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International Journal of Molecular... Apr 2022Organophosphorus pesticides (OPs) are widespread insecticides used for pest control in agricultural activities and the control of the vectors of human and animal... (Review)
Review
Organophosphorus pesticides (OPs) are widespread insecticides used for pest control in agricultural activities and the control of the vectors of human and animal diseases. However, OPs' neurotoxic mechanism involves cholinergic components, which, beyond being involved in the transmission of neuronal signals, also influence the activity of cytokines and other pro-inflammatory molecules; thus, acute and chronic exposure to OPs may be related to the development of chronic degenerative pathologies and other inflammatory diseases. The present article reviews and discusses the experimental evidence linking inflammatory process with OP-induced cholinergic dysregulation, emphasizing the molecular mechanisms related to the role of cytokines and cellular alterations in humans and other animal models, and possible therapeutic targets to inhibit inflammation.
Topics: Animals; Cholinergic Agents; Cytokines; Inflammation; Organophosphorus Compounds; Pesticides
PubMed: 35562914
DOI: 10.3390/ijms23094523 -
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 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 -
Asia-Pacific Journal of Ophthalmology... 2016Glaucoma comprises a group of progressive, neurodegenerative disorders characterized by retinal ganglion cell death and nerve fiber layer atrophy. Several randomized... (Review)
Review
Glaucoma comprises a group of progressive, neurodegenerative disorders characterized by retinal ganglion cell death and nerve fiber layer atrophy. Several randomized controlled trials have consistently demonstrated the efficacy of intraocular pressure lowering to slow or halt the measurable progression of the disease. Medical therapy, in places where it is easily accessible, is often the primary method to lower intraocular pressure. We review the medical options currently available and possible future options currently in development. The 5 contemporary classes of topical agents in use include prostaglandin analogs, beta blockers, carbonic anhydrase inhibitors, alpha agonists, and cholinergics. In addition, several fixed combination agents are commercially available. Agents from each of these classes have unique mechanisms of action, adverse effects, and other characteristics that impact how they are used in clinical practice. Despite the plethora of medical options available, there are limitations to topical ophthalmic therapy such as the high rate of noncompliance and local and systemic adverse effects. Alternate and sustained drug delivery models, such as injectable agents and punctal plug delivery systems, may in the future alleviate some such concerns and lead to increased efficacy of treatment while minimizing adverse effects.
Topics: Adrenergic alpha-Agonists; Adrenergic beta-Antagonists; Antihypertensive Agents; Carbonic Anhydrase Inhibitors; Cholinergic Agents; Clinical Trials as Topic; Drug Therapy, Combination; Glaucoma, Open-Angle; Humans; Prostaglandins, Synthetic
PubMed: 26886120
DOI: 10.1097/APO.0000000000000181 -
Journal of Neurochemistry Aug 2017Deciphering neuronal pathways that reactivate spinal central pattern generators (CPGs) and modulate the activity of spinal motoneurons in mammals in the absence of... (Review)
Review
Deciphering neuronal pathways that reactivate spinal central pattern generators (CPGs) and modulate the activity of spinal motoneurons in mammals in the absence of supraspinal control is important for understanding of neural control of movement and for developing novel therapeutic approaches to improve the mobility of spinal cord injury patients. Previously, we showed that the sacral and lumbar cholinergic system could potently modulate the locomotor CPGs in newborn rodents. Here, we review these and our more recent studies of sacral relay neurons with lumbar projections to the locomotor CPGs and to lumbar motoneurons and demonstrate that sacral and lumbar cholinergic components have the capacity to control the frequency of the locomotor CPGs and at the same time the motor output of the activated lumbar motoneurons during motor behavior. A model describing the suggested ascending sacro-lumbar connectivity involved in modulation of the locomotor rhythm by sacral cholinergic components is proposed and discussed. This is an article for the special issue XVth International Symposium on Cholinergic Mechanisms.
Topics: Acetylcholine; Animals; Cholinergic Agents; Humans; Locomotion; Lumbar Vertebrae; Motor Activity; Motor Neurons
PubMed: 28791705
DOI: 10.1111/jnc.14065 -
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 -
American Journal of Physiology. Heart... Nov 2022Cognitive decline is linked to decreased cerebral blood flow, particularly in women after menopause. Impaired cerebrovascular function precedes the onset of dementia,...
Cognitive decline is linked to decreased cerebral blood flow, particularly in women after menopause. Impaired cerebrovascular function precedes the onset of dementia, possibly because of reduced functional dilation in parenchymal arterioles. These vessels are bottlenecks of the cerebral microcirculation, and dysfunction can limit functional hyperemia in the brain. Large-conductance Ca-activated K channels (BK) are the final effectors of several pathways responsible for functional hyperemia, and their expression is modulated by estrogen. However, it remains unknown whether BK function is altered in cerebral parenchymal arterioles after menopause. Using a chemically induced model of menopause, the 4-vinylcyclohexene diepoxide (VCD) model, which depletes follicles while maintaining intact ovaries, we hypothesized that menopause would be associated with reduced functional vasodilatory responses in cerebral parenchymal arterioles of wild-type mice via reduced BK function. Using pressure myography of isolated parenchymal arterioles, we observed that menopause (Meno) induced a significant increase in spontaneous myogenic tone. Endothelial function, assessed as nitric oxide production and dilation after cholinergic stimulation or endothelium-dependent hyperpolarization pathways, was unaffected by Meno. BK function was significantly impaired in Meno compared with control, without changes in voltage-gated K channel activity. Cerebral functional hyperemia, measured by laser-speckle contrast imaging during whisker stimulation, was significantly blunted in Meno mice, without detectable changes in basal perfusion. However, behavioral testing identified no change in cognition. These findings suggest that menopause induces cerebral microvascular and neurovascular deficits. Cerebral parenchymal arterioles from menopause mice showed increased myogenic tone. We identified an impairment in smooth muscle cell BK channel activity, without a reduction in endothelium-dependent dilation or nitric oxide production. Microvascular dysfunction was associated with a reduction in neurovascular responses after somatosensory stimulation. Despite the neurovascular impairment, cognitive abilities were maintained in menopausal mice.
Topics: Animals; Arterioles; Cerebrovascular Disorders; Cholinergic Agents; Estrogens; Female; Hyperemia; Menopause; Mice; Nitric Oxide
PubMed: 36149767
DOI: 10.1152/ajpheart.00276.2022 -
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 -
Pharmacological Research Mar 2017Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics,... (Review)
Review
Sepsis is one of the main causes of mortality in hospitalized patients. Despite the recent technical advances and the development of novel generation of antibiotics, severe sepsis remains a major clinical and scientific challenge in modern medicine. Unsuccessful efforts have been dedicated to the search of therapeutic options to treat the deleterious inflammatory components of sepsis. Recent findings on neuronal networks controlling immunity raised expectations for novel therapeutic strategies to promote the regulation of sterile inflammation, such as autoimmune diseases. Interesting studies have dissected the anatomical constituents of the so-called "cholinergic anti-inflammatory pathway", suggesting that electrical vagus nerve stimulation and pharmacological activation of beta-2 adrenergic and alpha-7 nicotinic receptors could be alternative strategies for improving inflammatory conditions. However, the literature on infectious diseases, such as sepsis, is still controversial and, therefore, the real therapeutic potential of this neuroimmune pathway is not well defined. In this review, we will discuss the beneficial and detrimental effects of neural manipulation in sepsis, which depend on the multiple variables of the immune system and the nature of the infection. These observations suggest future critical studies to validate the clinical implications of vagal parasympathetic signaling in sepsis treatment.
Topics: Animals; Anti-Inflammatory Agents; Cholinergic Agents; Humans; Immune System; Inflammation; Sepsis; Signal Transduction; Vagus Nerve
PubMed: 27979692
DOI: 10.1016/j.phrs.2016.12.014 -
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