Cholinergic agents

Depletion of cholinergic neurons within the nucleus basalis of Meynert (nbM) is thought to contribute to the development of cognitive impairments in both Alzheimer's disease (AD) and Lewy body disorders (LBD). It has been reported that, in late stage AD, a network of fibres that contain the neuropeptide galanin displays significant hypertrophy and 'hyperinnervates' the surviving cholinergic neurons. Galanin is considered as a highly inducible neuroprotective factor and in AD this is assumed to be part of a protective tissue response. The aim of this study was to determine if a similar galanin upregulation is present in the nbM in post-mortem tissue from patients with LBD. Gallatin immunohistochemistry was carried out on anterior nbM sections from 76 LBD cases (27 PD, 15 PD with mild cognitive impairment (MCI), 34 PD with dementia (PDD) and 4 aged-matched controls. Galaninergic innervation of cholinergic neurons was assessed on a semi-quantitative scale. The LBD group had...

Roundup Original® (RD) is a glyphosate-based herbicide used to control weeds in agriculture. Contamination of Amazon waters has increased as a consequence of anthropogenic pressure, including the use of herbicides as RD. The central goal of this study was to evaluate the toxic effects of RD on juveniles of tambaqui (Colossoma macropomum). Our findings show that biomarkers in tambaqui are organ specific and dependent on RD concentration. Alterations in gills structural and respiratory epithelium were followed by changes in hematological parameters such as concentration of hemoglobin, particularly in fish exposed to the higher concentration tested (75% of RD LC50 96h). In addition, both RD concentrations affected the biotransformation process in gills of tambaqui negatively. Instead, liver responses suggest that a production of reactive oxygen species (ROS) occurred in fish exposed to RD, particularly in the animals exposed to 75% RD, as seen by imbalances in biotransformation and ant...

Rationale In schizophrenia, attentional disturbance is a core feature which may not only accompany the disorder, but may precede the onset of psychiatric symptoms. Objectives The five-choice serial reaction time task (5CSRTT) is a test of visuo-spatial attention that has been used extensively in rats for measuring the effects of systemic and central neurochemical manipulations on various aspects of attentional performance, including selective attention, vigilance and executive control. These findings are relevant to our understanding of the neural systems that may be compromised in patients with schizophrenia. Methods The 5CSRTT is conducted in an operant chamber that has multiple response locations, in which brief visual stimuli can be presented randomly. Performance is maintained using food reinforcers to criterion levels of accuracy. Various aspects of performance are measured, including attentional accuracy and premature responding, especially under different attentional challenges. Results The effects of systemic and intra-cerebral infusions of selective dopamine, serotonin and cholinergic receptor agents on the 5CSRTT are reviewed with a view to identifying attention-enhancing effects that may be relevant to the treatment of cognitive deficits in schizophrenia. In addition, some novel agents such as modafinil and histamine receptor agents are also considered. Examining the effects of selective neurochemical lesions helped define the neural locus of attentional effects. Similarly, findings from microdialysis studies helped identify the extracellular changes in neurotransmitters and their metabolites in freely moving rats during performance of the 5CSRTT. Conclusions The monoaminergic and cholinergic systems have independent but complementary roles in attentional function, as measured by the 5CSRTT. These functions are predominantly under the control of the prefrontal cortex and striatum. These conclusions are considered in the context of their application towards therapeutic approaches for attentional disturbances that are typically observed in schizophrenic patients.

Introduction: The plethora of studies indicated that there is a cross talk relationship between
harmaline and serotonergic (5-HT) system on cognitive and non-cognitive behaviors. Thus,
the purpose of this study is to assess the effects of hippocampal 5-HT4 receptor on memory
acquisition deficit induced by harmaline.
Methods: Harmaline was injected peritoneally, while 5-HT4 receptor agonist (RS67333) and
antagonist (RS23597-190) were injected intra-hippocampal. A single-trial step-down passive
avoidance, open field and tail flick tasks were used for measurement of memory, locomotor
activity and pain responses, respectively.
Results: The data revealed that pre-training injection of higher dose of harmaline (1 mg/kg),
RS67333 (0.5 ng/mouse) and RS23597-190 (0.5 ng/mouse) decreased memory acquisition
process in the adult mice. Moreover, concurrent pre-training administration of subthreshold dose
of RS67333 (0.005 ng/mouse) or RS23597-190 (0.005 ng/mouse) with subthreshold dose of
harmaline (0.5 mg/kg, i.p.) intensify impairment of memory acquisition. All above interventions
did not change locomotion and tail flick behaviors.
Discussion: The results demonstrated that the synergistic effect between both hippocampal
5-HT4 receptor agonist and antagonist with impairment of memory acquisition induced by
harmaline, indicating a modulatory effect for hippocampal 5HT4 receptor on Harmaline induced
amnesia.

Acetylcholinesterase (ACE) activity and lipid peroxidation (LPO) parameters were measured in the blood of patients with Alzheimer's disease (AD) during treatment with amiridine and gliatiline. Treatment was accompanied by inhibition of ACE. There was a statistically significant relationship between clinical efficacy and changes in ACE activity. AD was charactefized by significant changes in LPO parameters, with a three-fold increase in the level of primary oxidation products on the background of a sharp (seven-fold) increase in total lipid desaturatedness. There was a statistically significant relationship between ACE activity and the levels of primary oxidation products in the RBC of patients with AD before and after treatment with amiridine and gliatiline.

The synthesis, molecular modeling, and pharmacological analysis of new multipotent simple, and readily available 2-aminopyridine-3,5-dicarbonitriles (3–20), and 2-chloropyridine-3,5-dicarbonitriles (21–28), prepared from 2-amino-6-chloropyridine-3,5-dicarbonitrile (1) and 2-amino-6-chloro-4-phenylpyridine-3,5-dicarbonitrile (2) is described. The biological evaluation showed that some of these molecules were modest inhibitors of acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE), in the micromolar range. The 2-amino (3, 4), and 2-chloro derivatives 21–23, 25, 26 were AChE selective inhibitors, whereas 2-amino derivatives 5, 14 proved to be selective for BuChE. Only inhibitor 24 was equipotent for both cholinesterases. Kinetic studies on compound 23 showed that this compound is a mixed-type inhibitor of AChE showing a Ki of 6.33 μM. No clear SAR can be obtained form these data, but apparently, compounds bearing small groups such as the N,N′-dimethylamino or the pyrrolidino, regardless of the presence of a 2-amino, or 6-chloro substituent in the pyridine ring, preferentially inhibit AChE. Molecular modeling on inhibitors 4, 5, 22, and 23 has been carried out to give a better insight into the binding mode on the catalytic active site (CAS), and peripheral anionic site (PAS) of AChE. The most important differences in the observed binding relay on the modifications of the group at C2, as the amino group forms two hydrogen bonds that direct the binding mode, while in the case of compounds with a chlorine atom, this is not possible. The neuroprotective profile of these molecules has been investigated. In the LDH test, only compounds 26, 3, 22, and 24 showed neuroprotection with values in the range 37.8–31.6% in SH-SY5Y neuroblastoma cells stressed with a mixture of oligomycin-A/rotenone, but in the MTT test only compound 17 (32.9%) showed a similar profile. Consequently, these compounds can be considered as attractive multipotent therapeutic molecules on two key pharmacological receptors playing key roles in the progress of Alzheimer, that is, cholinergic dysfunction and oxidative stress, and neuronal vascular diseases.The target 2-aminopyridine-(I), and 2-chloropyridine-3,5-dicarbonitriles (II).

The involvement of the cholinergic septohippocampal system in strategies used to reach a spatial goal was examined by functionally inactivating this system with infusions of 192 IgG saporin, a potent cholinergic immunotoxin. Rats were initially trained on a win-shift radial arm maze (RAM) task and then given injections of either 192 IgG saporin (LES) or saline vehicle (CON) into the medial septum and vertical limb of the diagonal band. Rats were then retested postoperatively on the RAM to assess whether allocentric spatial strategies used to solve the task were impaired. The results indicated that injections of 192 IgG saporin into the septum of rats produced deficits in allocentric strategies used to locate the spatial goal when retested. In addition, place and response learning was also examined in a modified version of the Morris water maze task. In this task, rats with cholinergic lesions were mildly impaired in their ability to learn a place response. In order to clarify further whether rats may have been relying on allocentric or egocentric learning strategies to locate the platform, a probe trial was given on the final test day in which the visible platform was moved to a new location. Control rats swam either to the new platform location or the old platform location indicating the use of both an allocentric and egocentric response. However, rats with the cholinergic septal lesions swam to the new platform location indicating an egocentric response. Taken together, these results suggest that selective cholinergic lesions of the septum produce deficits in spatial strategies used to locate a spatial goal.

Two cases of urinary retention in male dromedaries due to silica uroliths are presented. The animals were urethrostomized and one dromedary was euthanized 7 months later due to urethrostomy obstruction. The estimated daily intake of silica was 84.44 g. Silica, calcium, phosphorus and pH in urine were determined in healthy animals from the same farms, and the following values were obtained: 174.78 +/- 3.46 mg/l (silica), 41.48 +/- 4.82 mg/l (calcium), 20.4 +/- 3.6 mg/l (phosphorus) and pH 8.2, respectively. Possible causes of urolithiasis were the early castration of the animals and the fact that salt was not added to the diet. To our knowledge, this is the first description of silica urolithiasis in the dromedary camel.

Four out of the eight possible stereoisomers of 1-methyl-2-(2-methyl-1,3-dioxolan-4-yl)pyrrolidine, 1-methyl-2-(2-methyl-1,3-oxathiolan-5-yl)pyrrolidine and the corresponding iodomethylates have been synthesised. They were formally derived from hybridisation of potent though unselective agonists studied before, such as 1,3-dioxolane 1 and 1,3-oxathiolane 2, with the structure of nicotine. It was expected that, by exalting the molecular complexity of the parent compounds, in particular through stereochemical complication in the proximity of the critical cationic head of the molecule, the chance to find agonists able to discriminate among cholinergic receptors subtypes would increase. The relative and absolute configuration of the compounds obtained has been established by means of NMR spectroscopy and X-ray crystallography. In preliminary studies, their binding affinity has been evaluated on rat brain nicotinic and muscarinic receptors. While none of the compounds showed any nicotinic affinity up to the dose of 10 microM, most of the iodomethylates were endowed with promising affinity for the muscarinic receptors.

Co-occurrence of tobacco smoking and alcohol consumption during adolescence is frequent and well documented. However, little is known about the basic neurobiology of the combined exposure in the adolescent brain. Since nicotine is a cholinergic agonist and it has been shown that ethanol interferes with nicotinic acetylcholine receptors (nAChRs), the current work focused on cholinergic systems. From the 30th to the 45th postnatal day (PN), C57BL/6 male and female mice were exposed to nicotine free base (NIC) and/or ethanol (ETOH). Four groups were analyzed: 1) concomitant NIC (50 μg/ml in 2% saccharin to drink) and ETOH (25%, 2 g/kg i.p. injected every other day) exposure; 2) NIC exposure; 3) ETOH exposure; 4) vehicle. We assessed nAChR binding, choline acetyltransferase (ChAT) activity and [3H]hemicholinium-3 (HC-3) binding in the cerebral cortex and midbrain of mice on PN45. In the cortex, ETOH had no effect on nAChRs. In contrast, NIC produced nAChR upregulation while NIC + ETOH elicited a more pronounced effect. In the midbrain, neither ETOH nor NIC had effects on nAChRs. NIC + ETOH, however, elicited a robust nAChR upregulation. Regarding ChAT activity, treatment effects differed between males and females in the cortex. Male NIC mice presented an increase in ChAT. However, ETOH reversed this effect. In contrast, female NIC mice presented decreased ChAT activity. In the midbrain, ETOH increased ChAT. HC-3 binding was not affected. These results indicate that the central cholinergic system is a site at which nicotine and ethanol interact. This interaction might underlie the association between tobacco and alcohol consumption during adolescence.

Abstract : 5-[76Br]Bromo-3-[[2(S)-azetidinyl]methoxy]-pyridine ([76Br]BAP), a novel nicotinic acetylcholine receptor ligand, was synthesized using [76Br]bromide in an oxidative bromodestannylation of the corresponding trimethylstannyl compound. The radiochemical yield was 25%, and the specific radioactivity was on the order of 1 Ci/μmol. The binding properties of [76Br]BAP were characterized in vitro and in vivo in rat brain, and positron emission tomography (PET) experiments were performed in two rhesus monkeys. In association experiments on membranes of the cortex and thalamus, >90% of maximal specific [76Br]BAP binding was obtained after 60 min. The dissociation half-life of [76Br]BAP was 51 ± 6 min in cortical membranes and 56 ± 3 min in thalamic membranes. Saturation experiments with [76Br]BAP revealed one population of binding sites with dissociation constant (KD) values of 36 ± 9 and 30 ± 9 pM in membranes of cortex and thalamus, respectively. The maximal binding site density (Bmax) values were 90 ± 17 and 207 ± 33 fmol/mg in membranes of cortex and thalamus, respectively. Scatchard plots were nonlinear, and the Hill coefficients were <1, suggesting the presence of a lower-affinity binding site. In vitro autoradiography studies showed that binding of [76Br]BAP was high in the thalamus and presubiculum, moderate in the cortex and striatum, and low in the cerebellum and hippocampus. A similar pattern of [76Br]BAP accumulation was observed by ex vivo autoradiography. In vivo, binding of [76Br]BAP in whole rat brain was blocked by preinjection of (S)(-)-nicotine (0.3 mg/kg) by 27, 52, 68, and 91% at survival times of 10, 25, 40, 120, and 300 min, respectively. In a preliminary PET study in rhesus monkeys, the highest [76Br]BAP uptake was found in the thalamus, and radioactivity was displaceable by ~60% with cytisine and by 50% with (S)(-)-nicotine. The data of this study indicate that [76Br]BAP is a promising radioligand for the characterization of nicotinic acetylcholine receptors in vivo.