Brain Cholinergic Neurotransmission Research Articles

Choline-Containing Phospholipids: Structure-Activity Relationships Versus Therapeutic Applications.

Choline is a quaternary ammonium salt, and being an essential component of different membrane phospholipids (PLs) contributes to the structural integrity of cell membranes. Choline-containing phospholipids (CCPLs) include phosphatidylcholine (PC), sphingomyelin (SM), and choline alphoscerate (GPC). PC is the major phospholipid in most eukaryotic cells. It is involved in SM synthesis, choline/choline metabolite re-generation, and fatty acid/GPC formation. This paper has reviewed chemical, biological and therapeutic features of CCPLs by analyzing: a) effects of exogenous CCPLs, b) influence of GPC treatment on brain cholinergic neurotransmission, and c) neuroprotective effects of GPC alone or in association with acetylcholinesterase inhibitors in animal models of brain vascular injury, d) synthesis of the choline analogs, containing a short alkyl chain instead of a methyl group. Cytidine-diphosphocholine and GPC, protect cell membranes and could be helpful in the sequelae of cerebrovascular accident treatment. Moreover, cellular membrane breakdown is suggested as a feature of neurodegeneration both in acute (stroke) and in chronic (Alzheimer and vascular dementia) brain disorders. Published data were focused to a larger extent on the biosynthesis, relevant role in cell life, and crucial involvement of CCPLs in cholinergic neurotransmission. The possibility of their use in the treatment of cerebrovascular and neurodegenerative disorders is suggested by published clinical studies. In line with these potential practical applications in pharmacotherapy, the need of further research in the field of the synthesis of new choline derivatives with possible activity in nervous system diseases characterized by cholinergic impairment is discussed.

Subchronic atrazine exposure changes defensive behaviour profile and disrupts brain acetylcholinesterase activity of zebrafish

Animal behaviour is the interaction between environment and an individual organism, which also can be influenced by its neighbours. Variations in environmental conditions, as those caused by contaminants, may lead to neurochemical impairments altering the pattern of the behavioural repertoire of the species. Atrazine (ATZ) is an herbicide widely used in agriculture that is frequently detected in surface water, affecting non-target species. The zebrafish is a valuable model organism to assess behavioural and neurochemical effects of different contaminants since it presents a robust behavioural repertoire and also all major neurotransmitter systems described for mammalian species. The goal of this study was to evaluate the effects of subchronic ATZ exposure in defensive behaviours of zebrafish (shoaling, thigmotaxis, and depth preference) using the split depth tank. Furthermore, to investigate a putative role of cholinergic signalling on ATZ-mediated effects, we tested whether this herbicide alters acetylcholinesterase (AChE) activity in brain and muscle preparations. Fish were exposed to ATZ for 14days and the following groups were tested: control (0.2% acetone) and ATZ (10 and 1000μg/L). The behaviour of four animals in the same tank was recorded for 6min and biological samples were prepared. Our results showed that 1000μg/L ATZ significantly increased the inter-fish distance, as well as the nearest and farthest neighbour distances. This group also presented an increase in the shoal area with decreased social interaction. No significant differences were detected for the number of animals in the shallow area, latency to enter the shallow and time spent in shallow and deep areas of the apparatus, but the ATZ 1000 group spent significantly more time near the walls. Although ATZ did not affect muscular AChE, it significantly reduced AChE activity in brain. Exposure to 10μg/L ATZ did not affect behaviour or AChE activity. These data suggest that ATZ impairs defensive behaviours of zebrafish, which could be related to its action on brain cholinergic neurotransmission. Moreover, the use of the split depth tank could be an alternative strategy to assess group behaviour and depth preference after exposure to chemical compounds.

Prevention of haloperidol-induced alterations in brain acetylcholinesterase activity by vitamins B co-administration in a rodent model of tardive dyskinesia

Tardive dyskinesia (TD) is an iatrogenic syndrome being a significant adverse outcome of typical and atypical antipsychotic therapy. Recently we demonstrated that vitamins B (B1, B6, B12 alone or in combination) were able to prevent haloperidol-induced orofacial dyskinesia (OD) possibly by their antioxidant activity in the striatum, using a well-established model of TD. Here, based on the fact that alterations in cholinergic neurotransmission are related to TD pathophysiology and that vitamins B seems to influence brain cholinergic neurotransmission, we decided to investigate the effects of vitamins B1, B6, B12 and their association, vitamin B cocktail in haloperidol-induced cholinergic alterations, evaluated by alterations in acetylcholinesterase (AChE) activity, in striatum, prefrontal cortex and hippocampus, as a way to determine the participation of cholinergic neurotransmission, in these vitamins antidyskinetic mechanism. Haloperidol 1mg/kg i.p. daily administration during 21days to Wistar rats caused OD while decreased AChE activity in all brain areas studied. Vitamins B administration (B1:B6:B12 at 60:60:0.6mg/kg, s.c) alone and vitamin B cocktail co-administered with haloperidol prevented OD development and increased AChE activity in all brain areas studied, with the maximum activity increment observed in the hippocampus of the animals co-treated with vitamin B12 and vitamin B cocktail. The antidyskinetic drug, clozapine did not induce OD and increased AChE activity similarly to the groups coadministered with vitamin B and HAL. The present data suggest that vitamins B can prevent haloperidol-induced alterations in AChE activity what can be related to the mechanism underlying their antidyskinetic effect.

Neuronal nicotinic receptor antagonist reduces anxiety-like behavior in mice

Brain cholinergic neurotransmission has been implicated in the modulation of anxiety in humans and evidence suggests that drugs targeting neuronal nicotinic acetylcholine receptor (nAChR) could have potential for the treatment of anxiety. The objective of present study was to examine anxiolytic effects of lobeline (0.04 or 0.1 mg/kg), a nAChR antagonist, in C57BL/6J mice using elevated plus-maze (EPM) and marble-burying test. Lobeline (0.04 mg/kg) significantly increased open arm time on EPM and reduced number of marbles buried. Similarly, mecamylamine (0.3 mg/kg) produced anxiolytic effects, while peripherally acting hexamethonium (0.3 mg/kg) failed to produce any response. These results provide evidence that lobeline has anxiolytic potential and nAChR antagonists may represent a new class of anxiolytics in humans.

Isolation of acetylcholinesterase inhibitory alkaloids from Nerine bowdenii

Alzheimer's disease (AD) is associated with a steady loss of attention and memory, which has been correlated with the impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons in the nucleus basalis of Meynert. Therefore, one of the methods that has proven successful in the treatment of AD is the use of inhibitors of acetylcholinesterase (AchE) to supplement the acetylcholine level. Herein we describe the isolation of several AchE-inhibiting alkaloids from the bulbs of Nerine bowdenii, an Amaryllidaceae species. For the first time 11-O-acetylambelline and filofiline, previously reported from Brunsvigia josephinea and Nerine filifolia, respectively, were isolated.

An update on the pharmacology of galantamine

Alzheimer's disease (AD) is associated with a gradual loss of attention and memory that has been related to impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons. The first therapeutic target that has demonstrated therapeutic efficacy on cognition, behaviour and functional daily activities has been the inhibition of acetylcholinesterase. The acetylcholinesterase inhibitors used to treat AD patients at present are donepezil, rivastigmine and galantamine. This review summarises the current state of the art concerning the pharmacology of galantamine, focusing on the most important details of its possibilities as an acetylcholinesterase inhibitor, an allosteric potentiator of neuronal nicotinic receptors for acetylcholine, a modulator of neurotransmitter release, and an agent causing neuroprotection through an antiapoptotic action. In so doing, galantamine will be discussed in the context of the treatment of dementia, both of AD type and of mixed vascular-Alzheimer type.

The Physiology of Learning and Memory: Role of Peptides and Stress

The neuropeptides, as well as their respective receptors, are widely distributed throughout the mammalian central nervous system. During learning and memory processes, besides structural synaptic remodeling, changes are observed at molecular and metabolic levels with the alterations in neurotransmitter and neuropeptide synthesis and release. While there is consensus that brain cholinergic neurotransmission plays a critical role in the processes related to learning and memory, it is also well known that these functions are influenced by a tremendous number of neuropeptides and non-peptide molecules. Arginine vasopressin (AVP), oxytocin, angiotensin II, insulin, growth factors, serotonin (5-HT), melanin concentrating hormone, histamine, bombesin and gastrin-releasing peptide (GRP), glucagon-like peptide-1 (GLP-1), cholecystokinin (CCK), dopamine, corticotropin releasing factor (CRF) have modulatory effects on learning and memory. Among these peptides CCK, 5-HT and CRF play strategic roles in the modulation of memory processes under stressful conditions. CRF is accepted as the main neuropeptide involved in both physical and emotional stress, with a protective role during stress, possibly through the activation of the hypothalamo-pitiuitary (HPA) axis. The peptide CCK has been proposed to facilitate memory processing and CCK-like immunoreactivity in the hypothalamus was observed upon stress exposure, suggesting that CCK may participate in the central control of stress response and stress-induced memory dysfunction. On the other hand, 5-HT appears to play a role in behaviors that involve a high cognitive demand and stress exposure activates serotonergic systems in a variety of brain regions. The physiological role and therapeutic efficacy of various neuropeptides and the impact of stress exposure in the acquisition and consolidation of memory will be reviewed thoroughly.

New Classes of AChE Inhibitors with Additional Pharmacological Effects of Interest for the Treatment of Alzheimers Disease

Alzheimer's disease (AD) is associated to a gradual loss of attention and memory that have been associated to impairment of brain cholinergic neurotransmission, particularly a deficit of cholinergic neurons in the nucleus basalis of Meynert. Thus, it is not surprising that the first therapeutic target that has demonstrated therapeutic efficacy on cognition, behaviour and functional daily activities has been the inhibitors of acetylcholinesterase (AChE), i.e. tacrine, donepezil, rivastigmine and galanthamine. But not all inhibitors of AChE have the same potency to block the enzyme and have a different pharmacological profile. For instance, rivastigmine is a dual inhibitor of AChE and butyrylcholinesterase (BuChE), and galanthamine is a mild inhibitor of AChE and an allosteric potentiating ligand of neuronal nicotinic receptors for acetylcholine (nAChRs). In addition, we have recently found that galanthamine has neuroprotective effects by inducing calcium signals and the induction of the antiapoptotic protein Bcl-2. In this frame, we have been synthesizing new tacrine derivatives that keep their ability to inhibit AChE but that interfere with neuronal calcium overloading and prevent apoptosis. Some of these compounds exhibit neuroprotecting properties and thus, could be useful in the treatment of neurodegenerative and ischaemic brain diseases.

Cholinergic Neurotransmission Has Different Effects on Cerebral Glucose Consumption and Blood Flow in Young Normals, Aged Normals, and Alzheimer's Disease Patients

Cerebral blood flow (CBF) and glucose consumption (GC) are both tracers of brain metabolic activity used to image the human brain in vivo.To know if both tracers reacted in the same manner when brain cholinergic neurotransmission was activated, CBF and GC were measured in young normals (YN), aged normals (AN), and Alzheimer's Disease patients (AD) using positron emission tomography (PET), H 2 15O, and 18F-FDG. Each subject was studied twice, under placebo and physostigmine, in randomized order and blind fashion using the maximal tolerated dose of physostigmine individually determined. Under physostigmine CBF increased significantly ( P = 0.0007) in posterior regions of the cerebral cortex and in the subcortical structures. Inversely, GC was decreased significantly in most regions. The largest decrease was seen in the prefrontal region of the cerebral cortex ( P < 0.0001). Significant regional decreases were registered in all three groups of subjects, but were larger in AD than in controls. Looking at the absolute values of prefrontal cortex metabolism we found no correlation ( r = 0.04) between the responses of CBF and GC. After normalization of the regional values for the mean we found a significant positive correlation between the responses of CBF and GC ( r = 0.71, P < 0.0001). These findings suggest two components in the CBF response to physostigmine: one metabolic, depressive, and regional which follows the GC response; and one vascular, larger, diffuse, and opposite in direction to the metabolic component. These results have implications for the interpretation of CBF values as tracer of brain metabolic activity when brain cholinergic neurotransmission is manipulated.

Rapid eye movement (REM) sleep deprivation reduces rat frontal cortex acetylcholinesterase (EC 3.1.1.7) activity

Rapid eye movement (REM) sleep deprivation induces several behavioral changes. Among these, a decrease in yawning behavior produced by low doses of cholinergic agonists is observed which indicates a change in brain cholinergic neurotransmission after REM sleep deprivation. Acetylcholinesterase (Achase) controls acetylcholine (Ach) availability in the synaptic cleft. Therefore, altered Achase activity may lead to a change in Ach availability at the receptor level which, in turn, may result in modification of cholinergic neurotransmission. To determine if REM sleep deprivation would change the activity of Achase, male Wistar rats, 3 months old, weighing 250-300 g, were deprived of REM sleep for 96 h by the flower-pot technique (N = 12). Two additional groups, a home-cage control (N = 6) and a large platform control (N = 6), were also used. Achase was measured in the frontal cortex using two different methods to obtain the enzyme activity. One method consisted of the obtention of total (900 g supernatant), membrane-bound (100,000 g pellet) and soluble (100,000 g supernatant) Achase, and the other method consisted of the obtention of a fraction (40,000 g pellet) enriched in synaptic membrane-bound enzyme. In both preparations, REM sleep deprivation induced a significant decrease in rat frontal cortex Achase activity when compared to both home-cage and large platform controls. REM sleep deprivation induced a significant decrease of 16% in the membrane-bound Achase activity (nmol thiocholine formed min-1 mg protein-1) in the 100,000 g pellet enzyme preparation (home-cage group 152.1 +/- 5.7, large platform group 152.7 +/- 24.9 and REM sleep-deprived group 127.9 +/- 13.8). There was no difference in the soluble enzyme activity. REM sleep deprivation also induced a significant decrease of 20% in the enriched synaptic membrane-bound Achase activity (home-cage group 126.4 +/- 21.5, large platform group 127.8 +/- 20.4, REM sleep-deprived group 102.8 +/- 14.2). Our results suggest that REM sleep deprivation changes Ach availability at the level of its receptors through a decrease in Achase activity.

Differential inhibition of rat brain acetylcholinesterase molecular forms by 7-methoxytacrine in vitro

The effects of 7-methoxytacrine (7-MEOTA), a less toxic derivative of tetrahydroaminoacridine, on the activity of acetylcholinesterase (AChE) molecular forms were investigated in vitro. AChE molecular forms were separated by sucrose gradient sedimentation from homogenates of the frontal cerebral cortex prepared with buffer containing Triton X-100 (soluble + membrane-bound enzyme). Two molecular forms, namely 10S and 4S corresponding to globular tetrameric (G 4) and monomeric (G 1) forms, respectively, were detected; their molecular weights were 220 000 and 54 000 Da. A significantly higher sensitivity to 7-MEOTA of G 4 than of G 1 forms was observed. The K i values were 0.21 ± 0.07 μM for the former and 0.70 ± 0.15 μM for the latter. The differential inhibition of AChE molecular forms by 7-MEOTA is discussed in relation to its possible clinical application for treatment of disorders such as Alzheimer's disease, in which a reduction of brain cholinergic neurotransmission is believed to play a role.

Metabolic effects of scopolamine and physostigmine in human brain measured by positron emission tomography

Two of the more consistent findings in Alzheimer's disease are depressions in frontal and temporoparietal glucose metabolism and a loss of cholinergic neurons in the nucleus basalis of Meynert. Nonetheless, cholinergic replacement strategies have had only minimal therapeutic successes. Whether this situation reflects the limited contribution of cholinergic deafferentation to the intellectual decline or the meager ability of the pharmaceuticals tested to exert their intended pharmacologic action remains unclear. To address this question, the distribution of cerebral abnormalities found in untreated Alzheimer patients, as revealed by positron emission tomography following 18F-fluorodeoxyglucose, were compared with the pattern of functional changes produced by drugs that block or stimulate cholinergic function. Physostigmine was administered to 6 Alzheimer patients to increase brain cholinergic neurotransmission. The anticholinergic scopolamine, given to normal volunteers, was administered to 6 age-matched controls. These data were compared to those obtained from the same subjects while receiving placebo. Amnestic doses of the anticholinergic, scopolamine increased glucose metabolism by up to 20% ( p < 0.001) in all brain regions studied, except thalamus. This response contrasted with the metabolic reductions of up to 17% ( p < 0.01), especially in parietal and frontal association cortices, occurring in unmedicated Alzheimer patients. Maximum tolerated doses of the anticholinesterase, physostigmine, rather than tending to normalize abnormalities in these patients, further reduced cerebral metabolism ( p < 0.01) and increased metabolism in thalamus in a pattern inversely correlated ( p < 0.001) with that produced by scopolamine. These results fail to support a cholinergic basis for the abnormal metabolic pattern in Alzheimer's disease.

Cholinergic influence on memory facilitation induced by angiotensin II in rats

The influence of the cholinesterase inhibitor galanthamine (Nivalin), of the cholinergic agonist oxotremorine, and of the muscarinic cholinergic antagonist scopolamine on the retention-improving effect of angiotensin II (AT II) was studied in male Wistar rats trained and tested for retention (24 h later) using two paradigms: two-way active avoidance (shuttle-box) and passive (step-through) avoidance. AT II and the cholinergic agonists, administered together potentiated their retention-improving effects, while scopolamine abolished the memory effect of AT II. It is suggested that brain cholinergic neurotransmission participates in the mechanisms of the memory-facilitating effect of AT II.