Central Cholinergic Transmission Research Articles

Association of Intravenous Neostigmine and Anticholinergics or Sugammadex with Postoperative Delirium: A Retrospective Cohort Study.

Administration of cholinesterase inhibitors in combination with anticholinergic drugs for reversal of neuromuscular blocks may precipitate delirium through impairment of central cholinergic transmission, which could be avoided by using sugammadex. Therefore, we tested the primary hypothesis that postoperative delirium is less common when neuromuscular block is reversed with sugammadex than with neostigmine combined with glycopyrrolate or atropine. We conducted a single-center retrospective cohort study, analyzing all adult patients having general anesthesia for noncardiac surgery who received neostigmine or sugammadex from January 2016 to March 2022. Inverse propensity score weighting and propensity score calibration were used to adjust for appropriate confounders. Our primary outcome was presence of delirium within the first 4 days after surgery, defined as at least 1 positive brief Confusion Assessment Method (bCAM) screening. The secondary outcome was the presence of early delirium within 24 hours of surgery. Among 49,468 cases in our analysis, 6881 received sugammadex and 42,587 received neostigmine. After propensity weighting, the incidence of delirium was 1.09% in the sugammadex group and 0.82% in the neostigmine group. The odds of postoperative delirium did not differ between the sugammadex and neostigmine groups, with an estimated odds ratio (95% confidence interval) of 1.33 (0.91-1.95), P = .147. A sensitivity analysis restricted to only include cases with at least 6 bCAM measurements over postoperative day (POD) 1 to 4 had consistent results, as sugammadex compared with neostigmine was associated with an estimated odds ratio for postoperative delirium of 1.20 (0.82-1.77), P = .346. Sugammadex was significantly associated with an increased incidence of early postoperative delirium, with an estimated odds ratio of 1.71 (1.07-2.72), P = .025. Further analysis showed no treatment-by-age interaction for either postoperative delirium (P = .637) or postoperative early delirium (P = .904). Compared to neostigmine, use of sugammadex for reversal of neuromuscular block was not associated with an increased risk of postoperative delirium in this retrospective single-center study. Though sugammadex was associated with a statistically significant increased risk of postoperative early delirium, the difference was small and not clinically relevant, and may reflect the presence of unknown confounders.

Central cholinergic transmission affects the compulsive-like behavior of mice in marble-burying test

The presence of the cholinergic system in the brain areas implicated in the precipitation of obsessive–compulsive behavior (OCB) has been reported but the exact role of the central cholinergic system therein is still unexplored. Therefore, the current study assessed the effect of cholinergic analogs on central administration on the marble-burying behavior (MBB) of mice, a behavior correlated with OCB. The result reveals that the enhancement of central cholinergic transmission in mice achieved by intracerebroventricular (i.c.v.) injection of acetylcholine (0.01 µg) (Subeffective: 0.1 and 0.5 µg), cholinesterase inhibitor, neostigmine (0.1, 0.3, 0.5 µg/mouse) and neuronal nicotinic acetylcholine receptor agonist, nicotine (0.1, 2 µg/mouse) significantly attenuated the number of marbles buried by mice in MBB test without affecting basal locomotor activity. Similarly, central injection of mAChR antagonist, atropine (0.1, 0.5, 5 µg/mouse), nAChR antagonist, mecamylamine (0.1, 0.5, 3 µg/mouse) per se also reduced the MBB in mice, indicative of anti-OCB like effect of all the tested cholinergic mAChR or nAChR agonist and antagonist. Surprisingly, i.c.v. injection of acetylcholine (0.01 µg), and neostigmine (0.1 µg) failed to elicit an anti-OCB-like effect in mice pre-treated (i.c.v.) with atropine (0.1 µg), or mecamylamine (0.1 µg). Thus, the findings of the present investigationdelineate the role of central cholinergic transmission in the compulsive-like behavior of mice probably via mAChR or nAChR stimulation.

The rate and Extent of absorption of oral Meptazinol 200 mg on healthy volunteer

Meptazinol is a centrally acting analgesic belonging to the hexahydro-azepine series, which has demonstrated mixed agonist and antagonist activity at opioid receptors.Receptor binding studies have shown that although meptazinol displays only a low affinity for μ and k opioid receptor sites, it has a some what higher affinity for the subpopulation of μ sites. These binding sites also displays a high affinity for the endogenous opioid peptides, and are thought to be responsible for, among other things, analgesia, but not for the mediation of respiratory depression. A component of its analgesic action is also attributable, in mice at least, to an effect on central cholinergic transmission. In this respect it differs from all conventional analgesic drugs which have been examined (1).Based on this information this drug requires no blocking of opioid receptor during the bioequivalence study. But to achieve the highest degree of safety, close monitoring will be performed to detect the occurrence of any side effect, As well as Anarchole 50mg tablets (Naltrexone, the opioid blocker) will be available at the emergency drugs store to treat any opioid side effect

The Cholinergic Brain in Parkinson's Disease.

The central cholinergic system includes the basal forebrain nuclei, mainly projecting to the cortex, the mesopontine tegmental nuclei, mainly projecting to the thalamus and subcortical structures, and other groups of projecting neurons and interneurons. This system regulates many functions of human behavior such as cognition, locomotion, and sleep. In Parkinson's disease (PD), disruption of central cholinergic transmission has been associated with cognitive decline, gait problems, freezing of gait (FOG), falls, REM sleep behavior disorder (RBD), neuropsychiatric manifestations, and olfactory dysfunction. Neuropathological and neuroimaging evidence suggests that basal forebrain pathology occurs simultaneously with nigrostriatal denervation, whereas pathology in the pontine nuclei may occur before the onset of motor symptoms. These studies have also detailed the clinical implications of cholinergic dysfunction in PD. Degeneration of basal forebrain nuclei and consequential cortical cholinergic denervation are associated with and may predict the subsequent development of cognitive decline and neuropsychiatric symptoms. Gait problems, FOG, and falls are associated with a complex dysfunction of both pontine and basal forebrain nuclei. Olfactory impairment is associated with cholinergic denervation of the limbic archicortex, specifically hippocampus and amygdala. Available evidence suggests that cholinergic dysfunction, alongside failure of the dopaminergic and other neurotransmitters systems, contributes to the generation of a specific set of clinical manifestations. Therefore, a "cholinergic phenotype" can be identified in people presenting with cognitive decline, falls, and RBD. In this review, we will summarize the organization of the central cholinergic system and the clinical correlates of cholinergic dysfunction in PD.

The relationship between cholinergic system brain structure and function in healthy adults and patients with mild cognitive impairment

We assessed the structure–function relationship of the human cholinergic system and hypothesized that structural measures are associated with short-latency sensory afferent inhibition (SAI), an electrophysiological measure of central cholinergic signal transmission. Healthy volunteers (n = 36) and patients with mild cognitive impairment (MCI, n = 20) underwent median nerve SAI and 3T structural MRI to determine the volume of the basal forebrain and the thalamus. Patients with MCI had smaller basal forebrain (p < 0.001) or thalamus volumes (p < 0.001) than healthy volunteers. Healthy SAI responders (> 10% SAI) had more basal forebrain volume than non-responders (p = 0.004) or patients with MCI (p < 0.001). More basal forebrain volume was associated with stronger SAI in healthy volunteers (r = 0.33, p < 0.05) but not patients with MCI. There was no significant relationship between thalamus volumes and SAI. Basal forebrain volume is associated with cholinergic function (SAI) in healthy volunteers but not in MCI patients. The in-vivo investigation of the structure–function relationship could further our understanding of the human cholinergic system in patients with suspected or known cholinergic system degeneration.

Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19

ObjectiveA high proportion of patients experience fatigue and impairment of cognitive functions after coronavirus disease 2019 (COVID-19). Here we applied transcranial magnetic stimulation (TMS) to explore the activity of the main inhibitory intracortical circuits within the primary motor cortex (M1) in a sample of patients complaining of fatigue and presenting executive dysfunction after resolution of COVID-19 with neurological manifestations. MethodsTwelve patients who recovered from typical COVID-19 pneumonia with neurological complications and complained of profound physical and mental fatigue underwent, 9 to 13 weeks from disease onset, a psychometric evaluation including a self-reported fatigue numeric-rating scale (FRS, Fatigue Rating Scale) and the Frontal Assessment Battery (FAB). Intracortical activity was evaluated by means of well-established TMS protocols including short-interval intracortical inhibition (SICI), reflecting GABAA-mediated inhibition, long-interval intracortical inhibition (LICI), a marker of GABAB receptor activity, and short-latency afferent inhibition (SAI) that indexes central cholinergic transmission. TMS data were compared to those obtained in a control group of ten healthy subjects (HS) matched by age, sex and education level. ResultsPost-COVID-19 patients reported marked fatigue according to FRS score (8.1 ± 1.7) and presented pathological scores at the FAB based on Italian normative data (12.2 ± 0.7). TMS revealed marked reduction of SICI, and disruption of LICI as compared to HS. SAI was also slightly diminished. ConclusionsThe present study documents for the first time reduced GABAergic inhibition in the M1 in patients who recovered from COVID-19 with neurological complications and manifested fatigue and dysexecutive syndrome. SignificanceTMS may serve as diagnostic tool in cognitive disturbances and fatigue in post-COVID-19 patients.

Mahanimbine-induced neuroprotection via cholinergic system and attenuated amyloidogenesis as well as neuroinflammation in lipopolysaccharides-induced mice

Background: Murraya koenigii leaves are traditionally used in India and other South Asian countries as a spice in regular food dishes to improve taste and aroma. These leaves are known for the rich content of mahanimbine, a key carbazole alkaloid. Although there are numerous reports that support the neuroprotective role of various alkaloids, the effect of mahanimbine against memory impairment remains to be elucidated. Objective: The present study aimed to explore the neuroprotective potential of mahanimbine against lipopolysaccharides (LPS)-induced memory deficit in Institute of Cancer Research (ICR) mice. Materials and Methods: Group of mice were being fed with mahanimbine (1, 2, and 5 mg/kg, p. o.) for 30 days. Subsequently, neuroinflammation was induced with LPS (250 μg/kg, i. p.) for 4 days. Morris water maze (MWM) assessment was conducted to assess spatial memory. The brain was then collected and subjected to amyloid-beta (Aβ) (Aβ1-42and Aβ1-40) measurement, acetylcholine (ACh) and acetylcholinesterase (AChE) assays and neuroinflammatory analyses (interleukin [IL]-1 β, tumor necrosis factor alpha [TNF-α], IL-10 transforming growth factor beta [TGF-β], and cyclooxygenase [COX]). Results: The MWM test showed that treatment with mahanimbine significantly enhanced memory of LPS-challenged mice by decreasing both escape latency as well as escape distance. Pretreatment of the LPS-challenged mice with mahanimbine improved central cholinergic transmission by increasing ACh level through inhibition of AChE. It also significantly attenuated Aβ1-40level. While anti-inflammatory cytokines (TGF-β and IL-10) were upregulated, mahanimbine significantly inhibited pro-inflammatory cytokines (IL-1 β and TNF-α), the total activity of COX, and expression of COX-2 gene in LPS-induced group. Conclusion: The overall findings supported the neuroprotective potential of mahanimbine against LPS-induced neuroinflammation.

Treatment with Dimethyl Fumarate Enhances Cholinergic Transmission in Multiple Sclerosis.

Dimethyl fumarate (DMF) exerts anti-inflammatory effects in multiple sclerosis by activating the Nrf2 antioxidant pathway, which is also stimulated by acetylcholine via alpha-7 nicotinic acetylcholine receptors. In animal models, Nrf2 potentiates cholinergic synaptic plasticity. The aim of this study was to test whether treatment with DMF modulates cholinergic pathways in relapsing-remitting multiple sclerosis (RRMS). Patients starting DMF (20) or IFN-β 1a (20) and healthy subjects (20) were enrolled. Short-latency afferent inhibition (SAI), which is a transcranial stimulation measure of central cholinergic transmission, was recorded in patients and controls at baseline and, in patients only, after 6months of treatment. Patients treated with DMF also underwent autonomic function testing to further explore peripheral and central cholinergic tone. At baseline, SAI was similar in patients and in controls (p = 0.983). Treatment with DMF significantly increased SAI (p = 0.01), while IFNβ had no effect (p = 0.80). In the cold face test, DMF treatment also increased reflex bradycardia (p = 0.013), and reduced diastolic blood pressure variation (p = 0.010), further indicating its ability to stimulate cholinergic transmission. Treatment of MS patients with DMF results in increased cholinergic stimulation, with possible implications for neuroinflammation and neuroprotection.

A genetically encoded fluorescent acetylcholine indicator for in vitro and in vivo studies.

The neurotransmitter acetylcholine (ACh) regulates a diverse array of physiological processes throughout the body. Despite its importance, cholinergic transmission in the majority of tissues and organs remains poorly understood owing primarily to the limitations of available ACh-monitoring techniques. We developed a family of G-protein-coupled receptor activation-based ACh (GACh) sensors with sensitivity, specificity, signal-to-noise ratio, kinetics and photostability suitable for monitoring ACh signals in vitro and in vivo. GACh sensors were validated with transfection, viral and/or transgenic expression in a dozen types of neuronal and non-neuronal cells prepared from multiple animal species. In all preparations, GACh sensors selectively responded to exogenous and/or endogenous ACh with robust fluorescence signals that were captured by epifluorescence, confocal and/or two-photon microscopy. Moreover, analysis of endogenous ACh release revealed firing pattern-dependent release and restricted volume transmission, resolving two long-standing questions about central cholinergic transmission. Thus, GACh sensors provide a user-friendly, broadly applicable tool for monitoring cholinergic transmission underlying diverse biological processes.

Effects of Aged Garlic Extract on Cholinergic, Glutamatergic and GABAergic Systems with Regard to Cognitive Impairment in Aβ-Induced Rats.

Alzheimer’s disease (AD) has been linked to the degeneration of central cholinergic and glutamatergic transmission, which correlates with progressive memory loss and the accumulation of amyloid-β (Aβ). It has been claimed that aged garlic extract (AGE) has a beneficial effect in preventing neurodegeneration in AD. Therefore, the objective of this study was to investigate the effects of AGE on Aβ-induced cognitive dysfunction with a biochemical basis in the cholinergic, glutamatergic, and GABAergic systems in rats. Adult male Wistar rats were orally administered three doses of AGE (125, 250, and 500 mg/kg) daily for 65 days. At day 56, they were injected with 1 μL of aggregated Aβ (1–42) into each lateral ventricle, bilaterally. After six days of Aβ injection, the rats’ working and reference memory was tested using a radial arm maze. The rats were then euthanized to investigate any changes to the cholinergic neurons, vesicular glutamate transporter 1 and 2 proteins (VGLUT1 and VGLUT2), and glutamate decarboxylase (GAD) in the hippocampus. The results showed that AGE significantly improved the working memory and tended to improve the reference memory in cognitively-impaired rats. In addition, AGE significantly ameliorated the loss of cholinergic neurons and increased the VGLUT1 and GAD levels in the hippocampus of rat brains with Aβ-induced toxicity. In contrast, the VGLUT2 protein levels did not change in any of the treated groups. We concluded that AGE was able to attenuate the impairment of working memory via the modification of cholinergic neurons, VGLUT1, and GAD in the hippocampus of Aβ-induced rats.

69. Impaired spike timing dependent cortico-cortical plasticity in Alzheimer’s Disease patients

Introduction Mechanisms of cortical plasticity have been widely investigated in Alzheimer’s disease (AD) patients with TMS protocols, showing a clear impairment of Long-Term Potentiation (LTP) cortical-like plasticity and a relative sparing of Long Term Depression (LTD) mechanisms. Recently a new TMS protocol, investigating the connections between posterior parietal cortex (PPC) and primary motor cortex (M1), elicited in a bidirectional way LTP and LTD effects. Objective We investigated mechanisms of spike-timing dependent plasticity in AD patients and the effects of the modulation of PPC-M1 pathway on cholinergic transmission, greatly impaired in AD patients. Material and methods Twelve AD patients and eight age-matched healthy subjects (HS) were evaluated. We used bifocal TMS to repeatedly activate the connections between the PPC and M1 of the left-dominant hemisphere. PPC TMS preceded or followed the M1 stimulation by 5 ms, respectively PAS +5 and PAS −5. To best activate the ipsilateral PPC-M1 connection, the conditioning stimulus was applied over the left PPC at an intensity of 90% of the ipsilateral resting motor threshold. For the PAS protocol, 100 pairs of stimuli were continuously delivered at a rate of 0.2 Hz for ∼8.3 min. Motor evoked potentials and central cholinergic way, evaluated with Short-latency afferent inhibition (SAI) protocol, were evaluated before and after PAS (+5 or −5) protocol. Results as expected HS showed an LTP-like cortical plasticity following PAS −5 protocol and an LTD-like cortical plasticity after PAS +5 protocol, while AD patients did not show any modification of the amplitude of MEP after repeated activation of PPC-M1 connections. As compared to HS, AD patients showed worst SAI values. Interestingly, after PAS +5 protocol, in AD patients SAI levels were restored. Conclusions The data here presented confirm that in AD patients there is an altered cortical plasticity. The central cholinergic way is altered in AD patients, but after the application of PAS +5 protocol his levels are restored, suggesting a possible role of PPC-M1 pathway on modulation of this inhibitory intracortical circuit. PAS protocol is able to investigate the mechanisms of altered cortical plasticity in AD patients. Central cholinergic transmission can be modulated by stimulation of PPC-M1 connections.

Reversal of LTP-Like Cortical Plasticity in Alzheimer's Disease Patients with Tau-Related Faster Clinical Progression.

Cerebrospinal fluid (CSF) concentrations of amyloid-β (Aβ), total tau (t-tau), and phosphorylated tau proteins are associated with different clinical progression in Alzheimer's disease (AD). We enrolled forty newly diagnosed AD patients, who underwent lumbar puncture, and carried out a K-means cluster analysis based on CSF biomarkers levels, resulting in two AD patient groups: Cluster 1 showed relatively high levels of Aβ and low levels of tau; Cluster 2 showed relatively low levels of Aβ and high levels of tau. Cortical plasticity was tested using the intermittent and continuous theta burst stimulation (iTBS and cTBS) protocols evoking respectively long-term potentiation (LTP) and depression (LTD). Cholinergic transmission was tested by the short-latency afferent inhibition protocol. Neurophysiological evaluation showed that the two AD groups differed in terms of cortical plasticity: after iTBS, Cluster 2 patients showed a remarkable reversal of LTP toward LTD that was not observed in Cluster 1. LTD and central cholinergic transmission did not differ between groups. Patients were assessed longitudinally with Mini-Mental State Examination at 6, 12, and 18 month follow-ups. Cluster 2 AD had a faster cognitive decline already evident at the 12 month follow-up. High tau CSF levels were associated with LTD-like cortical plasticity and faster clinical progression. These results suggest that more aggressive tau pathology is associated with prominent LTD-like mechanisms of cortical plasticity and faster cognitive decline.

Crinum zeylanicum memory enhancing effect is mediated via central cholinergic transmission system

Background: Crinum zeylanicum is widely used in the ethno-therapeutic management of folk management of epilepsy, pain, neuropsychiatric, and dementing disorders in Nigeria. The current study was carried out to evaluate the possible mechanism of the memory enhancing the effect of C. zeylanicum extract and alkaloidal rich fraction in Wistar rats. Methods: The effect of Crinum zeylanicum bulb extract (250, 500, and 1000 mg/kg body weight orally), alkaloidal rich fraction (10, 20, and 40 mg/kg body weight p.o.), normal saline (10 ml/kg orally), or Eserine (0.3 mg/kg body weight i.p.) on spatial memory in rats was evaluated using the Y-maze. The blood samples obtained from rats in all treatment groups were evaluated for cholinesterase activities using modified Michelle electrometric method. Results: The extract and the alkaloid significantly (p<0.05) and dose-dependently increased spontaneous alternation behavior of rats in Y-maze. The extract produced 20.00%, 35.55%, and 52.00% inhibition of cholinesterase activity in the blood at 250, 500, and 1000 mg/kg body weight, respectively. The alkaloid produced 56.67%, 62.67%, and 68.67% inhibition of cholinesterase activity in blood at 10, 20, and 40 mg/kg body weight (p.o.). Eserine a standard cholinesterase inhibitor at 0.3 mg/kg body weight produced a significant increase in spontaneous alternation behavior and produced 73.33% inhibition of blood cholinesterase activity. Data obtained from the study showed that the enhanced spontaneous alternation behavior observed in rats treated with the extract, and the alkaloid may be due to facilitation of cholinergic transmission resulting from inhibition of cholinesterase activity. Conclusion: The extract, as well as its partially purified alkaloid, possesses potential that may be employed for therapeutic management of Alzheimer’s disease.

Homotaurine induces measurable changes of short latency afferent inhibition in a group of mild cognitive impairment individuals.

Current treatment options for patients with Alzheimer’s disease (AD) are limited at providing symptomatic relief, with no effects on the underlying pathophysiology. Recently, advances in the understanding of the AD pathogenesis highlighted the role of ABeta (Aβ) oligomers particularly interfering with mechanisms of cortical plasticity such as long-term potentiation (LTP) and long-term depression (LTD). These findings led to the development of potential anti-amyloid therapies, and among them homotaurine, a glycosaminoglycan mimetic designed to interfere with the actions of Aβ early in the cascade of amyloidogenic events, and by its γ-aminobutyric acid type (GABA) A receptor affinity. Recently, we showed that AD patients have impaired LTP-like cortical plasticity, as measured by standard theta burst stimulation protocols applied over the primary motor cortex (M1). Furthermore, AD patients have a weakened short latency afferent inhibition (SLAI), a neurophysiological measure of central cholinergic transmission, which changes reflect the cholinergic dysfunction occurring in the pathology. Here, we aimed at investigating whether homotaurine administration could modulate in vivo measured mechanisms of synaptic plasticity, namely LTP and LTD, and also SLAI in a group of mild cognitive impaired patients. We observed that homotaurine administration did not induce relevant changes of both LTP and LTD recordings, while induced changes of SLAI in our group of patients. We suggest that homotaurine effects are dependent on changes of cortical GABA transmission suggesting a potential role for this compound in ameliorating the cholinergic transmission by modulating the inhibitory cortical activity.

Oxidized low density lipoprotein increases acetylcholinesterase activity correlating with reactive oxygen species production

Hyperlipidemia, low density lipoproteins (LDL) and their oxidized forms, and oxidative stress are suspected to be a key combination in the onset of AD and acetylcholinesterase (AChE) plays a part in this pathology. The present study aimed to link these parameters using differentiated SH-SY5Y human neuroblastoma cells in culture. Both mildly and fully oxidized human LDL (mox- and fox-LDL), but not native (non-oxidized) LDL were cytotoxic in dose- and time-dependent patterns and this was accompanied by an increased production of intracellular reactive oxygen species (ROS). Oxidized LDL (10–200μg/mL) augmented AChE activity after 4 and 24h treatments, respectively while the native LDL was without effect. The increased AChE with oxidized LDLs was accompanied by a proportionate increase in intracellular ROS formation (R=0.904). These findings support the notion that oxidized LDLs are cytotoxic and that their action on AChE may reduce central cholinergic transmission in AD and affirm AChE as a continued rational for anticholinesterase therapy but in conjunction with antioxidant/antihyperlipidemic cotreatments.

Water for thought: is there a role for aquaporin channels in delirium?

C. G. Jung believed that water was a symbol for the unconscious mind, the background from where our conscious thoughts emerge, and also the sea where they melt into the dream-like state of primary processes (1). Water comprises about 80% of the brain volume and water homeostasis is inextricably coupled to the CNS function. In this regard, neuroscience describes an inverse relationship between the intensity of the neuropil function and the amount of water it contains. For example, during high neuronal activity (such as information processing), water is transported away from the neuropil, shrinking the extracellular matrix (ECM). Conversely, during times of lower brain activity (such as during sleep), water is shifted back to the neuropil, expanding the ECM (2, 3). The movement of water in and out of the neuropil occurs with the help of the glymphatic system via special molecular pumps, aquaporin water channels (AQP 4) located in astrocyte end-feet. Water circulation is enabled by the exchange between the cerebrospinal fluid (CSF) and interstitial fluid (ISF). The pressure gradient for this exchange is probably provided by pericytes’ contraction and arterial pulsations along with the suction, pump-like action of AQP 4 channels (4–6). This movement of water in and out of the neuropil enables both, clearance of molecular waste and volume transmission (VT) of chemical signals (7). Conversely, delayed water movement (glymphatic stasis) may predispose to the accumulation of misfolded proteins (4) and ultimately to neuroinflammation (8). The relationship between water and delirium is complex. Both, brain edema and dehydration may predispose to delirium (9). Up-regulation of AQP 4 water channels seems to occur in both situations. In fact, a biphasic up-regulation was described in edema build-up and the resolution phase (10). Interestingly, AQP 4 receptors seem to be the common denominator between the neuropil water movement and neuroinflammation (10). Moreover, animal studies demonstrated that peripheral dehydration triggers central up-regulation of AQP 4 receptors (11–13). This in turn causes swelling and priming of astrocytes and microglia, predisposing to neuroinflammation (14). According to a recent study, two key factors, systemic inflammation and central cholinergic impairment must interact in order to produce delirium (15). The goal of this article is not to discuss VT or the relationship between AQP 4 channels and inflammation since extensive literature exists on these subjects. Instead, we attempt to answer three questions: Can an inefficient glymphatic clearance lead to impairment of central cholinergic transmission? Does glymphatic stasis contribute to microglia and astrocytes’ priming, the precursor of neuroinflammation? Do aquaporin blockers have a place in delirium? We hypothesize that failure of glymphatic clearance leads to impairment of acetylcholine volume transmission (AChVT), contributing to impaired arousal, attention, memory, and sleep as seen in delirium. We hypothesize further, that glymphatic failure is pro-inflammatory in nature, leading to up-regulation of AQP 4 channels, which in turn trigger astrocyte swelling and gliosis with the end result being microglial and astrocytic priming. The above phenomena may reconcile two theories of delirium: central cholinergic deficit and neuroinflammation.

A Platform for Screening Potential Anticholinesterase Fractions and Components Obtained from Anemarrhena asphodeloides Bge for Treating Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by progressive memory loss and cognitive impairment. Cholinesterase inhibitors are widely used for the symptomatic treatment of Alzheimer's disease to enhance central cholinergic transmission. In this study, a bioactivity-oriented screening platform based on a modified Ellman's method and HPLC-QTOF MS technique was developed to rapidly screen active agents of Anemarrhena asphodeloides Bge. The 60% ethanol fraction from an ethyl acetate extract exhibited the most potential anticholinesterase activity. Fifteen steroid saponins were identified by the mass spectrum, standards and literature reports. Twenty-five compounds were isolated from the active fraction. The results showed that compounds with the C6–C3–C6 skeleton probably had both AChE and BuChE inhibitory activities. Xanthone and benzene derivatives exhibited no or little activity. Lignans showed weak BuChE inhibitory activity. The steroidal saponins demonstrated moderate or weak AChE inhibitory activity.

Role of cholinergic-muscarinic receptors in visual discrimination performance of rats: Importance of stimulus load

Central cholinergic transmission has long been implicated in various cognitive processes, including memory acquisition, consolidation, and attentional processes. Here, we examined the role of muscarinic receptors in visual discrimination performance under conditions of altered visual information availability. Adult rats were trained to discriminate two visual cues (indicating the presence and absence of a hidden escape platform, respectively) in a water maze-based, trapezoidal-shaped apparatus. Following task acquisition, testing continued with two types of trials: regular trials (RTs; both visual cues present, identical to training conditions) and probe trials (PTs; only one of the two cues present). In Experiment 1, removal of one visual cue on PTs impaired discrimination performance. Moreover, scopolamine administration (0.125–1.0mg/kg, i.p.) tended to further suppress performance in a dose-dependent manner on PTs, while discriminations on RTs were left intact. In Experiment 2, these results were confirmed and extended by showing that PT (one visual cue) performance could improve with training in undrugged, but not in scopolamine-treated rats. Together, these experiments reveal that visual discrimination performance of rats benefits from the concurrent availability of two visual cues that provide complimentary and consistent information. Furthermore, muscarinic receptors are particularly important under conditions of reduced visual information availability, as well as in the adoption of new behavioral strategies, such as switching from two-cue to single-cue guided navigation.

Dopamine D2-agonist Rotigotine effects on cortical excitability and central cholinergic transmission in Alzheimer's disease patients

Dopamine is a neurotransmitter involved in several brain functions ranging from emotions control, movement organization to memory formation. It is also involved in the regulation of mechanisms of synaptic plasticity. However, its role in Alzheimer's disease (AD) pathogenesis is still puzzling. Several recent line of research instead indicates a clear role for dopamine in both amyloid β formation as well as in cognitive decline progression. In particular it has been shown that dopamine D2-like receptors (namely D3 and D2) could be mostly responsible for dopamine dysfunction in AD. Here we aimed to study the effects of the dopamine agonist Rotigotine on cortical excitability and on central cholinergic transmission in cases of AD. Rotigotine is a dopamine agonist with a pharmacological profile with high affinity for D3 and D2 receptors. We used paired pulse protocols assessing short intracortical inhibition (SICI) and intracortical facilitation (ICF) to asses cortical excitability over the primary motor cortex and Short Latency Afferent Inhibition (SLAI) protocols, to verify the effects of the drug on central cholinergic transmission in a group of AD patients compared to age-matched controls. We observed that rotigotine induces unexpected changes in both cortical excitability (increased) and central cholinergic transmission (restored) of AD patients. These unexpected effects might depend on the dopamine D2-like receptors dysfunction previously described in AD brains. The current findings could indicate that future strategies aimed to ameliorate symptoms of the related AD cognitive decline could also involve some dopaminergic drugs.This article is part of a Special Issue entitled ‘Cognitive Enhancers’.

Molecular design of O-phosphorylated oximes—Selective inhibitors of butyrylcholinesterase

Anticholinesterase compounds, including organophosphorus inhibitors (OPIs), are used to treat glaucoma, schistosomiasis, Alzheimer’s disease, myasthenia gravis, and other diseases. These compounds arealso widely used in agriculture as insecticides and inindustry [1]. The varied use of such compounds isbased on their common mechanism of action, which isassociated with the inhibition of acetylcholinesterase(AChE, EC 3.1.1.7), the biological role of which is thehydrolysis of the key neurotransmitter acetylcholine.In the treatment of Alzheimer’s disease (AD) underconditions of deficiency of central acetylcholine andreduced cholinergic transmission, the inhibition ofAChE in the brain provides cognition enhancement,which, however, may be accompanied by manifestations of acute toxicity and other side effects associatedwith inhibition of peripheral AChE [2].Many OPIs interact in the body with otheresterases. These interactions may lead to differentpharmacological and toxicological effects. For example, the neuropathy target esterase (NTE, EC 3.1.1.5),which normally catalyzes deacylation of phosphatidylcholine of cell membranes [3], is an “antitarget”responsible for the development of organophosphateinduced delayed neurotoxicity (OPIDN). This phenomenon is due to the fact that its inhibition and subsequent rapid “aging” initiates distal degeneration ofsensory and motor axons in the peripheral nervous system and/or spinal cord, causing paralysis [1]. This disease is characterized by a latent period of up to severalweeks; specific drugs for its treatment are still notknown. Thus, the possibility of initiation of delayedneurotoxicity is an important risk factor in industrialand medical applications of OPIs.Other serine esterases, such as butyrylcholinesterase (BChE, EC 3.1.1.8) and carboxylesterase (CaE,EC 3.1.1.1), function as stoichiometric scavengers,providing protection against the toxic effect of anticholinesterase agents [4]. BChE and CaE of bloodplasma and liver are also in volved in the metabolism ofmany drugs containing ester groups, significantlyaffecting their pharmacokinetics.Recent studies have shown that BChE is alsoinvolved in cholinergic transmission and is able tocompensate for some functions of AChE, optimizingthe cholinergic neurotransmission by hydrolysis ofacetylcholine under conditions when AChE is, forsome reason, unable to perform this function(for example, in severe forms of AD, when the activityof AChE is significantly reduced). It was found thatselective inhibitors of BChE increase the level of acetylcholine in the brain and provide cognition enhancement in rodents, having no side effects of classicalinhibitors of AChE. In this regard, the development ofselective inhibitors of BChE is a new strategy toimprove the quality of life of patients with AD, especially in severe cases, when the activity of AChE in thebrain is depleted along with a decrease in the level ofacetylcholine, whereas the activity of BChE isincreased [2].Within the considered scheme of interaction withthe four serine esterases, the esterase profile of aninhibitor can be described by four activity values(the inhibitory activity with respect to AChE