Changes of biochemical indexes in patients with acute cerebral infarction after treatment with simvastatin

BACKGROUND: At present, it is believed that the important causes of cerebral infarction are the disorders of lipid metabolism and endothelial function, and the outcomes of clinical treatment can be improved by regulating serum lipids and antiinflammation, etc. OBJECTIVE: To observe the effect of simvastatin, inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on the levels of serum lipids, serum enzymic indexes and inflammatory metabolic indexes in patients with cerebral infarction. DESIGN: A comparative observation. SETTING: Department of Geriatrics, Longquanshan Hospital of Liuzhou City. PARTICIPANTS: Forty-eight patients with acute cerebral infarction were selected from the Department of Geriatrics of Longquanshan Hospital of Liuzhou from March 2004 to February 2006, including 24 males and 24 females, the mean age was (54±12) years, average disease course was (10.0±4.5) days. They were all accorded with the diagnostic standard for cerebral infarction set by the Fourth National Academic Meeting for Cerebrovascular Disease in 1999, and cerebral hemorrhage was excluded by cranial CT scanning. The 48 patients were randomly divided into control group (n =24) and treatment group (n =24). Informed consents were obtained from all the participants. METHODS: ① All the patients were treated according to the symptoms, besides those in the treatment group were given simvastatin (Harbin Pharm. Group Sanjing Pharmaceutical Shareholding, Co.,Ltd., No. H20010454; Batch number: 20040218; 5 mg/tablet). The initial dosage was 10 mg per day for 4 weeks, and then increased to 30 mg per day for another 4 weeks. ② Before treatment and within 1 week after treatment, the total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), creatine kinase and C reactive protein in serum were determined with Beckman-cx7 automatic biochemical analytical apparatus in both groups. ③ The differences of intergroup and intragroup data were compared with the independent-samples t test and paired samples t test. MAIN OUTCOME MEASURES: Changes of total cholesterol, triglyceride, HDL-C, LDL-C, AST, creatine kinase and C reactive protein before and treatment in both groups. RESULTS: All the 48 patients with cerebral infarction were involved in the analysis of results. ① Changes of serum lipids: The levels of serum lipids were close between the two groups before treatment (P > 0.05). After treatment, the HDL-C level in the treatment group was obviously higher than that in the control group and that before treatment [(1.34±0.12), (0.92±0.33), (0.93±0.21) mmol/L, t =7.922, 11.699, P < 0.01], and the levels of total cholesterol, triglyceride and LDL-C were obviously lower than those in the control group and those before treatment (t =2.780-7.591, P < 0.01). ② Changes of serum enzymic indexes and C reactive protein in serum: The levels of enzymes and C reactive protein in serum had no obvious differences between the two groups before treatment (P > 0.05). The levels of AST, creatine kinase and C reactive protein in serum after treatment were obviously lower than those before treatment in both groups (t =7.259-17.996, P < 0.01). The levels of levels of creatine kinase and C reactive protein in serum after treatment in the treatment group were obviously lower than those in the control group [(3.061±0.522) μkat/L, (4.6±3.1) mg/L; (4.348±0.580) μkat/L, (12.3±4.8) mg/L, t =7.910, 6.463, P < 0.01]. CONCLUSION: Compared with common treatment according to symptoms, the additional administration of simvastatin is better for improving the serum lipids, serum enzymic indexes of patients with cerebral infarction at acute period, and benefit for repairing their inflammatory damages.     

Changes of biochemical indexes in patients with acute cerebral infarction after treatment with simvastatin

BACKGROUND: At present, it is believed that the important causes of cerebral infarction are the disorders of lipid metabolism and endothelial function, and the outcomes of clinical treatment can be improved by regulating serum lipids and antiinflammation, etc. OBJECTIVE: To observe the effect of simvastatin, inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A reductase, on the levels of serum lipids, serum enzymic indexes and inflammatory metabolic indexes in patients with cerebral infarction. DESIGN: A comparative observation. SETTING: Department of Geriatrics, Longquanshan Hospital of Liuzhou City. PARTICIPANTS: Forty-eight patients with acute cerebral infarction were selected from the Department of Geriatrics of Longquanshan Hospital of Liuzhou from March 2004 to February 2006, including 24 males and 24 females, the mean age was (54±12) years, average disease course was (10.0±4.5) days. They were all accorded with the diagnostic standard for cerebral infarction set by the Fourth National Academic Meeting for Cerebrovascular Disease in 1999, and cerebral hemorrhage was excluded by cranial CT scanning. The 48 patients were randomly divided into control group (n =24) and treatment group (n =24). Informed consents were obtained from all the participants. METHODS: ① All the patients were treated according to the symptoms, besides those in the treatment group were given simvastatin (Harbin Pharm. Group Sanjing Pharmaceutical Shareholding, Co.,Ltd., No. H20010454; Batch number: 20040218; 5 mg/tablet). The initial dosage was 10 mg per day for 4 weeks, and then increased to 30 mg per day for another 4 weeks. ② Before treatment and within 1 week after treatment, the total cholesterol, triglyceride, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), aspartate aminotransferase (AST), creatine kinase and C reactive protein in serum were determined with Beckman-cx7 automatic biochemical analytical apparatus in both groups. ③ The differences of intergroup and intragroup data were compared with the independent-samples t test and paired samples t test. MAIN OUTCOME MEASURES: Changes of total cholesterol, triglyceride, HDL-C, LDL-C, AST, creatine kinase and C reactive protein before and treatment in both groups. RESULTS: All the 48 patients with cerebral infarction were involved in the analysis of results. ① Changes of serum lipids: The levels of serum lipids were close between the two groups before treatment (P > 0.05). After treatment, the HDL-C level in the treatment group was obviously higher than that in the control group and that before treatment [(1.34±0.12), (0.92±0.33), (0.93±0.21) mmol/L, t =7.922, 11.699, P < 0.01], and the levels of total cholesterol, triglyceride and LDL-C were obviously lower than those in the control group and those before treatment (t =2.780-7.591, P < 0.01). ② Changes of serum enzymic indexes and C reactive protein in serum: The levels of enzymes and C reactive protein in serum had no obvious differences between the two groups before treatment (P > 0.05). The levels of AST, creatine kinase and C reactive protein in serum after treatment were obviously lower than those before treatment in both groups (t =7.259-17.996, P < 0.01). The levels of levels of creatine kinase and C reactive protein in serum after treatment in the treatment group were obviously lower than those in the control group [(3.061±0.522) μkat/L, (4.6±3.1) mg/L; (4.348±0.580) μkat/L, (12.3±4.8) mg/L, t =7.910, 6.463, P < 0.01]. CONCLUSION: Compared with common treatment according to symptoms, the additional administration of simvastatin is better for improving the serum lipids, serum enzymic indexes of patients with cerebral infarction at acute period, and benefit for repairing their inflammatory damages.     

Neurological assessments after treatment with the antimalarial β-arteether in neonatal and adult rats

The World Health Organization currently recommends combinatorial treatment including artemisinins as first-line therapy against drug-resistant Plasmodium falciparum malaria. Although highly efficacious, artemisinin and its derivatives, including β-arteether (βAE), are associated with ototoxicity, tremors, and other autonomic and motor impairments in the clinic. Similar neurological symptoms, as well as brainstem lesions, have been observed in adult laboratory species (mice, rats, dogs, and non human primates) following acute treatment with βAE; however, few long-term, nonclinical studies have been conducted. Furthermore, the majority of deaths attributed to malarial infection occur in children under age five, yet no laboratory studies have been initiated in neonatal or juvenile animals. In the current study, neonatal 7-day-old rats were administered intramuscular doses of 1-90 mg/kg βAE in sesame oil for up to eight treatment cycles (one cycle=7 days treatment+7 days without treatment). Neonates were tested for changes in sensorimotor function, and the same animals were tested as adults in the Functional Observational Battery, for motor activity, and in the 8-arm radial maze. Pups receiving a single cycle of 60 or 90 mg/kg died within a week of treatment but had few behavioral changes and no brainstem pathology. In the long-term study, behavioral and motor changes and brainstem lesions were observed in a dose- and time-related manner. Rats given repeated cycles of 1 or 5mg/kg βAE showed subtle motor abnormalities (e.g., slight loss of righting reflex) while repeated cycles of 10mg/kg βAE treatment resulted in obvious motor and behavioral changes. Rats receiving 1mg/kg βAE had no brainstem lesions whereas some rats treated with 5mg/kg βAE and all rats treated with 10 mg/kg βAE had brainstem lesions. Brainstem lesions were observed after as few as five cycles and were characterized by gliosis, satellitosis and progressive necrosis in motor neurons of the trapezoid, vestibular, and olivary nuclei. This study shows that repeated treatment with clinically relevant doses of βAE causes motor deficits associated with brainstem damage in rodents and suggests that repeated treatment with βAE in children may elicit neurological damage.     

Effect of Angelica sinensis on neural stem cell proliferation in neonatal rats following intrauterine hypoxia★

BACKGROUND： Angelica sinensis is a widely used herb in Chinese traditional medicine. It has been shown to improve hypoxia in embryonic rats and reduce nestin expression in neural stem cells, resulting in proliferation of neural stem cells.
OBJECTIVE： To study the protective effect of Angelica on neural stem cell proliferation in neonatal rats after intrauterine hypoxia.
DESIGN, TIME AND SETTING： The randomized, controlled, experiment was performed at the Department of Histology and Embryology, Luzhou Medical College, China from July 2007 to January 2008.
MATERIALS： Because gestational days 14-15 are a key stage in rat nervous system development, 21 healthy, pregnant Sprague Dawley rats （14 days after conception） were used for this study. Nestin monoclonal primary antibody was obtained from Chemicon, USA. Angelica parenteral solution （250 g/L） was obtained from Pharmaceutical Preparation Section, Second Affiliated Hospital of Wuhan University, China.
METHODS： Rats were randomly divided into a control group （n = 5）, a hypoxia group （n = 8）, and an Angelica group （n = 8）. Saline （8 mL/kg） was injected into the caudal vein of rats in the hypoxia group once a day for seven consecutive days. Intrauterine hypotonic hypoxia was induced using 13% O2 for two hours per day on three consecutive days. Rats in the Angelica group received injections of Angelica parenteral solution （250 g/L）; all other protocols were the same as the hypoxia group. The control group procedures were identical to the hypoxia group, but under normal, non-hypoxic conditions. After birth, brain tissues were immediately obtained from neonatal rats and prepared for nestin immunohistochemistry.
MAIN OUTCOME MEASURES： Nestin-positive cells in hippocampal CA3 area of neonatal rats in each group were quantified using image analysis to detect signal absorbance.
RESULTS： The number of nestin-positive cells increased in the hippocampal CA3 area of neonatal rats in the hypoxia group. The number of nestin-pos     

Effects of topiramate on hippocampal neuronal apoptosis in rats after kainic acid-evoked seizures*☆

BACKGROUND： Apoptosis plays an important role in brain injury after seizures and the formation of chronic epilepsy. It is important to investigate whether topiramate exhibits either antiepileptic and/or antiapoptotic effects on hippocampal neurons. OBJECTIVE： To observe neuronal apoptosis in hippocampus of rat seizure models, and to investigate the antagonizing effect of topiramate on neuronal apoptosis after seizures.
DESIGN： An animal experiment of comparative observation.
SETTING： First Affiliated Hospital of Guangxi Medical University. MATERIALS： Sixty healthy male Sprague Dawley （SD） rats, 4-6 weeks old and weighing 160-220 g, were provided by the Experimental Animal Center of Guangxi Medical University. Main apparatus and reagents were as follows： Rat brain solid positioner （SR-6N, made in Japan）; kainic acid by Sigma （USA）; pathological image analyzer （DMR＋550） by Leica （Germany）; in situ apoptosis detection kit by Wuhan Boster Biological Technology Co., Ltd; topiramate by Xi＇an-Janssen Pharmaceutical, Ltd. The treatment on animals in the experiment was in accordance with the standards of animal ethics. METHODS： The experiments were performed at the Scientific Experimental Center of Guangxi Medical University from June to December 2006. The rats were randomly divided into a topiramate-treated group （n = 30） and a model group （n = 30）. ① After anesthesia, all rats were administered a kainic acid injection （0.2 μL, 2 g/L） into the right lateral ventricle. Grade Ⅲ and greater Racine standards were considered to be a successful model establishment. Thirty minutes after seizure , rats in the topiramate-treated group were treated with an intraperitoneal （i.p.） injection of topiramate every day （40 mg/kg/d） for 2 weeks. The rats in the model group were treated with an equal volume of saline for 2 weeks. ③ Six rats in the topiramate-treated group were sacrificed at 1 day, and 1, 2, 3, and 4 weeks after treatment, respectively. The model group ani     

WITHDRAWN. Neurological assessments after treatment with the antimalarial β-arteether in neonatal and adult rats

The World Health Organization currently recommends combinatorial treatment including artemisinins as first-line therapy against drug-resistant Plasmodium falciparum malaria. Although highly efficacious, artemisinin and its derivatives, including β-arteether (βAE), are associated with ototoxicity, tremors, and other autonomic and motor impairments in the clinic. Similar neurological symptoms, as well as brainstem lesions, have been observed in adult laboratory species (mice, rats, dogs, and non human primates) following acute treatment with βAE; however, few long-term, nonclinical studies have been conducted. Furthermore, the majority of deaths attributed to malarial infection occur in children under age five, yet no laboratory studies have been initiated in neonatal or juvenile animals. In the current study, neonatal 7-day-old rats were administered intramuscular doses of 1-90mg/kg βAE in sesame oil for up to eight treatment cycles (one cycle=7days treatment+7days without treatment). Neonates were tested for changes in sensorimotor function, and the same animals were tested as adults in the Functional Observational Battery, for motor activity, and in the 8-arm radial maze. Pups receiving a single cycle of 60 or 90mg/kg died within a week of treatment but had few behavioral changes and no brainstem pathology. In the long-term study, behavioral and motor changes and brainstem lesions were observed in a dose- and time-related manner. Rats given repeated cycles of 1 or 5mg/kg βAE showed subtle motor abnormalities (e.g., slight loss of righting reflex) while repeated cycles of 10mg/kg βAE treatment resulted in obvious motor and behavioral changes. Rats receiving 1mg/kg βAE had no brainstem lesions whereas some rats treated with 5mg/kg βAE and all rats treated with 10mg/kg βAE had brainstem lesions. Brainstem lesions were observed after as few as five cycles and were characterized by gliosis, satellitosis and progressive necrosis in motor neurons of the trapezoid, vestibular, and olivary nuclei. This study shows that repeated treatment with clinically relevant doses of βAE causes motor deficits associated with brainstem damage in rodents and suggests that repeated treatment with βAE in children may elicit neurological damage.     

Changes of biochemical indices in brain, liver tissue and serum in mice with Alzheimer disease after Chinese medicine treatment

BACKGROUND: Alzheimer disease is a main type of dementia, and the important clinical characteristic is the rapid declines of memory and cognitive ability. OBJECTIVE: To study changes of biochemical indices in brain, liver tissue and serum, as well as memory of mice with Alzheimer disease after Chinese medicine treatment. DESIGN: A comparative animal experimental observation. SETTING: Haierfu Research Center of Youjiang Medical College for Nationalities. MATERIALS: Forty-eight healthy Kunming mice (24 males and 24 females), 3 months old, were provided by the animal room of Youjiang Medical College for Nationalities. The animals were divided into four groups according to sex and body mass: control group, model group, Wuyuan Buxue treated group, Haierfu treated group, and 12 mice in each group. Wuyuan Buxue oral liquid was extracted from Polygonum multiflorum Thunb (red, radix) and longan meat (country medicine quasi- word B20020828). Haierfu oral liquid was extracted from Yinhua, poriacocos, licorice, etc (Q/452600RYYLC01-92). METHODS: The experiment was completed in Haierfu Research Center and Institute of Heavy Metal and Fluorosis-Arsenism of Youjiang Medical College for Nationalities from May 2006 to December 2006. ① All animals except those in the control group were given feed which was mixed with AlCl3 (12 g/L), and they could freely drink 3 g/L Al(NO3)3. The mice in the control group were given normal feed. Wuyuan Buxue oral liquid and Haierfu oral liquid were distilled by distilled water for one time respectively. Five months after model establishment, mice in the Wuyuan Buxue treated group and Haierfu treated group were given intrapastric perfusion of Wuyuan Buxue oral liquid and Haierfu oral liquid respectively, and those in the model group and control group were given intrapastric perfusion of distilled water of the same volume. All the mice were treated for 45 days. ② The swimming time (s) and error times were determined with Y-shape water maze before and after experiment; Hemoglobin was determined by method of HICN. After treatment, serum was isolated from eyeballs to determine the activities of glutathione peroxidase (GSH-PX), urea and cholesterol. The animals were executed to remove brain and liver, then 10% homogenate was prepared to determine the activity of acetylcholinesterase (AChE), clearance of O2–?, content of malondialdehyde (MDA), activities of superoxide dismutase (SOD) and GSH-PX. MAIN OUTCOME MEASURES: ① Swimming time and error times in the water maze, and the content of hemoglobin; ② alanine aminotransferase (ALT) activity and contents of urea and cholesterol in serum after treatment; ③ Activities of GSH-PX, AChE and SOD, and MDA content in liver, and AChE activity in brain after treatment. RESULTS: Totally 48 mice were used, and some of them died due to unknown reasons, finally 32 mice (8 in each group) were involved in the analysis of results. ① Content of hemoglobin before and after treatment: There were obvious changes in the groups (P < 0.05). ② Comparison of ALT, cholesterol and urea in serum: The contents of urea in the Wuyuan Buxue treated group and Haierfu treated group were obviously higher than those in the control group and model group (P < 0.05, 0.01); ALT and cholesterol had no significant differences among the groups (P > 0.05). ③ Comparisons of the activities of AChE, GSH-PX and SOD in brain homogenate: The activity of AChE was significantly higher in the control group than the model group and Haierfu treated group, also higher in the Wuyuan Buxue treated group than in the model group (P < 0.05). The activity of GSH-PX in the model group was significantly higher than those in the treated groups (P < 0.01). The activity of SOD in the control group was significantly higher than those in the treated groups (P < 0.05, P < 0.01). ④ Comparison of activities of GSH-PX and SOD, and MDA content in liver homogenate: The activities of GSH-PX and SOD in the model group were obviously lower than those in the Wuyuan Buxue treated group (P < 0.05). MDA content had no obvious differences among the groups (P > 0.05). ⑤ Comparison of MDA content, and clearance of O2–? in brain and liver: The MDA content in brain in the model group was significantly higher than those in the treated groups; The clearances of O2–? in liver in the treated groups were significantly higher than those in the control group and model group (P < 0.01). ⑥ Swimming time and error rate in water maze: Before treatment, the swimming speed had no obvious difference among the groups, while the error rate was obviously different. After treatment, there was no obvious difference in the control group; The swimming time was prolonged as compared with that before treatment in the other three groups, and there were no obvious differences among the three group; The error rate was the highest in the model group (25%), and the lowest in the Wuyuan Buxue treated group (8.3%). CONCLUSION: Both the Chinese medicines of Wuyuan Buxue oral liquid and Haierfu oral liquid can improve the biochemical indices in serum, liver and brain, and the memory ability of mice with Alzheimer disease.     

Changes in beta-endorphin neuron numbers and serum hormone levels in the arcuate nucleus of ovariectomized rats undergoing treadmill exercise★

BACKGROUND： The arcuate nucleus, when damaged in young rats, can lead to pathological changes in adults, such as osteoporosis. Ovariectomized rats suffer from osteoporosis at eight weeks following surgery and the number of β -endorphin immunoreactive neurons in the arcuate nucleus of the hypothalamus is significantly decreased. OBJECTIVE： To establish a rat model of osteoporosis using ovariectomy and to explore changes in the number of β-endorphin neurons and to correlate any such change with serum hormone levels in response to exercise or rest. DESIGN, TIME AND SETTING： The completely randomized block design, neural morphology study was performed at the Key Laboratory of Physiology, Guangdong Medical College, China between March 2004 and January 2005. MATERIALS： Sixteen healthy female rats were selected for ovariectomy. METHODS： Following model establishment, rats were assigned to either rest or exercise groups and each rat was housed individually. Rats in the exercise group underwent an exercise regimen using a treadmill. MAIN OUTCOME MEASURES： Eight weeks following exercise, radioimmunoassay was performed to detect serum growth hormone, estrogen and osteocalcin levels. Immunohistochemistry was used to measure changes in the number of β -endorphin neurons in the arcuate nucleus of the hypothalamus. Changes in bone metabolism were assessed using bone histomorphometry. RESULTS： In the exercise group, the β -endorphin immunoreactive neurons were high in number, darkly stained, and the nucleus was not obvious. In the rest group, the β -endorphin immunoreactive neurons were low in number and lightly stained. The number of β-endorphin immunoreactive neurons in the exercise group was higher compared with the rest group （t = 2.83, P 〈 0.05）. Estrogen levels were similar between the rest and exercise groups （P 〉 0.05）. Serum osteocalcin and growth hormone levels were significantly higher in the exercise group compared with the rest group （t = 2.78, 2.32, P 〈 0.05）. Compared with the     

Chronic treatment with fluoxetine decreases seizure threshold in naïve but not in rats exposed to the learned helplessness paradigm: Correlation with the hippocampal glutamate release

The proconvulsive effect of the new generation of antidepressants remains controversial. The authors investigated in na?ve rats the effect of chronic treatment with fluoxetine (FLX) on the convulsive threshold and on two parameters of the hippocampal glutamatergic neurotransmission: the in vitro glutamate release and the binding of [3H] MK801 to NMDA receptors. While the acute treatment with FLX provoked no change either in seizure susceptibility or in the glutamate release, the chronic treatment decreased the convulsive threshold in coincidence with an increment in the in vitro glutamate release. No significant effects on the binding of [3H] MK801 to NMDA receptors were found to be attributable to the FLX treatment. We also assessed the effect of the chronic treatment with FLX on the seizure threshold in rats exposed to an experimental model of depression, the learned helplessness paradigm (LH). While a decrease in the K+-stimulated glutamate release was observed in non treated LH animals, when they were chronically injected with FLX, no changes in the epileptic susceptibility and no increments in the glutamate release were found. Our results indicate that chronic treatment with FLX decreases the epileptic threshold in na?ve but not in LH rats and that this effect correlates with the levels of the hippocampal glutamate release.     

Why does a high-fat diet induce preeclampsia-like symptoms in pregnant rats？

Changes in neurotransmitter levels in the brain play an important role in epilepsy-like attacks after pregnancy-induced preeclampsia-eclampsia. Metabotropic glutamate receptor 1 participates in the onset of lipid metabolism disorder-induced preeclampsia. Pregnant rats were fed with a high-fat diet for 20 days. Thus, these pregnant rats experienced preeclampsia-like syndromes such as hyper-tension and proteinuria. Simultaneously, metabotropic glutamate receptor 1 mRNA and protein ex-pressions were upregulated in the rat hippocampus. These findings indicate that increased expres-sion of metabotropic glutamate receptor 1 promotes the occurrence of high-fat diet-induced pree-clampsia in pregnant rats.     

Cortical acetylcholine release elicited by stimulation of histamine H1 receptors in the nucleus basalis magnocellularis: a dual-probe microdialysis study in the freely moving rat

Perfusion of the nucleus basalis magnocellularis (NBM) with histamine agonists and antagonists modulates the spontaneous release of cortical acetylcholine (ACh) in freely moving rats. Perfusion of the NBM with Ringer solution containing 100 mM K+ strongly stimulated the spontaneous release of cortical ACh in freely moving rats, whereas perfusion with 1 microM tetrodotoxin reduced cortical ACh spontaneous release by more than 50%. Administration of histamine to the NBM concentration-dependently increased the spontaneous release of cortical ACh. Administration of H1 (methylhistaprodifen) but not H2 (dimaprit) or H3 (R-alpha-methylhistamine) receptor agonists to the NBM mimicked the effect of histamine. Perfusion of the NBM with either H1 (mepyramine or triprolidine) or H2 (cimetidine) receptor antagonists failed to alter ACh spontaneous release from the cortex, however, H1 but not H2 receptor antagonists antagonized the releases of cortical ACh elicited by histamine and methylhistaprodifen. Local administration of H3 receptor antagonists (clobenpropit and thioperamide) to the NBM increased the spontaneous release of ACh from the cortex; this effect was antagonized by H1 receptor antagonism. Conversely local administration of MK-801, a noncompetitive receptor antagonist of the N-methyl-D-aspartate receptor, to the NBM failed to alter ACh spontaneous release from the cortex and to antagonize ACh release elicited by histamine. This study demonstrates that activation of histamine H1 receptors in the NBM increases ACh spontaneous release from the cortex.     

Zucker obese rats: defect in brain histamine control of feeding

Manipulation of hypothalamic histamine produced different effects on feeding between the Zucker obese (fa/fa) and their lean littermate rats (Fa/−). Infusion of a histamine H₁-receptor antagonist into the third cerebroventricle elicited feeding in the lean and Wistar King A rats, but it did not affect feeding in the obese rats. To enhance hypothalamic neuronal histamine, thioperamide, an H₃-receptor antagonist, was similarly infused. The lean and Wistar rats decreased their food intake after the infusion, but thioperamide produced no significant effect on feeding in the obese rats. Infusion of histamine into the third cerebroventricle mimicked the effects of thioperamide on feeding: reduction of food intake in the lean and Wistar rats, but no significant change in the obese rats. Hypothalamic histamine of the obese rats (0.430 nmol/g) was significantly lower than the lean (1.209 nmol/g) and Wistar rats (4.838 nmol/g). The histamine concentration of the cerebral cortex in the obese rats was also lower than the non-obese animals. The results indicate that the feeding abnormality of Zucker obese rats may be at least due to disturbance of histamine suppressive signals both at presynaptic and postsynaptic levels.     

Endogenous histamine in the medial septum-diagonal band complex increases the release of acetylcholine from the hippocampus: a dual-probe microdialysis study in the freely moving rat

The effects of histaminergic ligands on both ACh spontaneous release from the hippocampus and the expression of c-fos in the medial septum-diagonal band (MSA-DB) of freely moving rats were investigated. Because the majority of cholinergic innervation to the hippocampus is provided by MSA-DB neurons, we used the dual-probe microdialysis technique to apply drugs to the MSA-DB and record the induced effects in the projection area. Perfusion of MSA-DB with high-KCl medium strongly stimulated hippocampal ACh release which, conversely, was significantly reduced by intra-MSA-DB administration of tetrodotoxin. Histamine or the H2 receptor agonist dimaprit, applied directly to the hippocampus, failed to alter ACh release. Conversely, perfusion of MSA-DB with these two compounds increased ACh release from the hippocampus. Also, thioperamide and ciproxifan, two H3 receptor antagonists, administered into MSA-DB, increased the release of hippocampal ACh, whereas R-alpha-methylhistamine, an H3 receptor agonist, produced the opposite effect. The blockade of MSA-DB H2 receptors, caused by local perfusion with the H2 receptor antagonist cimetidine, moderated the spontaneous release of hippocampal ACh and antagonized the facilitation produced by H3 receptor antagonists. Triprolidine, an H1 receptor antagonist, was without effect. Moreover, cells expressing c-fos immunoreactivity were significantly more numerous in ciproxifan- or thioperamide-treated rats than in controls, although no colocalization of anti-c-fos and anti-ChAT immunoreactivity was observed. These results indicate a role for endogenous histamine in modulating the cholinergic tone in the hippocampus.     

Homologous down-regulation of histamine H3 receptors in rat striatal slices

Preincubation of striatal slices with the selective histamine H3-receptor agonist immepip (100 nM) decreased the specific binding of N-alpha-[methyl-3H]-histamine ([3H]-NMHA) to membranes obtained from the treated slices. The binding decrease was significant after 5 min, remained at similar reduced levels between 5- and 30-min incubations with agonist, and only a partial recovery was observed after 90-min washout (34, 41, and 44% at 90, 120, and 150 min, respectively). Saturation analysis showed a significant decrease in both receptor density (-44% +/- 9%) and affinity (dissociation constant, Kd 1.15 +/- 0.23 nM from 0.59 +/- 0.17 nM). The effect of immepip was mimicked by histamine and the H3 agonists imetit and R-alpha-methylhistamine, and was blocked by the H3 antagonist thioperamide. The reduction in [3H]-NMHA binding was fully and partially prevented by incubation at 4 degrees C and in hypertonic medium, respectively, but not by the endocytosis inhibitor phenylarsine oxide (10 microM). None of the following protein kinase inhibitors, Ro-318220 and G?-6976 (PKC), H-89 (PKA) and staurosporine (general inhibitor) prevented the effect of immepip. In [3H]-adenine-labeled slices the preincubation with immepip (100 nM, 15 min) prevented the inhibitory effect of H3 receptor activation on forskolin-induced [3H]-cAMP accumulation (99% +/- 9% vs. 76% +/- 4% of control values). Taken together our results indicate that agonist binding promotes the down-regulation of striatal H3 receptors resulting in a significant loss of function.     

The histaminergic system in human thalamus: correlation of innervation to receptor expression

The mRNA expression of three histamine receptors (H1, H2 and H3) and H1 and H3 receptor binding were mapped and quantified in normal human thalamus by in situ hybridization and receptor binding autoradiography, respectively. Immunohistochemistry was applied to study the distribution of histaminergic fibres and terminals in the normal human thalamus. mRNAs for all three histamine receptors were detected mainly in the dorsal thalamus, but the expression intensities were different. Briefly, H1 and H3 receptor mRNAs were relatively enriched in the anterior, medial, and part of the lateral nuclei regions; whereas the expression level was much lower in the ventral and posterior parts of the thalamus, and the reticular nucleus. H2 receptor mRNA displayed in general very low expression intensity with slightly higher expression level in the anterior and lateropolar regions. H1 receptor binding was mainly detected in the mediodorsal, ventroposterolateral nuclei, and the pulvinar. H3 receptor binding was detected mainly in the dorsal thalamus, predominantly the periventricular, mediodorsal, and posterior regions. Very high or high histaminergic fibre densities were observed in the midline nuclear region and other nuclei next to the third ventricle, ventroposterior lateral nucleus and medial geniculate nucleus. In most of the core structures of the thalamus, the fibre density was very low or absent. The results suggest that histamine in human brain regulates tactile and proprioceptory thalamocortical functions through multiple receptors. Also, other, e.g. visual areas and those not making cortical connections expressed histamine receptors and contained histaminergic nerve fibres.     

Decreased histamine H1 receptor binding in the brain of depressed patients

The central histaminergic neuron system modulates the wakefulness, sleep-awake cycle, appetite control, learning and memory, and emotion. Previous studies have reported changes in neuronal histamine release and its metabolism under stress conditions in the mammalian brain. In this study, we examined, using positron emission tomography (PET) and [(11)C]-doxepin, whether the histaminergic neuron system is involved in human depression. Cerebral histamine H1 receptor (H(1)R) binding was measured in 10 patients with major depression and in 10 normal age-matched subjects using PET and [(11)C]-doxepin. Data were calculated by a graphical analysis on voxel-by-voxel and ROI (region of interests) basis. Binding potential (BP) values for [(11)C]-doxepin binding in the frontal and prefrontal cortices, and cingulate gyrus were significantly lower in the depressed patients than those in the normal control subjects. There was no area of the brain where [(11)C]-doxepin binding was significantly higher in the depressed patients than in the controls. ROI-based analysis also revealed that BP values for [(11)C]-doxepin binding in the frontal cortex and cingulate gyrus decreased in proportion to self-rating depressive scales scores. The results of this study demonstrate that depressed patients have decreased brain H(1)R binding and that this decrease correlates with the severity of depression symptoms. It is therefore suggested that the histaminergic neuron system plays an important role in the pathophysiology of depression and that its modulation may prove to be useful in the treatment of depression.     

H_1 and H_2 receptors in the locus ceruleus are involved in the intracere-broventricular histamine-induced carotid sinus baroreceptor reflex reset-ting in rats

1 Introduction Central histamine (HA) has been regarded as one of the important neurotransmitters or neuromodulators[1]. Brain HA keeps in close touch with the changes of cardio- vascular activities[1-3]. Carotid sinus baroreceptor reflex (CSR) with negative feedback regulation is a predominant approach to maintaining the spontaneous and simultaneous blood pressure homeostasis in mammal. It has been evi- denced that intracerebroventricular (i.c.v.) administration of HA can bring CSR reset…     

H(1) and H(2) receptors in the locus ceruleus are involved in the intracerebroventricular histamine-induced carotid sinus baroreceptor reflex resetting in rats

Objective To investigate the role of H1 and H2 receptors in the locus ceruleus （LC） in carotid sinus baroreceptor reflex （CSR） resetting induced by intracerebroventricular （i.c.v.） injection of histamine （HA）. Methods The left and right carotid sinus regions were isolated from the systemic circulation in 18 male Sprague-Dawley rats anesthetized with pentobarbital sodium. The intracarotid sinus pressure （ISP） was altered in a stepwise manner in vivo. ISP-mean arterial pressure （MAP） relationship curve and its characteristic parameters were constructed by fitting to the logistic function with five parameters. The changes in CSR performance induced by i.c.v. HA and the effects of pretreatment with H1 or H2 receptors selective antagonist, chlorpheniramine （CHL） or cimetidine （CIM） into the LC, on the responses of CSR to HA were examined. Results I.c.v. HA （100 ng in 5 μl） significantly shifted the ISP-MAP relationship curve upwards （P 〈 0.05） and obviously decreased the value of the reflex parameters such as MAP range and maximum gain （P 〈 0.05）, but increased the threshold pressure, saturation pressure and ISP at maximum gain （P 〈 0.05）. The pretreatment with CHL （0.5 μg in 1 μl） or CIM （1.5 μg in 1 μl） into the LC could obviously attenuate the changes mentioned above in CSR performance induced by HA, but the alleviative effect of CIM was less remarkable than that of CHL （P 〈 0.05）. Respective microinjection of CHL or CIM alone into the LC with the corresponding dose and volume did not change CSR performance significantly （P 〉 0.05）. Conclusion Intracerebroventricular administration of HA results in a rapid resetting of CSR and a decrease in reflex sensitivity, and the responses of CSR to HA may be mediated, at least in part, by H1 and H2 receptors activities in the LC, especially by H1 receptors. Moreover, the effects of the central HA on CSR might be related to a histaminergic descending pathway from the hypothalamus to LC.     

Histamine receptors of cones and horizontal cells in Old World monkey retinas

In primates the retina receives input from histaminergic neurons in the posterior hypothalamus that are active during the day. In order to understand how this input contributes to information processing in Old World monkey retinas, we have been localizing histamine receptors (HR) and studying the effects of histamine on the neurons that express them. Previously, we localized HR3 to the tips of ON bipolar cell dendrites and showed that histamine hyperpolarizes the cells via this receptor. We raised antisera against synthetic peptides corresponding to an extracellular domain of HR1 between the 4th and 5th transmembrane domains and to an intracellular domain near the carboxyl terminus of HR2. Using these, we localized HR1 to horizontal cells and a small number of amacrine cells and localized HR2 to puncta closely associated with synaptic ribbons inside cone pedicles. Consistent with this, HR1 mRNA was detected in horizontal cell perikarya and primary dendrites and HR2 mRNA was found in cone inner segments. We studied the effect of 5 μM exogenous histamine on primate cones in macaque retinal slices. Histamine reduced I(h) at moderately hyperpolarized potentials, but not the maximal current. This would be expected to increase the operating range of cones and conserve ATP in bright, ambient light. Thus, all three major targets of histamine are in the outer plexiform layer, but the retinopetal axons containing histamine terminate in the inner plexiform layer. Taken together, the findings in these three studies suggest that histamine acts primarily via volume transmission in primate retina.