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Central Nervous System Agents in... 2017Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) characterized by leucocytes infiltration, demyelination,... (Review)
Review
BACKGROUND
Multiple sclerosis (MS) is an inflammatory and neurodegenerative disease of the central nervous system (CNS) characterized by leucocytes infiltration, demyelination, axonal degeneration and neuronal death. Although the etiology of MS is still unkwon, inflammation and autoimmunity are considered to be key players of the disease. Nervous System: The severe alterations affecting the nervous system contribute to the motor and cognitive disabilities and are in large part dependent on severe inflammatory processes active in both central nervous system and immune system. Acetylcholine (ACh) appears to be involved in the modulation of central and peripheral inflammation. Immune cells as well as astrocytes and microglia respond to ACh stimuli by activation of cholinergic receptors. Muscarinic and nicotinic receptors differently contribute to the modulation of immunological and inflammatory processes stimulating pro- and anti-inflammatory cytokines respectively. The role played by ACh in MS is not yet fully understood, although some results point to its involvement in different neurological disorders such as Alzheimer's disease and schizophrenia.
CONCLUSION
In the present review we summarize the evidence indicating the correlation between nervous system dysfunction in MS, with inflammation and cholinergic system alterations. Experiments performed in MS animal models and analyses on biological fluids from MS patients such as blood, serum and cerebrospinal fluid suggest that cholinergic alterations may contribute to the dysregulated inflammatory processes of MS. Many current therapeutic approaches in MS are based on anti-inflammatory drugs. We also discuss how the use of cholinesterase inhibitors or ACh mimetics may represent a new interesting therapeutic approach in MS.
Topics: Animals; Anti-Inflammatory Agents; Cholinergic Agents; Cholinesterase Inhibitors; Humans; Inflammation; Inflammation Mediators; Multiple Sclerosis
PubMed: 27550615
DOI: 10.2174/1871524916666160822115133 -
Cell Reports Oct 2022Cholinergic interneurons (CINs) are essential elements of striatal circuits and functions. Although acetylcholine signaling via muscarinic receptors (mAChRs) has been...
Cholinergic interneurons (CINs) are essential elements of striatal circuits and functions. Although acetylcholine signaling via muscarinic receptors (mAChRs) has been well studied, more recent data indicate that postsynaptic nicotinic receptors (nAChRs) located on striatal GABAergic interneurons (GINs) are equally critical. One example is that CIN stimulation induces large disynaptic inhibition of striatal projection neurons (SPNs) mediated by nAChR activation of GINs. Although these circuits are ideally positioned to modulate striatal output, the neurons involved are not definitively identified because of an incomplete mapping of CINs-GINs interconnections. Here, we show that CINs modulate four GINs populations via an intricate mechanism involving co-activation of presynaptic and postsynaptic mAChRs and nAChRs. Using optogenetics, we demonstrate the participation of tyrosine hydroxylase-expressing GINs in the disynaptic inhibition of SPNs via heterotypic electrical coupling with neurogliaform interneurons. Altogether, our results highlight the importance of CINs in regulating GINs microcircuits via complex synaptic/heterosynaptic mechanisms.
Topics: Acetylcholine; Tyrosine 3-Monooxygenase; Corpus Striatum; Interneurons; Cholinergic Agents; Receptors, Muscarinic; Receptors, Nicotinic; Cholinergic Neurons
PubMed: 36288709
DOI: 10.1016/j.celrep.2022.111531 -
Journal of Physiology, Paris Sep 2016
Topics: Animals; Cholinergic Agents; Humans; Non-Neuronal Cholinergic System; Visual Perception
PubMed: 27987551
DOI: 10.1016/j.jphysparis.2016.12.001 -
Journal of Neurochemistry Sep 2021Advances in understanding the regulatory functions of the nervous system have revealed neural cholinergic signaling as a key regulator of cytokine responses and... (Review)
Review
Advances in understanding the regulatory functions of the nervous system have revealed neural cholinergic signaling as a key regulator of cytokine responses and inflammation. Cholinergic drugs, including the centrally acting acetylcholinesterase inhibitor, galantamine, which are in clinical use for the treatment of Alzheimer's disease and other neurodegenerative and neuropsychiatric disorders, have been rediscovered as anti-inflammatory agents. Here, we provide a timely update on this active research and clinical developments. We summarize the involvement of cholinergic mechanisms and inflammation in the pathobiology of Alzheimer's disease, Parkinson's disease, and schizophrenia, and the effectiveness of galantamine treatment. We also highlight recent findings demonstrating the effects of galantamine in preclinical and clinical settings of numerous conditions and diseases across the lifespan that are characterized by immunological, neurological, and metabolic dysfunction.
Topics: Acetylcholinesterase; Animals; Anti-Inflammatory Agents; Brain; Cholinergic Agents; Cholinesterase Inhibitors; Galantamine; Humans; Longevity; Mental Disorders; Neurodegenerative Diseases
PubMed: 33219523
DOI: 10.1111/jnc.15243 -
ACS Chemical Neuroscience Feb 2019Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode... (Review)
Review
Alzheimer's disease (AD) is well-known as a severe neurodegeneration disease involving complicated etiologies, and cholinesterase inhibition remain the prevailing mode of clinical intervention in AD management. Although most clinically applied cholinesterase inhibitors (ChEIs) achieve limited clinical outcomes, research on the central cholinergic system is still thriving. Recently, an impressive amount of knowledge regarding novel acetylcholinesterase functions, as well as the close association between the central cholinergic system and other key elements for AD pathogenesis, has accumulated, highlighting that this field still has great potential for future drug development. In contrast to the overwhelmingly disappointing clinical therapeutic effects of various disease-modifying drug candidates, interesting evidence has continued to emerge over the past 20 years from the wealth of preclinical and clinical data on the usage of ChEIs, indicating underestimated clinical benefits due to physician ambivalence, a lack of persistent treatment, and inappropriate medication times or doses. Here we pinpoint several topics fit for future attention, focusing on the updated cholinergic hypothesis, especially the pleiotropic relationships with key pathogenetic signaling pathways and functions in AD, as well as possible novel therapeutic strategies, including novel ChEIs and cholinesterase inhibition-based innovative multifunctional therapeutic candidates. We intend to strengthen the future value of the precise application of cholinergic drugs, especially novel ChEIs, as a cornerstone pharmacological approach to AD treatment, either alone or in combination with other targets, to relieve symptoms and to modify disease progression.
Topics: Acetylcholinesterase; Alzheimer Disease; Animals; Cholinergic Agents; Cholinesterase Inhibitors; Drug Development; Humans
PubMed: 30521323
DOI: 10.1021/acschemneuro.8b00391 -
Neuroscience Feb 2021Long-term changes in synaptic transmission between neurons in the brain are considered the cellular basis of learning and memory. Over the last few decades, many studies... (Review)
Review
Long-term changes in synaptic transmission between neurons in the brain are considered the cellular basis of learning and memory. Over the last few decades, many studies have revealed that the precise order and timing of activity between pre- and post-synaptic cells ("spike-timing-dependent plasticity; STDP") is crucial for the sign and magnitude of long-term changes at many central synapses. Acetylcholine (ACh) via the recruitment of diverse muscarinic receptors is known to influence STDP in a variety of ways, enabling flexibility and adaptability in brain network activity during complex behaviors. In this review, we will summarize and discuss different mechanistic aspects of muscarinic modulation of timing-dependent plasticity at both excitatory and inhibitory synapses in the hippocampus to shape learning and memory.
Topics: Action Potentials; Cholinergic Agents; Hippocampus; Neuronal Plasticity; Synapses; Synaptic Transmission
PubMed: 32828940
DOI: 10.1016/j.neuroscience.2020.08.015 -
Behavioural Brain Research Feb 2023Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events....
Evidence has demonstrated the hippocampal cholinergic system and the mammalian target of rapamycin (mTOR) participation during the memory formation of aversive events. This study assessed the role of these systems in the hippocampus for the extinction memory process by submitting male Wistar rats to fear-motivated step-down inhibitory avoidance (IA). The post-extinction session administration of the nicotinic and muscarinic cholinergic receptor antagonists, mecamylamine and scopolamine, respectively, both at doses of 2 µg/µl/side, and rapamycin, an mTOR inhibitor (0.02 µg/µl/side), into the CA1 region of the dorsal hippocampus, impaired the IA extinction memory. Furthermore, the nicotinic and muscarinic cholinergic receptor agonists, nicotine and muscarine, respectively, had a dose-dependent effect on the IA extinction memory when administered intra-CA1, immediately after the extinction session. Nicotine (0.6 µg/µl/side) and muscarine (0.02 µg/µl/side), respectively, had no effect, while the higher doses (6 and 2 µg/µl/side, respectively) impaired the IA extinction memory. Interestingly, the co-administration of muscarine at the lower dose blocked the impairment that was induced by rapamycin. This effect was not observed when nicotine at the lower dose was co-administered. These results have demonstrated the participation of the cholinergic receptors and mTOR in the hippocampus for IA extinction, and that the cholinergic agonists had a dose-dependent effect on the IA extinction memory. This study provides insights related to the behavioural aspects and the neurobiological properties underlying the early stage of fear-motivated IA extinction memory consolidation and suggests that there is hippocampal muscarinic receptor participation independent of mTOR in this memory process.
Topics: Animals; Male; Rats; Avoidance Learning; Fear; Hippocampus; Muscarine; Muscarinic Antagonists; Nicotine; Rats, Wistar; Receptors, Cholinergic; Sirolimus; TOR Serine-Threonine Kinases; Extinction, Psychological; Memory
PubMed: 36179804
DOI: 10.1016/j.bbr.2022.114129 -
CNS Drugs Nov 2018Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is... (Review)
Review
Opioid overdoses recently became the leading cause of accidental death in the US, marking an increase in the severity of the opioid use disorder (OUD) epidemic that is impacting global health. Current treatment protocols for OUD are limited to opioid medications, including methadone, buprenorphine, and naltrexone. While these medications are effective in many cases, new treatments are required to more effectively address the rising societal and interpersonal costs associated with OUD. In this article, we review the opioid and cholinergic systems, and examine the potential of acetylcholine (ACh) as a treatment target for OUD. The cholinergic system includes enzymes that synthesize and degrade ACh and receptors that mediate the effects of ACh. ACh is involved in many central nervous system functions that are critical to the development and maintenance of OUD, such as reward and cognition. Medications that target the cholinergic system have been approved for the treatment of Alzheimer's disease, tobacco use disorder, and nausea. Clinical and preclinical studies suggest that medications such as cholinesterase inhibitors and scopolamine, which target components of the cholinergic system, show promise for the treatment of OUD and further investigations are warranted.
Topics: Acetylcholine; Analgesics, Opioid; Animals; Cholinergic Agents; Humans; Non-Neuronal Cholinergic System; Opioid-Related Disorders
PubMed: 30259415
DOI: 10.1007/s40263-018-0572-y -
International Immunopharmacology Jun 2020Acetylcholine (ACh) was created by nature as one of the first signaling molecules, expressed already in procaryotes. Based on the positively charged nitrogen, ACh could... (Review)
Review
Acetylcholine (ACh) was created by nature as one of the first signaling molecules, expressed already in procaryotes. Based on the positively charged nitrogen, ACh could initially mediate signaling in the absence of receptors. When evolution established more and more complex organisms the new emerging organs systems, like the smooth and skeletal muscle systems, energy-generating systems, sexual reproductive system, immune system and the nervous system have further optimized the cholinergic signaling machinery. Thus, it is not surprising that ACh and the cholinergic system are expressed in the vast majority of cells. Consequently, multiple common interfaces exist, for example, between the nervous and the immune system. Research of the last 20 years has unmasked these multiple regulating mechanisms mediated by cholinergic signaling and thus, the biological role of ACh has been revised. The present article summarizes new findings and describes the role of both non-neuronal and neuronal ACh in protecting the organism from external and internal health threats, in providing energy for the whole organism and for the individual cell, controling immune functions to prevent inflammatory dysbalance, and finally, the involvement in critical brain functions, such as learning and memory. All these capacities of ACh enable the organism to attain and maintain homeostasis under changing external conditions. However, the existence of identical interfaces between all these different organ systems complicates the research for new therapeutic interventions, making it essential that every effort should be undertaken to find out more specific targets to modulate cholinergic signaling in different diseases.
Topics: Animals; Cholinergic Agents; Homeostasis; Humans; Immune System; Immunity; Immunologic Factors; Learning; Memory; Signal Transduction
PubMed: 32203906
DOI: 10.1016/j.intimp.2020.106345 -
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