肥胖大鼠下丘脑nesfatin-1与ghrelin水平来减少大鼠的摄食量，抑制其体质量增长，降低其Lee’s指数，但具体机制需待进一步研究。 ORCID: 0000-0002-1519-7825(范锦勤) 中国组织工程研究杂志出版内容重点：组织构建；骨细胞；软骨细胞；细胞培养；成纤维细胞；血管内皮细胞；骨质疏松；组织工程     

Postischemic regulation of central histamine receptors

This study characterizes changes occurring in the central histaminergic system associated with ischemia-reperfusion pathology in the rat. Specifically, after a postocclusion time period of 48 h, we have analyzed histamine H(1) receptor mRNA expression, histamine H(2) receptor protein amount and binding densities, and histamine H(3) receptor mRNA expression and binding densities in brain regions that have been suggested to be selectively vulnerable to transient global ischemia, i.e. hippocampus, thalamus, caudate-putamen, and cerebral cortex. We found an increase in H(1) receptor mRNA expression in the caudate-putamen: given that ischemia reduces glucose uptake and H(1) receptor activation has been shown to decrease this effect, an increase of expression levels may result in mitigating tissue damage due to energy failure observed in ischemia. A decrease in H(2) receptor binding densities in the caudate-putamen was also observed; the ischemia-induced decrease in H(2) receptor protein was also detectable by Western blot analysis. This phenomenon may underlie the previously reported ischemia induced striatal dopamine release. H(3) receptor mRNA expression was increased in the caudate putamen of the postischemic brain but was decreased in the globus pallidus and the thalamus; in association with this, H(3) receptor binding densities were increased in the cortex, caudate-putamen, globus pallidus, and hippocampus. The upregulation of H(3) receptor ligand binding may be involved in the previously reported continuous neuronal histamine release. Our data suggest that central histamine receptor expression and ligand binding are altered in brain ischemia in distinct areas, and may participate in neuroprotection and/or ischemia-associated neuronal damage.