Administration Of L-histidine Research Articles

Chenodeoxycholic Acid Improves Embryo Implantation and Metabolic Health through Modulating Gut Microbiota-Host Metabolites Interaction during Early Pregnancy.

Fetus loss in early pregnancy is of major concern to both humans and animals, and this issue is largely influenced by embryo implantation. Chenodeoxycholic acid (CDCA), a primary bile acid, contributes to metabolic improvements and protects against intrahepatic cholestasis of pregnancy. However, the effect of CDCA on embryo implantation during early pregnancy has not been investigated. The present study demonstrated that CDCA administration during early pregnancy improved embryo implantation in sows and rats, thereby improving the pregnancy outcomes of sows. CDCA significantly reduced inflammation, oxidative stress, and insulin resistance. The metabolomics analysis indicated significant differences in the fecal metabolome, especially regarding the level of secondary bile acids, between the control and CDCA-treated sows. CDCA also influenced the serum metabolite profiles in sows, and the serum L-Histidine level was significantly correlated with the abundance of 19 differential fecal metabolites. Importantly, L-Histidine administration improved embryo implantation and metabolic health in rats during early pregnancy. Moreover, CDCA administration during early pregnancy also led to long-term metabolic improvements in sows. Our data indicated that CDCA improved embryo implantation by alleviating inflammation and oxidative stress, improving insulin sensitivity, and modulating the interaction between the gut microbiota and host metabolites. Therefore, CDCA intervention is a potential therapeutic strategy regarding embryo loss during pregnancy.

Carnosine Reduces Oxidative Stress and Reverses Attenuation of Righting and Postural Reflexes in Rats with Thioacetamide-Induced Liver Failure.

Cerebral oxidative stress (OS) contributes to the pathogenesis of hepatic encephalopathy (HE). Existing evidence suggests that systemic administration of l-histidine (His) attenuates OS in brain of HE animal models, but the underlying mechanism is complex and not sufficiently understood. Here we tested the hypothesis that dipeptide carnosine (β-alanyl-l-histidine, Car) may be neuroprotective in thioacetamide (TAA)-induced liver failure in rats and that, being His metabolite, may mediate the well documented anti-OS activity of His. Amino acids [His or Car (100 mg/kg)] were administrated 2 h before TAA (i.p., 300 mg/kg 3× in 24 h intervals) injection into Sprague–Dawley rats. The animals were thus tested for: (i) brain prefrontal cortex and blood contents of Car and His, (ii) amount of reactive oxygen species (ROS), total antioxidant capacity (TAC), GSSG/GSH ratio and thioredoxin reductase (TRx) activity, and (iii) behavioral changes (several models were used, i.e. tests for reflexes, open field, grip test, Rotarod). Brain level of Car was reduced in TAA rats, and His administration significantly elevated Car levels in control and TAA rats. Car partly attenuated TAA-induced ROS production and reduced GSH/GSSG ratio, whereas the increase of TRx activity in TAA brain was not significantly modulated by Car. Further, Car improved TAA-affected behavioral functions in rats, as was shown by the tests of righting and postural reflexes. Collectively, the results support the hypothesis that (i) Car may be added to the list of neuroprotective compounds of therapeutic potential on HE and that (ii) Car mediates at least a portion of the OS-attenuating activity of His in the setting of TAA-induced liver failure.

Changes of the thioredoxin system, glutathione peroxidase activity and total antioxidant capacity in rat brain cortex during acute liver failure: modulation by L-histidine.

Glutathione and thioredoxin are complementary antioxidants in the protection of mammalian tissues against oxidative–nitrosative stress (ONS), and ONS is a principal cause of symptoms of hepatic encephalopathy (HE) associated with acute liver failure (ALF). We compared the activities of the thioredoxin system components: thioredoxin (Trx), thioredoxin reductase (TrxR) and the expression of the thioredoxin-interacting protein, and of the key glutathione metabolizing enzyme, glutathione peroxidase (GPx) in the cerebral cortex of rats with ALF induced by thioacetamide (TAA). ALF increased the Trx and TrxR activity without affecting Trip protein expression, but decreased GPx activity in the brains of TAA-treated rats. The total antioxidant capacity (TAC) of the brain was increased by ALF suggesting that upregulation of the thioredoxin may act towards compensating impaired protection by the glutathione system. Intraperitoneal administration of l-histidine (His), an amino acid that was earlier reported to prevent acute liver failure-induced mitochondrial impairment and brain edema, abrogated most of the acute liver failure-induced changes of both antioxidant systems, and significantly increased TAC of both the control and ALF-affected brain. These observations provide further support for the concept of that His has a potential to serve as a therapeutic antioxidant in HE. Most of the enzyme activity changes evoked by His or ALF were not well correlated with alterations in their expression at the mRNA level, suggesting complex translational or posttranslational mechanisms of their modulation, which deserve further investigations.

Targeted Disruption of Organic Cation Transporter 3 (Oct3) Ameliorates Ischemic Brain Damage through Modulating Histamine and Regulatory T Cells

The organic cation transporters OCT1, 2, and 3 (SLC22A1-3) have been implicated in the elimination of biogenic amines such as histamine. Among them, OCT3 was identified as an uptake-2 transporter, responsible for clearance of histamine. Because increasing evidence suggests the involvement of histamine in cerebral ischemia, we investigated the effects of targeted disruption of organic cation transporter-3 (Oct3) on the severity of ischemic brain damage. Transient focal ischemia for 1 hour was induced by occlusion of the middle cerebral artery (MCA) of homozygous Oct3-deficient mice and their wild-type (Wt) littermates. Although targeted disruption of Oct3 did not affect physiological parameters after MCA occlusion, this disruption significantly increased histamine content in the ischemic cortex and significantly reduced the infarct volume after cerebral ischemia. Furthermore, targeted disruption of Oct3 prevented the reduction of regulatory T-cell proportion after cerebral ischemia while this disruption did not affect Th1 and Th2 cells proportions after ischemia. Since repeated administration of L-histidine (a precursor of histamine) to Wt mice also showed the same effects, our observations suggested that OCT3 is the molecule responsible for clearance of ischemia-induced histamine in the brain and targeted disruption of Oct3 ameliorated ischemic brain damage through an increase in regulatory T cells.

Effect of histidine administration to female rats during pregnancy and lactation on enzymes activity of phosphoryltransfer network in cerebral cortex and hippocampus of the offspring

Histidinemia is an inborn error of metabolism of amino acids caused by deficiency of histidase activity in liver and skin with consequent accumulation of histidine in plasma and tissues. Histidinemia is an autosomal recessive trait usually considered harmless to patients and their offspring, but some patients and children born from histidinemic mothers have mild neurologic alterations. Considering that histidinemia is one of the most frequently identified metabolic conditions, in the present study we investigated the effect of L-histidine load to female rats during pregnancy and lactation on some parameters of phosphoryltransfer network in cerebral cortex and hippocampus of the offspring. Pyruvate kinase, cytosolic and mitochondrial creatine kinase activities decreased in cerebral cortex and in hippocampus of rats at 21days of age and this pattern remained in the cerebral cortex and in hippocampus at 60days of age. Moreover, adenylate kinase activity was reduced in the cerebral cortex and in hippocampus of the offspring at 21days of age, whereas the activity was increased in the two tissues at 60days of age. These results suggest that administration of L-histidine to female rats in the course of pregnancy and lactation could impair energy homeostasis in the cerebral cortex and hippocampus of the offspring. Considering that histidinemia is usually a benign condition and little attention has been given to maternal histidinemia, it seems important to perform more studies in the children born from histidinemic mothers.

Modulation of the state of the antiepileptic cerebral system by the influence of a ketogenic diet under conditions of the resistant epileptic syndrome

In experiments on rats subjected to a procedure of corazole kindling with the development of antiepileptic drug-resistant seizures, we found that manifestations of resistance were suppressed under conditions of feeding the rats with a ketogenic diet (KD) including 80% lipids and 16.6% proteins. Against the background of using this diet, such means as electrical stimulations of the paleocerebellum, irradiation with extremely high-frequency electromagnetic waves (length 7.1 mm), and administration of L-histidine (300 mg/kg) were more effective from the aspect of inhibition of the above seizure activity. At the same time, keeping rats on the KD modified the action of L-arginine on the epileptic activity to a significantly weaker extent.

Reduction of the infarct size by simultaneous administration of l-histidine and diphenhydramine in ischaemic rat brains

Aims While diphenhydramine is a histamine H 1 receptor antagonist, the agent has been shown to inhibit histamine- N-methyltransferase, a histamine inactivating enzyme in the brain. Since an increase in the brain concentration of histamine ameliorates reperfusion injury after cerebral ischaemia, effects of postischaemic administration of diphenhydramine were evaluated in rats treated with l-histidine, a precursor of histamine. Methods The right middle cerebral artery was occluded for 2 h, and the infarct size was determined 24 h after reperfusion of cerebral blood flow. Brain oedema was evaluated by comparing the area of the right hemisphere to that of the left hemisphere. Results Focal cerebral ischaemia provoked marked damage in saline-treated control rats, and infarct volumes in the striatum and cerebral cortex were 56 (49–63) mm 3 and 110 (72–148) mm 3, respectively (means and 95% confidence intervals, n = 6). Administration of l-histidine (1000 mg/kg, intraperitoneal) immediately after reperfusion did not affect the infarct size. Simultaneous administration of diphenhydramine (20 mg/kg, intraperitoneal) with l-histidine reduced the infarct size to 25% and 21% of that in the control group, respectively. The combination therapy completely reduced ischaemia-induced brain oedema. Conclusion Because histamine H 1 action does not influence ischaemic brain damage, elevation of the central histamine concentration by blockade of histamine- N-methyltransferase may be a likely mechanism responsible for the alleviation.

Oral l‐histidine exerts antihypertensive effects via central histamine H3 receptors and decreases nitric oxide content in the rostral ventrolateral medulla in spontaneously hypertensive rats

1. L-histidine is generally found in meat, poultry and fish. To investigate its effects on blood pressure, L-histidine was administered to 9-week-old spontaneously hypertensive rats (SHR). 2. Oral administration of L-histidine (100 mg / kg) increased histamine content in cerebrospinal fluid and reduced mean arterial pressure (MAP) in SHR. Intracerebroventricular injection of L-histidine (0.01 microg / 5 microL) also caused a decrease in MAP, which was reversed by cotreatment with the histamine H3 receptor antagonist thioperamide (20.4 microg / 5 microL, i.c.v.). There was a significant, time-dependent increase (over 6 h) in the NOx (NO2- + NO3-) content of the dialysate from the rostral ventrolateral medulla (RVLM), a major vasomotor centre, after oral administration of L-histidine. 3. In another experiment, SHR were treated with l-histidine (100 mg / kg) twice a day for 4 weeks. Chronic treatment with L-histidine inhibited the age-dependent increases in systolic blood pressure and urinary noradrenaline excretion seen in vehicle-treated SHR. Conversely, intracerebroventricular injection of thioperamide (20.4 microg / 5 microL, i.c.v.) reversed the decrease in MAP in response to L-histidine in SHR. 4. Reverse transcription-polymerase chain reaction analysis revealed that the aortic expression of angiotensin-converting enzyme mRNA was suppressed by chronic treatment with L-histidine. 5. These results suggest that L-histidine decreases blood pressure by attenuating sympathetic output via the central histamine H3 receptor in SHR. In addition, the antihypertensive effects of L-histidine appear to be associated with an increase in nitric oxide in the RVLM.

Role of histamine in brain protection in surgical brain injury in mice

Surgical resection of brain tissue is associated with tissue damage at the resection margin. Studies of ischemic brain injury in rodents have shown that administration of l-histidine and thioperamide reduces ischemic tissue loss, in part by inhibition of apoptotic cell death. In this study we tested administration of l-histidine and thioperamide in surgical brain injury in mice. Mice were randomized to one of three groups: Sham surgery ( n = 18), surgical brain injury without treatment (SBI) ( n = 33), and surgical brain injury with combined l-histidine and thioperamide treatment (SBI + H) ( n = 29). Surgical brain injury was induced via right frontal craniotomy with resection of the right frontal lobe. l-histidine (1000 mg/kg) and thioperamide (5 mg/kg) were administered to the SBI + H group immediately following surgical resection. Postoperative assessment included neurobehavioral scores, Evans blue measurement of blood–brain barrier breakdown, brain water content, Nissl histology, and immunohistochemistry for IgG and cleaved caspase 3. Postoperative findings included equivalent neurobehavioral outcomes at 24 and 72 h in the SBI and SBI + H groups, similar histological outcomes between SBI and SBI + H, and similar qualitative staining for cleaved caspase 3. SBI + H had increased BBB breakdown on Evans blue analysis and a trend towards increased brain edema which was significant at 72 h. We conclude that combined treatment with l-histidine and thioperamide leads to increased BBB breakdown and brain edema in surgical brain injury.

Alleviation of Ischemia-Induced Brain Edema by Activation of the Central Histaminergic System in Rats

We have reported that facilitation of central histaminergic activity prevents the development of ischemia-induced brain injury. Since cerebral edema is a major cause of brain damage, we studied effects on brain edema of postischemic administration of l-histidine, a precursor of histamine, and thioperamide, a histamine H3–receptor antagonist, both of which enhance central histaminergic activity. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery in rats, and the water content and infarct size were determined 24 h after reperfusion. Changes in the extracellular concentration of histamine were examined in the striatum by a microdialysis procedure, and effects of these compounds were evaluated. Repeated administration of l-histidine (1000 mg/kg × 2, i.p.), immediately and 6 h after reperfusion, reduced the increase in the water contents in ischemic regions. Simultaneous administration of thioperamide (5 mg/kg, s.c.) with l-histidine (1000 mg/kg, i.p.) completely prevented edema formation and alleviated brain infarction, although a single dose of l-histidine, immediately after reperfusion, showed no benefits. The striatal histamine level was gradually increased after reperfusion as well as during ischemia. Simultaneous administration of thioperamide with l-histidine markedly increased the brain histamine concentration, and the value increased up to 230% of that in the saline group 5 – 6 h after reperfusion. l-histidine alone did not affect the increase in the histamine output after ischemia. These findings suggest that further activation of the central histaminergic system after initiation of cerebral ischemia prevents development of ischemia-induced brain edema.

Histaminergic H1 receptors mediate L-histidine-induced anxiety in elevated plus-maze test in mice

The central histaminergic system is reported to mediate behavioural, hormonal and physiological homeostasis of living organisms. Recent reports indicate its prominent role in various neurobehavioural disorders such as depression and psychosis. This study evaluated the effect of activation of the central histaminergic system in anxiety-like conditions, using the elevated plus-maze test in mice, and elucidated the role of different histaminergic receptors mediating such effects. Peripheral administration of L-histidine (L-His), in a dose-dependent manner, significantly decreased the exploration time in open arms and number of entries into open arms without modifying the number of entries into closed arms of the elevated plus-maze, indicating anxiogenesis. Further, such effects of central histamine were significantly attenuated, in a dose-dependent manner, by pretreatment with pyrilamine (H1 receptor antagonist). Pretreatment with either zolantidine (H2 receptor antagonist) or thioperamide (H3 receptor antagonist), however, failed to attenuate the L-His-induced anxiogenesis. Our results indicate that anxiogenic effects of central histaminergic system appear to be mediated prominently by activation of H1 receptors.

Histaminergic Involvement in Neuropathic Pain Produced by Partial Ligation of the Sciatic Nerve in Rats

Because the histaminergic system in the brain is involved in regulation of pain, the relationship between central histaminergic activity and neuropathic pain is of interest. Neuropathic pain was induced in rats by partial ligation of the left sciatic nerve, and changes in the extracellular concentration of histamine in the right striatum were examined by a microdialysis procedure 2 weeks later. The nociceptive threshold was determined with von Frey tests, and effects of histaminergic ligands were examined. Although the extracellular concentration of histamine did not differ between the sham-operated and ligated groups, histaminergic activity assessed by metoprine-induced accumulation of histamine was facilitated in ligated animals. The metoprine treatment ameliorated neuropathic pain in ligated animals, although the agent did not affect the threshold in sham-operated rats. Either intracerebroventricular (ICV) administration of histamine (30 microg) or intraperitoneal (IP) administration of L-histidine (370 mg/kg) decreased the nociceptive threshold in ligated rats. However, a high dose of histamine (180 microg ICV) increased the nociceptive threshold. Ranitidine (100 microg ICV), an H2 antagonist, increased the threshold, whereas pyrilamine (15 microg ICV), an H1 antagonist, showed no remarkable change. Administration of thioperamide (30 microg ICV), an H3 antagonist, increased the threshold, although systemic administration of the agent (3.6 mg/kg IP) decreased it. Blockade of supraspinal histamine H2 receptors or stimulation of spinal H3 receptors may contribute to alleviation of neuropathic pain.

Suppression of inflammatory cell recruitment by histamine receptor stimulation in ischemic rat brains

Inflammation is a crucial factor in the development of ischemia-induced brain injury. Since facilitation of central histaminergic activity ameliorates reperfusion injury, effects of postischemic administration of l-histidine, a precursor of histamine, and thioperamide, a histamine H 3 receptor antagonist, on inflammatory cell infiltration were evaluated in a rat model of transient occlusion of the middle cerebral artery. After reperfusion for 12, 24, or 72 h following 2 h of occlusion, brain slices were immunohistochemically stained with antibodies against myeloperoxidase and CD68, which were markers of polymorphonuclear leukocytes and macrophages/microglia, respectively. After reperfusion for 12–24 h, the number of neutrophils on the ischemic side increased markedly, whereas the increase was not observed on the contralateral side. Administration of l-histidine (1000 mg/kg × 2, i.p.), immediately and 6 h after reperfusion, reduced the number of neutrophils to 52%. Simultaneous administration of thioperamide (5 mg/kg, s.c.) further decreased the number of neutrophils to 32%. Likewise, the ischemia induced increase in the number of CD68-positive cells after 24 h was suppressed by l-histidine injections. The l-histidine administration decreased the number of CD4 +T lymphocytes on both ischemic and contralateral sides after 12 h, and concurrent administration of thioperamide prolonged the effect. Although administration of mepyramine (3 nmol, i.c.v.) did not affect suppression of leukocyte infiltration, ranitidine tended to reverse the effect of l-histidine. These data suggest that enhancement of central histaminergic activity suppresses inflammatory cell recruitment after ischemic events through histamine H 2 receptors, which may be a mechanism underlying the protective effect of l-histidine.

A comparison of protective effects between l-histidine and hypothermia against ischemia-induced neuronal damage in gerbil hippocampus

An increase in the histamine concentration in the brain has been demonstrated to provide protective effects against ischemia/reperfusion brain injury. Since hypothermia and barbiturates are also regarded to protect ischemic brains, effects of postischemic treatments were compared in gerbils between mild hypothermia and intraperitoneal administration of l-histidine, a precursor of histamine. Furthermore, effects of thioperamide, a histamine H 3 receptor antagonist, were evaluated in histidine-treated gerbils after 60 days. Transient forebrain ischemia for 4 min at 37 °C provoked severe neuronal damage in the hippocampal CA1 pyramidal cells after 7 days. Postischemic hypothermia (33 °C) for 3 h under pentobarbital anesthesia alleviated neuronal death, and the number of preserved neurons was 77 ± 56/mm (mean ± S.D., n = 14). The effect of l-histidine injected three times, immediately, 6 h, and 24 h after reperfusion (1000 mg/kg, i.p., each), was more prominent than that of hypothermia, and the number of preserved neurons was 142 ± 55/mm ( n = 14). When the histologic outcome was evaluated after 60 days, most neurons were damaged in both the hypothermic and histidine groups. The improvement of the histologic outcome was observed even after 60 days in animals injected with thioperamide, immediately and 6 h after reperfusion (5 mg/kg, s.c., each), with three injections of l-histidine. The number of preserved neurons was 133 ± 88/mm ( n = 10), while that in the hypothermic group was 7 ± 15 ( n = 10). Activation of the central histaminergic system provides beneficial effects against cerebral ischemia.

Reduction in brain infarction by augmentation of central histaminergic activity in rats

Inflammation is a factor in the aggravation of reperfusion injury after cerebral ischemia. Since histamine H 2 receptor stimulation suppresses inflammatory reactions, effects of the central histaminergic activation on brain infarction were examined in rats. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery, and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride stain after 24 h. Effects of postischemic administration of thioperamide, an H 3 antagonist, and metoprine, an inhibitor of histamine- N-methyltransferase, were evaluated in rats treated with l-histidine, a precursor of histamine. Furthermore, effects of these agents on changes in the striatal histamine level were examined by a microdialysis procedure. Focal ischemia provoked marked damage in rats treated with l-histidine (1000 mg/kg) alone. Administration of l-histidine (1000 mg/kg) with either thioperamide (5 mg/kg) or metoprine (10 mg/kg) alleviated brain infarction. The size of brain infarction was 27% and 10% of that in animals treated solely with l-histidine, respectively. The combination treatment with thioperamide and metoprine decreased the size of brain infarction in rats given l-histidine (500 mg/kg), although protective effects were not clear without l-histidine. A marked increase in the histamine concentration was observed in the histidine plus metoprine group, the value being 363% of that in the saline-injected group after 2–3 h. The histamine concentrations in the histidine group and histidine plus thioperamide group were 188% and 248%, respectively. These findings indicate that facilitation of central histaminergic activity reduced the brain infarction.

P.2.08 Acute hypercapnic gas challenge increases c-Fos in topographically organised histaminergic neurones

Inflammation is a factor in the aggravation of reperfusion injury after cerebral ischemia. Since histamine H2 receptor stimulation suppresses inflammatory reactions, effects of the central histaminergic activation on brain infarction were examined in rats. Focal cerebral ischemia for 2 h was provoked by transient occlusion of the right middle cerebral artery, and the infarct size was determined by 2,3,5-triphenyltetrazolium chloride stain after 24 h. Effects of postischemic administration of thioperamide, an H3 antagonist, and metoprine, an inhibitor of histamine-N-methyltransferase, were evaluated in rats treated with l-histidine, a precursor of histamine. Furthermore, effects of these agents on changes in the striatal histamine level were examined by a microdialysis procedure. Focal ischemia provoked marked damage in rats treated with l-histidine (1000 mg/kg) alone. Administration of l-histidine (1000 mg/kg) with either thioperamide (5 mg/kg) or metoprine (10 mg/kg) alleviated brain infarction. The size of brain infarction was 27% and 10% of that in animals treated solely with l-histidine, respectively. The combination treatment with thioperamide and metoprine decreased the size of brain infarction in rats given l-histidine (500 mg/kg), although protective effects were not clear without l-histidine. A marked increase in the histamine concentration was observed in the histidine plus metoprine group, the value being 363% of that in the saline-injected group after 2–3 h. The histamine concentrations in the histidine group and histidine plus thioperamide group were 188% and 248%, respectively. These findings indicate that facilitation of central histaminergic activity reduced the brain infarction.

Brain histamine and histamine H 3 receptors following repeated l-histidine administration in rats

In order to assess the importance of the chronic increase in precursor availability on central histaminergic mechanisms in rats, nine male Wistar rats received l-histidine orally at a dose of 1000 mg/kg, twice daily (07.00 h and 19.00 h) for 1 week; 9 rats were used as controls. Brain tissue histamine and tele-methylhistamine levels, as well as plasma histamine concentration were assayed. Binding properties and regional distribution of the autoregulatory histamine H 3 receptors in brain were studied with [ 3H]-R-α-methylhistamine receptor binding and autoradiography. In l-histidine loaded rats, tissue histamine levels in cortex, hypothalamus, and rest of the brain were significantly increased by 40%–70%. Histamine concentrations in cerebellum and plasma, and tele-methylhistamine concentrations in cortex and hypothalamus did not change. The binding properties of H 3 receptors in cortex were not altered. However, there were changes in the regional distribution of [ 3H]-R-α-methylhistamine binding sites, suggestive of a region-selective up-/down-regulation of histamine H 3 receptors or their receptor sub-types. These results imply that following repeated l-histidine administration in the rat (1) there is enhanced synthesis of brain histamine not reflected in its functional release; (2) the excess of histamine is sequestered and stored rather than being metabolized; (3) histamine H 3 receptor binding properties are not altered, whereas receptor density is changed in selected regions. In conclusion, these results demonstrate that the neuronal mechanisms controlling histamine synthesis, storage, and release are adaptable and allow the sequestration of the excess of histamine in order to prevent excessively high neuronal activity.

Copper Complexation by Amino Acid:l-Glutamine–Copper(II)–l-Histidine Ternary System

Abstract Menkes disease is a lethal genetic disorder of copper transport in humans. Its current treatment is the administration of copper–l-histidine complex. However, this therapy is only effective in some cases and when started early in life. In order to develop an improved treatment, copper(II) mixed ligand amino acid complexes were studied because these complexes play an important role in the physiological copper pathway. A promising strategy is the administration of l-histidine–copper(II)–l-glutamine complex, which has been reported to be the predominant low molecular-weight copper(II) complex in human blood serum. Before the biopharmaceutical studies of l-histidine–copper(II)–l-glutamine complex, a physicochemical study of this ternary system must be performed. The stoichiometry and the stability of l-histidine–copper(II)–l-glutamine relative to copper(II)–l-histidine and copper(II)–l-glutamine were established at pH 7 in solution by polarography and UV–visible spectroscopy. Nevertheless, it has been demonstrated that the species [Cu(His)2] and [Cu(His)2(OH)] coexist in the same solution. This study has been complemented by EPR analysis which suggests copper in [Cu(His)(Gln)] complex has a distorted octahedral geometry. The first shell of copper coordination is 3 N, 1 O, histidine, and glutarnine being bidentate.

Histidine induces lipolysis through sympathetic nerve in white adipose tissue.

Hypothalamic neuronal histamine has been shown to increase lipolysis in white adipose tissue. The present study aimed to clarify whether peripheral loading with L-histidine, a precursor of neuronal histamine, may affect lipid metabolism in adipose tissue. The in vivo microdialysis study was used to assess lipolysis in rat epididymal adipose tissue by measuring the release of glycerol in response to administration of L-histidine. In addition, electrophysiological measurements were performed to record changes in activity of sympathetic nerve innervating adipose tissue following histidine treatment. Sequential administration of isoproterenol, a beta-adrenoceptor agonist, through the microdialysis cannula at concentrations of 10(-)8 to 10(-6) M increased the glycerol concentration in the dialysate dose-dependently (P < 0.05). Intraperitoneal administration of L-histidine at a dosage of 0.35 mmol kg(-1) also increased the glycerol concentration compared to that of phosphate buffered saline (P < 0.05). Concomitantly, the administration of histidine increased the serum concentration of free fatty acid compared to control treatment (P < 0.05). The accelerating effects of histidine on lipolysis were mimicked by the infusion of 10(2) nmol rat(-1) L-histamine into the third cerebroventricle (P < 0.05). Electrophysiological measurement demonstrated that administration of histidine at a dosage of 0.35 mmol kg(-1) increased the activity of efferent sympathetic nerve, innervating adipose tissue more than the infusion of phosphate buffered saline (P < 0.05). The present results indicate that histidine accelerates lipolysis in white adipose tissue through activation of the sympathetic nerve. The regulation of lipolysis may therefore involve histamine neurons in the brain, probably through the conversion of L-histidine to histamine in the hypothalamus.

Cholera toxin-induced PGE 2 activity is reduced by chemical reaction with l-histidine

Mediators of cholera toxin (CT)-induced fluid secretion include 3′,5′-adenosine monophosphate (cAMP), prostaglandin E 2 (PGE 2), and 5-hydroxytryptamine (5-HT). Administration of l-histidine significantly reduced the net secretory response of the small intestine of mice challenged with CT and reduced the capacity of PGE 2 to stimulate Na + transport in Ussing chambers. We demonstrated that l-histidine chemically modified the structure of PGE 2 but had no direct effect on cAMP or 5-HT. l-Histidine and imidazole reacted with PGE 2 in vitro in cell-free mixtures incubated at 37°C and pH 7.0 under an atmosphere of N 2 with the formation of PGE 2–imidazole and PGE 2–histidine covalent adducts. Nuclear magnetic resonance (NMR) spectroscopy and mass spectrometry (MS) analysis of the purified adduct showed that imidazole catalyzed the dehydration of PGE 2. A Michael adduct then was formed between C11 of 11-deoxy-Δ 10 PGE 2 (PGA 2) and the tau nitrogen in the imidazole ring of l-histidine. Importantly, the isolated PGE 2–imidazole and PGE 2–histidine adducts inhibited CT-induced fluid loss and cAMP accumulation in mouse intestinal loops. The protection provided by PGE 2–imidazole, PGE 2–histidine, and l-histidine against intestinal fluid loss could provide a basis for future therapy against cholera.