Experimental autoimmune myocarditis in rats and therapeutic histamine H1 - H4 receptor inhibition.

Myocarditis, a life threatening disease, is still not adequately treated. Histamine plays an important role in physiology and pathophysiology of cardiovascular system. All four histamine receptors (H1R - H4R), are present in the heart. Experimental autoimmune myocarditis (EAM) was used to investigate which histamine receptor had a greater impact on the disease's progression. EAM was evoked in Lewis rats by porcine myosin immunization. Mepyramine, ranitidine and ciproxifan were used to inhibit H1R, H2R and H3R receptors, respectively, and 2,4-diaminopyrimidines: ST994, ST1012, ST1006 were ligands of H4R. Quinapril, an ACE inhibitor, served as a reference drug. Drugs were administered daily, either from 0 - 2 weeks or from 2 to 4 weeks post EAM induction. Cardiac dysfunction developed with significant decreases in left ventricular ejection fraction and fractional shortening due to dilatation and wall thickening. EAM rats treated with mepyramine and ST994 in weeks 0 - 2 had the lowest decreases. These treated with ST994, ST1012 or quinapril performed much better the following 2 weeks without therapy than did the other groups. On autopsy their hearts were smaller, less fibrotic, histopathological changes in them of a lower grade. When the treatment started with 2 weeks' delay, the ST994-treated EAM rats showed the highest median survival. H4 receptor antagonism inhibits heart remodelling, preserves heart contractility, improves survival and may be of potent therapeutic relevance in human clinics. The blockade of H1 receptor inhibits heart dilatation but does not prolong the life.

Effects of novel monoamine oxidases and cholinesterases targeting compounds on brain neurotransmitters and behavior in rat model of vascular dementia.

Neurodegenerative disorders are associated with different neurochemical and morphological alterations in the brain leading to cognitive and behavioural impairments. New therapeutic strategies comprise multifunctional drugs. The aim of the presented studies is to evaluate in vivo the novel compounds - ASS188 and ASS234 - which combine the benzylpiperidine moiety of the acetylcholinesteras (AChE) inhibitor donepezil and the indolyl propargylamino moiety of the monoaminooxidase (MAO) inhibitor, N-[(5-benzyloxy-1- methyl-1H-indol-2-yl)methyl]-N-methylprop-2-yn-1-amine, with respect to their influence on cerebral amine neurotransmitters systems and neuroprotective activity. The presumed therapeutic potential of these compounds has been evaluated following their administration to rats with experimental vascular dementia. A rat model of the permanent bilateral occlusion of the common carotid arteries (BCCAO) and the holeboard memory test were employed for this purpose. Wistar rats were used, either intact or 1 day after BCCAO. ASS188 (1 mg/kg) and ASS234 (5 mg/kg) were given s.c. for 5 consecutive days. Working and reference memory in rats was evaluated by holeboard tests before- and 7 and 12 days after BCCAO. The activities of MAOs, AChE and histamine N-methyltransferase (HMT), as well as cerebral amines concentrations were assayed. A significant inhibition of brain MAO A (>95%) and weaker MAO B (ca 60%) and HMT (<30%) and reduced AChE activities were recorded with a pronounced (2 - 10 fold) increase in the cerebral concentrations of serotonin, dopamine, and noradrenaline and smaller rises (up to 30%) of histamine. The BCCAO rats treated with ASS188 or ASS234 tended to perform holeboard tests better than the BCCAO untreated group, indicating a beneficial effect of the administered therapeutics.

The central histamine level in rat model of vascular dementia.

The histaminergic system plays an important role in memory and learning. Deficient histaminergic transmission in the human brain in vascular dementia (VD) has been suggested. To get a better insight into the problem, a rat model of VD based on permanent bilateral occlusion of the common carotid arteries (BCCAO) leading to chronic cerebral hypoperfusion was used. Prior to the BCCAO, male Wistar rats underwent 7 days training and only those animals that positively passed the holeboard memory test were chosen for the study. The rats which were operated on were injected i.p. daily for 6 days with either a monoamine oxidase B inhibitor - PF9601N (40 mg/kg), an acetycholinesterase inhibitor - tacrine (3 mg/kg), a histamine H(3) receptor blocker - DL76 (6 mg/kg) or saline. The first retest (R1) was performed one week after the surgery while each subsequent test was 5-7 days apart. The rats were euthanized 2 or 4 weeks following the operation. The concentration of brain histamine (HA) and the activity of histamine metabolising enzymes were measured using current procedures. The BCCAO drastically increased latency and run time (p<0.001) 54 ± 30 vs. 3.4 ± 1.2 and 268 ± 18 vs. 74 ± 9, respectively, and affected working memory rather than reference memory as measured by the 1(st) retest (R1). Treatment with either PF9601N or tacrine seems to exert a positive effect on working memory. This tendency disappeared after the drug treatment stopped. Latency and run time, although they improved in R2-R4, never attained the preoperative values. The brain tissues from rats treated with PF9601N showed only 15% and 50% of untreated rat MAO B and MAO A activity, respectively, despite the drug administration having been discontinued for 3 weeks. Other drugs examined did not influence MAO enzymes. Neither did histamine N-methyltransferase activity show changes related to BCCAO nor to the treatments. The hypothalamic HA concentration was significantly reduced after BCCAO: 1.13 ± 0.1 vs. 1.91 ± 0.16. Noteworthy, the rats treated with PF9601N or DL76 had brain HA levels not significantly different from their intact counterparts. The rat vascular dementia model supports deficiency in histaminergic system in VD.

Involvement of the histaminergic system in cytidine 5'-diphosphocholine-induced reversal of critical haemorrhagic hypotension in rats.

Cytidine 5'-diphosphocholine (CDP-choline) is an endogenously synthesized mononucleotide which exerts a variety of physiological effects by altering central cholinergic transmission. Administered intracerebroventricularly (i.c.v.) or intravenously, it reverses haemorrhagic hypotension in rats, apparently by the activation of central cholinergic receptors. The study was undertaken to investigate the involvement of the central histaminergic system in CDP-choline-mediated reversal of haemorrhagic hypotension. Experiments were carried out in male ketamine/xylazine-anaesthetised Wistar rats subjected to haemorrhagic hypotension of 20-26 mmHg. CDP-choline (2 micromol; i.c.v.) administered at 5 min of critical hypotension produced a long-lasting pressor effect with increases in mean arterial pressure (MAP), heart rate (HR), and renal, hindquarters and mesenteric blood flows, resulting in a 100% survival at 2 h. The action was accompanied by approximately a 26% increase in extracellular histamine concentration at the posterior hypothalamus, as measured by microdialysis. Cardiovascular effects mediated by CDP-choline were almost completely blocked by pretreatment with H(1) receptor antagonist chlorpheniramine (50 nmol; i.c.v.), but not with H(2) receptor blocker ranitidine (25 nmol; icv) or H(3)/H(4) receptor antagonist thioperamide (50 nmol; i.c.v.). In conclusion, the present results show that he central histaminergic system, through the activation of H(1) histaminergic receptors, is involved in CDP-choline-induced resuscitating effect in haemorrhage-shocked rats.

[Transcraniel ultrasound in the differential diagnosis of Parkinson's disease]. / Stellenwert der Hirnparenchym-Sonografie in der Differenzial- und Frühdiagnose des Parkinson-Syndroms.

Imaging of the brain structure with transcranial ultrasound has become an important tool for the diagnosis and differential diagnosis of Parkinson's Disease. In up to 90 % of parkinsonian patients abnormal echogenity of the substantia nigra could be demonstrated. Particularly in the early diagnosis in subjects with only very mild extrapyramidal features and in the differential diagnosis to other neurodegenerative disorders with parkinsonian features, such as the parkinsonian variant of multisystematrophy (MSA-P) and progressive supranuclear paralysis (PSP) ultrasound has a high diagnostic yield. Because of a prevalence of about 10 % in the normal population, the evidence of an abnormal echogenity of the substantia nigra has to be interpreted carefully in the context of a clinical examination. Although there are a number of studies indicating that in some of these subjects a vulnerability of the nigrostriatal system can be found, the meaning of an abnormal echogenicity of the substantia nigra in the healthy population needs to be further elucidated in already ongoing research projects.

[Deep brain stimulation for essential tremor. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei essenziellem Tremor. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

In Germany, deep brain stimulation (DBS) of the thalamic ventralis intermedius nucleus (VIM) is licensed for treatment of essential tremor in cases unresponsive to pharmacotherapy. Especially a bothersome hand tremor interfering with activities of daily living will improve, whereas head, tongue or vocal tremor shows less response. DBS was proven to be superior to lesional thalamotomy with better functional outcome and less adverse effects. The consensus statement presented here reflects the current recommendations of the German Deep Brain Stimulation Study Group for inclusion and exclusion criteria as well as for peri-, intra- and postoperative neurological management.

[Deep brain stimulation for dystonia. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei Dystonie. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

Medical treatment of dystonia, particularly generalised forms of the disorder, is often not satisfactory or causes intolerable side effects. In focal dystonia, a reasonable treatment option with botulinum toxin exists but some patients either do not respond well or develop neutralising antibodies with secondary therapy failure. Deep brain stimulation (DBS) of the globus pallidus internus has been shown to be effective in both generalised and focal dystonia. This paper gives recommendations regarding the use of DBS in different forms of dystonia based on the currently available scientific data as well as the longstanding personal experience of the authors. The inclusion criteria for DBS candidates as well as the peri- and postoperative patient management are addressed. These recommendations were developed in a consensus procedure in the German Deep Brain Stimulation Association.

[Deep brain stimulation for tremor in multiple sclerosis : consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei Multiple-Sklerose-Tremor : Empfehlungen der Arbeitsgemeinschaft Tiefe Hirnstimulation.

Deep brain stimulation (DBS) in the nucleus ventralis intermedius thalami (VIM) is a common procedure to treat disabling tremor in multiple sclerosis which is refractory to pharmacological treatment. The sparse studies on DBS in multiple sclerosis tremor remain controversial regarding the clinical effect on postural and action tremor of hands, trunk and head. Furthermore, it remains unclear whether DBS in multiple sclerosis tremor is superior to thalamotomy and whether patients show an overall improvement in quality of life and activities of daily living. Therefore, the consensus recommendations of the German Deep Brain Stimulation Study Group rely primarily on expert opinion and include (1) extensive preoperative characterisation of tremor, ataxia with accompanying disabilities, status of the multiple sclerosis, co-morbidities and burden of disease, (2) careful intraoperative testing of effects and side effects and (3) intensive postoperative testing and programming as well as regular re-evaluation of the therapeutic effect.

[Deep brain stimulation for Parkinson's disease. Consensus recommendations of the German Deep Brain Stimulation Association]. / Tiefe Hirnstimulation bei idiopathischem Parkinson-Syndrom. Empfehlungen der Deutschen Arbeitsgemeinschaft Tiefe Hirnstimulation.

Deep brain stimulation (DBS) has been shown to be effective for levodopa-responsive symptoms and tremor in Parkinson's disease (PD). The subthalamic nucleus (STN) is the preferred target for most patients suffering from late stage motor complications of the disorder. STN DBS is superior to best medical treatment concerning the control of motor fluctuations and the increase of on-time without dyskinesias. In contrast to DBS of the internal pallidum (GPi), STN stimulation also permits a reduction of the dopaminergic medication. Long-term data demonstrated sustained effectiveness of STN DBS despite progressive disease. DBS of the thalamic ventral intermediate nucleus (VIM) is an alternative target in older PD patients with severe PD tremor refractory to medication. In order to minimize potential risks and side effects, the use of DBS needs careful adherence to inclusion and exclusion criteria for eligible PD patients. This paper summarizes the current consensus recommendations of the German Deep Brain Stimulation Association for DBS in PD.

Satiety signalling histaminergic system and brain-gut peptides in regulation of food intake in rats with portocaval anastomosis.

Brain histamine plays a regulatory role in feeding behaviour, acting as an inhibitory modulator. Portocaval anastomosis (PCA) is associated with cerebral aminergic systems alterations, including high histamine accumulation and release from neurons. Despite that, the rats with PCA eat significantly more, their body mass being lower than sham-operated animals. To disclose underlying regulatory mechanisms, food intake was measured before and after treatment with antagonists of histamine H(1) and H(2), orexin type 1 (OX(1)) and cannabinoid type 1 (CB(1)) receptors in adult male Lewis rats 6 months following the end-to-side PCA or sham operation. Hypothalamic concentrations of orexin A and histamine as well as serum concentrations of leptin, insulin and cholecystokinin (CCK) were analysed. PCA rats with body mass lower by 30%, have consumed more feed and water 150% and 200%, respectively. The modifying effects of pyrilamine, ranitidine, SB 334867 and rimonabant were less pronounced in PCA compared with sham-operated rats. Hypothalamic orexin A and histamine concentrations were higher in PCA rats than in the control group with intact portocaval system. In PCA rats, serum concentrations of CCK were higher, leptin concentrations lower, while there were no differences between the groups in insulin levels. In conclusion, the adaptive mechanisms efficiently render PCA rats less sensitive to peripheral and central anorexigenic signals. Orexin A appears to be involved in the counteracting mechanisms preventing further body mass loss in PCA rats.

High voluntary alcohol consumption, in experimental liver cirrhosis is hardly responsive to opioid antagonist treatment.

BACKGROUND: Rats with liver cirrhosis, evoked by chronic administration of thioacetamide (TAA), consumed voluntarily more alcohol than their healthy counterparts. Seeking the mechanisms underlying this phenomenon, the opioid system was screened for involvement and alterations. In vivo, the influence of chronically administered Naloxone and Naltrexone, non-specific opioid receptor antagonists, on alcohol intake was examined in free choice tests between 10% alcohol and tap water and ex vivo receptor binding studies were performed on cerebral membrane preparations. METHODS: TAA rats, selected for the study, had confirmed liver insufficiency: their plasma bilirubin concentrations were about 3 times higher, the prothrombin time was 50% longer and they consumed voluntarily 3 times more alcohol than the control animals. The drugs were given s.c. for five days, at the beginning of the dark phase of a 24h cycle, in a daily dose of 10 mg per kg body mass. Throughout the treatment, the rats were kept individually in metabolic cages with a free access to water, alcohol solution and food. Feed and fluid consumption, as well as the urine outputs, were recorded on the 2h, 4h, 6h and 24h after the drug administration. The mu opioid ligand - [(3)H]-(D-Ala(2), -N-MePhe(4), Glyol(5)) Enkephalin was used to obtain binding characteristics of the control and TAA rat brain membranes. RESULTS: The drugs, if modified drinking behaviours, they did it transiently; alcohol, water and thus the total fluid intake by the cirrhotic and control rats was significantly less after 2h - 6h from either naloxone or naltrexone administration. Both drugs decreased general fluid consumption as such rather than the consumption of alcohol only, as observed from the recordings related to TAA rats. The binding data: K(d) of 2.62 +/- 0.98 nM and B(max) of 43.71 +/- 6.12 fmol/mg protein for cirrhotic rats, versus K(d) of 4.63 +/- 1.98 nM and B(max) 95.61 +/- 18.33 fmol/mg protein for the control ones, suggest that while the affinity of radioligand to cerebral mu receptors was similar for the two groups, there was a lower density of those receptors in the cirrhotic rats. CONCLUSIONS: The results indicate some disturbances in the opioid system in cirrhotic rats. However, the low response to opioid therapy suggests that the opioid system may have only be partly involved in the development of the observed increased alcohol drinking in the rats with liver cirrhosis.

Histamine in food: is there anything to worry about?

Biogenic mono-, di- and poly-amines are widely distributed among living organisms. The amines fulfil many important functions in the human body both in the periphery and brain. Some authors suggest that foods rich in biogenic amines, especially histamine, present high health hazards for consumers. However, this is conditional on a range of other factors. The alimentary tract is well equipped with enzymes that inactivate amines and the blood-brain barrier prevents them entering the brain from the circulation. Oxidative deamination, methylation, acetylation and transglutamylation are the degradation pathways which operate efficiently in the stomach, intestines and liver. Particularly important is oxidative deamination. Food histamine poisoning or cheese reaction, manifested itself in patients treated with drugs that inhibit amine oxidases or in patients showing an enterocytic diamine oxidase deficit. It is rather food allergy, which should worry us more, as endogenous histamine release from mast cells is more dangerous. Preventive measures should be undertaken against increases in food allergies.

Gait analysis in patients with advanced Parkinson disease: different or additive effects on gait induced by levodopa and chronic STN stimulation.

The aim of our study was to observe the effects on gait parameters induced by STN stimulation and levodopa medication in patients with advanced Parkinson's disease in order to determine different or additive effects. Therefore we examined 12 patients with advanced Parkinson disease after bilateral implantation of DBS into the STN. We assessed the motor score of the UPDRS and quantitative gait analysis under 4 treatment conditions: with and without stimulation as well as with and without levodopa. The mean improvement of the UPDRS motor score was almost the same with levodopa and DBS. Combining both therapies we saw a further improvement of the motor score. Gait parameters of patients with PD treated either with levodopa or STN stimulation were greatly improved. A significant difference between levodopa and STN stimulation could only be shown for the parameters velocity and step length. These parameters improved more with levodopa than with stimulation. The combination of both therapeutic methods showed the best results on the UPDRS motor score and gait parameters.

Mammary histidine decarboxylase vulnerability to enzyme antisense oligonucleotides: histamine and polyamine systems cross-talk.

Histamine system is suggested to have a role in mammary gland growth regulation, differentiation and functioning during pregnancy and lactation. Histidine decarboxylase activity undergoes significant changes during pregnancy and lactation. Pregnancy associated elevation of HDC activity and mRNA transcript in mouse mammary gland was successfully affected by enzyme antisense oligonucleotides treatment. The enzyme activity of resting mammae was unaffected as it lacked inducible pool of HDC. The short-term mammary histamine shortage evoked influenced the mRNA expression of histamine receptors (H1 and H2) and ornithine decarboxylase during pregnancy. There were essentially no morphological changes in the mammary gland upon the treatment, however, adipocytes neighbouring alveolar structures were more pronounced. These findings further substantiate the role of histamine in mammary gland physiology and emphasise presence of common motifs of biogenic amines and polyamine metabolism as well as mutual interferences implicating observed "cross-talk" phenomenon.