In this case/control study, serum levels of oxidative stress related parameters such as Fe-binding lactoferrin (LTF), Mn- and Zn.Cu-superoxide dismutase (SOD) were determined by enzyme linked ...immunoassays in patients suffering from the Alzheimer's dementia as well as in non-demented controls. The Mn-SOD concentration was significantly (P < 0.05, U-test) reduced in patients suffering from Alzheimer's disease if compared to non-demented controls. The other parameters investigated did not differ significantly between both groups. Our findings give evidence for the hypothesis of a disturbed free radical metabolism in Alzheimer's disease. The specificity of these results remains to be clarified. Further studies are needed to elucidate the relevance of oxidative stress in the etiopathogenesis of the Alzheimer's disease.
Abstract Selective estrogen receptor (ER) agonists can indicate which receptor subtypes are implicated in neuroprotection. This study investigated the contribution of ERβ, using the selective agonist ...diarylpropiolnitrile (DPN), in a rat model of stroke. Lister Hooded rats were ovariectomized and implanted with mini-pumps containing either DPN (8 mg kg − 1 day − 1 ) ( n = 7) or vehicle ( n = 5). Sensorimotor function was assessed using a neurological score and the spontaneous forelimb use asymmetry (cylinder) test. One week later the animals received a middle cerebral artery occlusion (MCAO), and T2 -weighted MRI at 48 h post-MCAO quantified ischemic damage. Functional recovery was tested for 7 days post-MCAO and brains processed for histological verification of infarct size. The MRI images revealed no significant differences in hemispheric lesion volumes between vehicle- and DPN-treated groups (35.6 ± 3.5% and 30.8 ± 1.7%, respectively mean ± SEM; Student's unpaired t -test df = 10, t = − 1.357, p = 0.453); this was confirmed histologically at 7 days. MCAO induced significant decline in neurological score performance (from 22 to 11 at 2 h post-MCAO) in the vehicle-treated animals, which was not significantly influenced by DPN. MCAO also induced significant changes in forelimb use in the cylinder test (10% reduction in contralateral, 20% reduction in both, and 30% increase in ipsilateral forelimb use) but this response was not significantly different between groups F (1,1) =2.929, p = 0.118, repeated-measures ANOVA. In conclusion, pretreatment with the ERβ agonist DPN did not influence infarct size or sensorimotor function in rats exposed to MCAO.
Platelet monoamine oxidase B (MAO-B) activity has been found to increase significantly in demented patients. For the first time, a 4-year follow-up of platelet MAO-B activity and Mini-Mental State ...(MMS) was performed in patients with probable dementia of the Alzheimer type (DAT) and age-matched controls. MAO-B activity of DAT patients increased significantly 2 years after the beginning of the study as compared with controls and remained significantly higher for the entire period of the examinations (p < 0.0001). The decrease of the MMS scores did not correlate with the time course of the increase of platelet MAO-B activity (Spearman rank correlation test). The decline of the MMS scores of DAT patients preceded the elevation of MAO-B activity. Since degenerative processes in brain areas which are responsible for cognitive function and are reflected by the MMS scores rather affect cerebral cholinergic than monoaminergic neurotransmitter systems, degeneration of the latter at late stages of DAT might be reflected by increased platelet MAO-B activity.
The nature of the discrepancy between short-term pharmacokinetic data (hours) on the one hand and long-term pharmacodynamic effects and the clinical latency of therapeutic amelioration on the other ...hand by tricyclic antidepressants is still unclear. A relapsed sensibilization of neuronal, immunologic, and endocrinologic systems by changes in receptor sensitivity has been proposed. However, the discrepancy may have a strong influence on many aspects of antidepressive therapy in humans. The aim of our study was to demonstrate long-term pharmacodynamic effects by single-dose antidepressive treatment in humans by measuring heart rate parameters in response to neurochemical parameters. 25 young healthy probands, divided into three treatment groups (amitriptyline, n = 10; clomipramine, n = 10; placebo, n = 5), were challenged by a noradrenaline infusion test at baseline and one and 21 days after a single dose of antidepressant. Heart rate and blood pressure as well as plasma levels of antidepressants and of noradrenaline and adrenaline were measured in response to noradrenaline infusion test. Noradrenaline infusion rate to reach an increase in blood pressure of RR > 30 mmHg was significantly decreased for both antidepressants on day 1. The same effect was true for the amitriptyline group on day 21. Furthermore, pretreated probands respond to antidepressants in a different way when compared to untreated probands. Like depressed patients under therapy they respond with a dramatic increase in sensitivity of the alphal-adrenergic receptor. We could demonstrate that the long-term pharmacodynamic effects have a strong influence on antidepressive therapy. A prolonged pharmacodynamic effect influences further clinical studies as well as our thinking about adverse drug effects. In clinical studies, washout periods may be to short to overcome the benefits of a previous medication. Adverse drug effects are often seen during periods when drugs were changed. The negative effect may be due to an additional effect of both medicaments.
Four different methods to measure acetylcholine (ACh) and choline (Ch) concentration, i.e. thermospray/mass spectroscopy (TS/MS), high pressure liquid chromatography/mass spectroscopy (HPLC/MS), high ...pressure liquid chromatography/electrochemical detection (HPLC/ECD) and gas chromatography/mass spectroscopy (GC/MS), both latter methods coupled to a solid phase extraction system were compared for their applicability to human lumbar cerebrospinal fluid (CSF). Furthermore, samples from 15 control persons and 11 patients with dementia of Alzheimer-type (DAT) were compared to search for an ACh deficit in the CSF in DAT. GC/MS was the most sensitive, but most laborious method, and HPLC/ECD was acceptably sensitive, reliable and more specific. TS/MS was not specific enough for CSF extracts and HPLC/MS was more specific, but far less sensitive. Thus, only GC/MS and HPLC/ECD were qualified to detect ACh in human CSF extracts. Comparison of GC/MS and HPLC/ECD revealed highly correlated levels of ACh (r = 0.999). Using HPLC/ECD, ACh concentrations were greatly reduced in the DAT group (3.75 +/- 1.40 pmol/ml CSF) as compared to the controls (6.14 +/- 1.39 pmol/ml CSF), but the difference between controls and DAT patients was not statistically significant due to the number of samples below detection limit (8 out of 11 samples in DAT, 7 out of 15 in controls). Ch concentrations were not statistically significant between the two groups. The data show that methodological limitations preclude a widespread clinical application of determining ACh in the human CSF. Despite of reductions of ACh in the CSF in DAT, the determination of Ach in the CSF is not suitable for diagnostic purposes.
Oxidative stress-associated parameters concentrations of lactoferrin, Cu,Zn-superoxide dismutase (SOD) and Mn-SOD were determined in sera of 20 patients suffering from alcohol dependence immediately ...after detoxification and in 15 non-dependent healthy subjects as controls. In the patient group, the mean Mn-SOD concentration reached almost double the values of those from the control group (142.9 vs 76.0 ng/ral, P < 0.01). The other parameters tended to be increased in patients, but did not differ significantly between index and control groups. The findings are consistent with increased oxidative stress due to chronic alcohol intake, which might be responsible for secondary diseases such as brain atrophy, peripheral polyneuropathy and liver fibrinogenesis.
We present the results of a meta-analysis of neurochemical changes in human post mortem brains of Alzheimer type (AD), vascular type (VD) and mixed type (MF) dementias, and matched controls based on ...275 articles published between January 1980 and February 1994. Severity of degeneration between the different neurochemical systems is as follows, although ranking is difficult with regard to limited numbers of investigations in some neurochemical systems: Cholinergic system > serotonergic system > excitatory amino acids > GABAergic system > energy metabolism > NA > oxidative stress parameters > neuropeptides > DA. But, within a neurochemical system, degeneration is not evenly distributed. Spared parameters, e.g. muscarinic receptors and MAO-B, allow to make some suggestions for future therapeutic strategies.
Objective
Angiotensin II (Ang II) is known to have proinflammatory actions, and Ang II type 1 (AT1) receptors are up‐regulated in the rheumatoid synovium, suggesting that this receptor could be a ...therapeutic target. The purpose of this study was to investigate the antiinflammatory potential of the selective AT1 receptor antagonist losartan, which is currently used for the treatment of cardiovascular disease.
Methods
Dose‐ranging studies of losartan (1–50 mg/kg) were initially conducted in a rat model of acute (carrageenan/kaolin) arthritis, with subsequent evaluation in a rat model of adjuvant‐induced arthritis (Freund's complete adjuvant). Losartan (10–10 to 10–6M) was further tested ex vivo in human inflammatory synovitis, using collagenase‐digested synovium.
Results
Western blot and immunohistochemical analyses both revealed a substantial increase in AT1 receptor protein content in synovium from acutely and chronically inflamed rat knee joints. Similarly, synovial Ang I/II protein content was elevated during inflammation. Losartan inhibited acute joint inflammation in a dose‐dependent manner, with 15 mg/kg being the optimal dose (and used in subsequent studies). Both prophylactic and therapeutic administration of 15 mg/kg of losartan substantially reduced knee joint swelling in rats with adjuvant monarthritis (≥50%; P < 0.0001). Losartan also suppressed tumor necrosis factor α generation from inflamed human synovium in a dose‐dependent manner (P < 0.05).
Conclusion
Targeting the angiotensin pathway, particularly AT1 receptors, could have significant therapeutic potential. Randomized placebo‐controlled trials are now warranted to establish the extent to which angiotensin receptor blockers may provide antiinflammatory benefits.
A group of twelve patients with idiopathic Parkinson's disease was assessed both on and off L-Dopa medication on a range of tests of cognitive performance. Withdrawal of L-Dopa produced impairments ...in tests sensitive to frontal lobe dysfunction such as verbal fluency and the Tower of London task. Another test of frontal lobe function, the Wisconsin Card Sorting Test, was not affected in the absence of L-Dopa. Memory functions such as short-term span and verbal paired associate memory were not impaired by L-Dopa withdrawal. The results suggest that some of the cognitive impairments observed in Parkinson's disease, namely frontal lobe deficits, are related to a loss of central dopaminergic function.
The synthesis and pharmacological evaluation of methoxyindazoles as new inhibitors of neuronal nitric oxide synthase are presented. The 7-methoxyindazole, although less potent than 7-NI, is the most ...active compound of the series in an in vitro enzymatic assay of neuronal nitric oxide synthase activity. This result shows that the nitro-substitution is not indispensable to the biological activity of the indazole ring. 7-Methoxyindazole possesses in vivo NOS inhibitory as well and related antinociceptive properties.
The synthesis and pharmacological evaluation of a novel inhibitor of nNOS (7-MI) is reported.
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