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Nature Neuroscience May 2023
Topics: Auditory Pathways; Cholinergic Agents; Auditory Cortex
PubMed: 37029204
DOI: 10.1038/s41593-023-01300-z -
Psychopharmacology May 2023The M/M preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer's disease or schizophrenia in... (Randomized Controlled Trial)
Randomized Controlled Trial
RATIONALE
The M/M preferring muscarinic receptor agonist xanomeline demonstrated antipsychotic and procognitive effects in patients with Alzheimer's disease or schizophrenia in prior studies, but further clinical development was limited by cholinergic adverse events (AEs). KarXT combines xanomeline with the peripherally restricted muscarinic receptor antagonist trospium with the goal of improving tolerability and is in clinical development for schizophrenia and other neuropsychiatric disorders.
OBJECTIVE
Test the hypothesis that trospium can mitigate cholinergic AEs associated with xanomeline.
METHODS
Healthy volunteers enrolled in this phase 1 (NCT02831231), single-site, 9-day, double-blind comparison of xanomeline alone (n = 33) versus KarXT (n = 35). Rates of five prespecified cholinergic AEs (nausea, vomiting, diarrhea, excessive sweating, salivary hypersecretion) were compared between treatment arms. Vital signs, electrocardiograms (ECGs), safety laboratory values, and pharmacokinetic (PK) analyses were assessed. A self-administered visual analog scale (VAS) and clinician-administered scales were employed.
RESULTS
Compared with xanomeline alone, KarXT reduced composite incidences of the five a priori selected cholinergic AEs by 46% and each individual AE by ≥ 29%. There were no episodes of syncope in KarXT-treated subjects; two cases occurred in the xanomeline-alone arm. The rate of postural dizziness was 11.4% in the KarXT arm versus 27.2% with xanomeline alone. ECG, vital signs, and laboratory values were not meaningfully different between treatment arms. The VAS and clinician-administered scales tended to favor KarXT. PK analysis revealed that trospium did not affect xanomeline's PK profile.
CONCLUSIONS
Trospium was effective in mitigating xanomeline-related cholinergic AEs. KarXT had an improved safety profile compared with xanomeline alone.
Topics: Humans; Muscarinic Agonists; Cholinergic Agents; Pyridines; Thiadiazoles; Receptors, Muscarinic
PubMed: 37036495
DOI: 10.1007/s00213-023-06362-2 -
Handbook of Clinical Neurology 2021Cholinergic signaling is critical for cognitive function. The basal forebrain is the major cholinergic output of the central nervous system. Degeneration of basal... (Review)
Review
Cholinergic signaling is critical for cognitive function. The basal forebrain is the major cholinergic output of the central nervous system. Degeneration of basal forebrain cholinergic neurons is a hallmark of Alzheimer's disease (AD). Mouse models are invaluable tools in disease research and have been used to study AD for over 25 years. However, animal models of AD vary greatly with respect to the degree of cholinergic degeneration observed. The following review will outline the most influential animal models of AD with an emphasis on the basal forebrain cholinergic system.
Topics: Alzheimer Disease; Animals; Basal Forebrain; Cholinergic Agents; Cholinergic Neurons; Disease Models, Animal; Humans; Mice
PubMed: 34266592
DOI: 10.1016/B978-0-12-819973-2.00013-7 -
Acta Pharmacologica Sinica Apr 2020Motor control in the striatum is an orchestra played by various neuronal populations. Loss of harmony due to dopamine deficiency is considered the primary pathological... (Review)
Review
Motor control in the striatum is an orchestra played by various neuronal populations. Loss of harmony due to dopamine deficiency is considered the primary pathological cause of the symptoms of Parkinson's disease (PD). Recent progress in experimental approaches has enabled us to examine the striatal circuitry in a much more comprehensive manner, not only reshaping our understanding of striatal functions in movement regulation but also leading to new opportunities for the development of therapeutic strategies for treating PD. In addition to dopaminergic innervation, giant aspiny cholinergic interneurons (ChIs) within the striatum have long been recognized as a critical node for balancing dopamine signaling and regulating movement. With the roles of ChIs in motor control further uncovered and more specific manipulations available, striatal ChIs and their corresponding receptors are emerging as new promising therapeutic targets for PD. This review summarizes recent progress in functional studies of striatal circuitry and discusses the translational implications of these new findings for the treatment of PD.
Topics: Animals; Antiparkinson Agents; Cholinergic Agents; Cholinergic Neurons; Humans; Parkinson Disease
PubMed: 32132659
DOI: 10.1038/s41401-020-0380-z -
The Neuroscientist : a Review Journal... Oct 2019
Topics: Acetylcholine; Cholinergic Agents; Interneurons; Neurosciences; Nucleus Accumbens
PubMed: 31554493
DOI: 10.1177/1073858419868689 -
Brain : a Journal of Neurology Jun 2022This scientific commentary refers to ‘Cholinergic and hippocampal systems facilitate cross-domain cognitive recovery after stroke’ by O’Sullivan...
This scientific commentary refers to ‘Cholinergic and hippocampal systems facilitate cross-domain cognitive recovery after stroke’ by O’Sullivan (https://doi.org/10.1093/brain/awac070).
Topics: Cholinergic Agents; Cognition; Hippocampus; Humans; Stroke
PubMed: 35438715
DOI: 10.1093/brain/awac142 -
Progress in Retinal and Eye Research Sep 2019The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye... (Review)
Review
The cholinergic system has a crucial role to play in visual function. Although cholinergic drugs have been a focus of attention as glaucoma medications for reducing eye pressure, little is known about the potential modality for neuronal survival and/or enhancement in visual impairments. Citicoline, a naturally occurring compound and FDA approved dietary supplement, is a nootropic agent that is recently demonstrated to be effective in ameliorating ischemic stroke, traumatic brain injury, Parkinson's disease, Alzheimer's disease, cerebrovascular diseases, memory disorders and attention-deficit/hyperactivity disorder in both humans and animal models. The mechanisms of its action appear to be multifarious including (i) preservation of cardiolipin, sphingomyelin, and arachidonic acid contents of phosphatidylcholine and phosphatidylethanolamine, (ii) restoration of phosphatidylcholine, (iii) stimulation of glutathione synthesis, (iv) lowering glutamate concentrations and preventing glutamate excitotoxicity, (v) rescuing mitochondrial function thereby preventing oxidative damage and onset of neuronal apoptosis, (vi) synthesis of myelin leading to improvement in neuronal membrane integrity, (vii) improving acetylcholine synthesis and thereby reducing the effects of mental stress and (viii) preventing endothelial dysfunction. Such effects have vouched for citicoline as a neuroprotective, neurorestorative and neuroregenerative agent. Retinal ganglion cells are neurons with long myelinated axons which provide a strong rationale for citicoline use in visual pathway disorders. Since glaucoma is a form of neurodegeneration involving retinal ganglion cells, citicoline may help ameliorate glaucomatous damages in multiple facets. Additionally, trans-synaptic degeneration has been identified in humans and experimental models of glaucoma suggesting the cholinergic system as a new brain target for glaucoma management and therapy.
Topics: Acetylcholine; Choline; Cholinergic Agents; Cytidine Diphosphate Choline; Glaucoma; Humans; Neuroprotective Agents; Retinal Ganglion Cells; Signal Transduction; Visual Cortex
PubMed: 31242454
DOI: 10.1016/j.preteyeres.2019.06.003 -
International Journal of Molecular... Feb 2024Commercially available 2-deoxy-D-ribose was used to synthesize the appropriate oxolane derivative-(2,3)-2-(hydroxymethyl)oxolan-3-ol-by reduction and...
Commercially available 2-deoxy-D-ribose was used to synthesize the appropriate oxolane derivative-(2,3)-2-(hydroxymethyl)oxolan-3-ol-by reduction and dehydration/cyclization in an acidic aqueous solution. Its monotosyl derivative, as a result of the quaternization reaction, allowed us to obtain eight new muscarine-type derivatives containing a quaternary nitrogen atom and a hydroxyl group linked to the oxolane ring. Their structure was fully confirmed by the results of NMR, MS and IR analyses. The crystal structure of the pyridinium derivative showed a high similarity of the conformation of the oxolane ring to previously published crystal structures of muscarine. Two reference strains of Gram-negative bacteria ( ATCC 25922 and ATCC 27853), two reference strains of Gram-positive staphylococci ( ATCC 25923 and ATCC 29213) and four reference strains of pathogenic yeasts of the genus spp. ( SC5314, DSM 11226, DSM 6128 and DSM 5784) were selected for the evaluation of the antimicrobial potential of the synthesized compounds. The derivative containing the longest (decyl) chain attached to the quaternary nitrogen atom turned out to be the most active.
Topics: Muscarine; Salts; Microbial Sensitivity Tests; Nitrogen; Ammonium Compounds; Anti-Bacterial Agents
PubMed: 38397044
DOI: 10.3390/ijms25042368 -
Journal of Neurochemistry Sep 2021Cholinergic signaling is crucial in cognitive processes, and degenerating cholinergic projections are a pathological hallmark in dementia. Use of cholinesterase... (Review)
Review
Cholinergic signaling is crucial in cognitive processes, and degenerating cholinergic projections are a pathological hallmark in dementia. Use of cholinesterase inhibitors is currently the main treatment option to alleviate symptoms of Alzheimer's disease and has been postulated as a therapeutic strategy in acute brain damage (stroke and traumatic brain injury). However, the benefits of this treatment are still not clear. Importantly, cholinergic receptors are expressed both by neurons and by astrocytes and microglia, and binding of acetylcholine to the α7 nicotinic receptor in glial cells results in anti-inflammatory response. Similarly, the brain fine-tunes the peripheral immune response over the cholinergic anti-inflammatory axis. All of these processes are of importance for the outcome of acute and chronic neurological disease. Here, we summarize the main findings about the role of cholinergic signaling in brain disorders and provide insights into the complexity of molecular regulators of cholinergic responses, such as microRNAs and transfer RNA fragments, both of which may fine-tune the orchestra of cholinergic mRNAs. The available data suggest that these small noncoding RNA regulators may include promising biomarkers for predicting disease course and assessing treatment responses and might also serve as drug targets to attenuate signaling cascades during overwhelming inflammation and to ameliorate regenerative capacities of neuroinflammation.
Topics: Acetylcholine; Animals; Central Nervous System Diseases; Cholinergic Agents; Cholinergic Neurons; Cholinesterase Inhibitors; Humans; RNA; Signal Transduction
PubMed: 33638173
DOI: 10.1111/jnc.15332 -
Hearing Research Mar 2021Age-related hearing loss is a complex disorder affecting a majority of the elderly population. As people age, speech understanding becomes a challenge especially in... (Review)
Review
Age-related hearing loss is a complex disorder affecting a majority of the elderly population. As people age, speech understanding becomes a challenge especially in complex acoustic settings and negatively impacts the ability to accurately analyze the auditory scene. This is in part due to an inability to focus auditory attention on a particular stimulus source while simultaneously filtering out other sound stimuli. The present review examines the impact of aging on two neurotransmitter systems involved in accurate temporal processing and auditory gating in auditory thalamus (medial geniculate body; MGB), a critical brain region involved in the coding and filtering of auditory information. The inhibitory neurotransmitter GABA and its synaptic receptors (GABARs) are key to maintaining accurate temporal coding of complex sounds, such as speech, throughout the central auditory system. In the MGB, synaptic and extrasynaptic GABARs mediate fast phasic and slow tonic inhibition respectively, which in turn regulate MGB neuron excitability, firing modes, and engage thalamocortical oscillations that shape coding and gating of acoustic content. Acoustic coding properties of MGB neurons are further modulated through activation of tegmental cholinergic afferents that project to MGB to potentially modulate attention and help to disambiguate difficult to understand or novel sounds. Acetylcholine is released onto MGB neurons and presynaptic terminals in MGB activating neuronal nicotinic and muscarinic acetylcholine receptors (nAChRs, mAChRs) at a subset of MGB afferents to optimize top-down and bottom-up information flow. Both GABAergic and cholinergic neurotransmission is significantly altered with aging and this review will detail how age-related changes in these circuits within the MGB may impact coding of acoustic stimuli.
Topics: Acoustic Stimulation; Aged; Aging; Cholinergic Agents; Geniculate Bodies; Humans; Synaptic Transmission; Thalamus; gamma-Aminobutyric Acid
PubMed: 32703637
DOI: 10.1016/j.heares.2020.108003