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Journal of the Neurological Sciences Sep 2018Multiple sclerosis (MS) commonly affects young adults and leads to a decreased quality of life due to different signs and symptoms that induce physical, cognitive,... (Review)
Review
Multiple sclerosis (MS) commonly affects young adults and leads to a decreased quality of life due to different signs and symptoms that induce physical, cognitive, social, and psychological challenges. This disease, an autoimmune neurological disorder, is characterized by chronic inflammatory demyelination and axonal degeneration of the central nervous system (CNS). To date, its etiology is unknown. A large number of physiological functions are regulated by the cholinergic system because the acetylcholine (ACh) is released from cholinergic neurons and acts on other neurons, most of them not cholinergic in the brain, as well as in various nonneuronal cells, such as those of the immune system and blood; thus, it is considered an important modulatory pathway of both the central and peripheral nervous systems. Furthermore, the purinergic system has a significant role in neurotransmission as well as immune and inflammatory responses. Accumulating evidence has suggested the presence of a strong association between these systems and MS. Therefore, this review aims to present and discuss the main mechanisms that potentially explain the influence of the cholinergic and purinergic systems in multiple sclerosis. These mechanisms are discussed in light of available scientific evidence in humans and animal experimental models of MS. We hope that this review provides a better understanding of this subject, helping to guide future research and potential novel therapeutic strategies for patients with MS.
Topics: Acetylcholine; Animals; Humans; Multiple Sclerosis; Purines; Signal Transduction
PubMed: 30097157
DOI: 10.1016/j.jns.2018.06.020 -
Journal of Neurophysiology May 2023Many behaviors and types of information storage are mediated by lengthy changes in neuronal activity. In bag cell neurons of the hermaphroditic sea snail , a transient...
Many behaviors and types of information storage are mediated by lengthy changes in neuronal activity. In bag cell neurons of the hermaphroditic sea snail , a transient cholinergic synaptic input triggers an ∼30-min afterdischarge. This causes these neuroendocrine cells to release egg laying hormone and elicit reproductive behavior. When acetylcholine is pressure-ejected onto a current-clamped bag cell neuron, the evoked depolarization is far longer than the current evoked by acetylcholine under voltage clamp, suggesting recruitment of another conductance. Our earlier studies found bag cell neurons to display a voltage-dependent persistent Ca current. Hence, we hypothesized that this current is activated by the acetylcholine-induced depolarization and sought a selective Ca current blocker. Rapid Ca current evoked by 200-ms depolarizing steps in voltage-clamped cultured bag cell neurons demonstrated a concentration-dependent sensitivity to Ni, Co, Zn, and verapamil but not Cd or ω-conotoxin GIVa. Leak subtraction of Ca current evoked by 10-s depolarizing steps using the IC (concentration required to eliminate maximal current) of Ni, Co, Zn, or verapamil revealed persistent Ca current, demonstrating persistent current block. Only Co and Zn did not suppress the acetylcholine-induced current, although Zn appeared to impact additional channels. When Co was applied during an acetylcholine-induced depolarization, the amplitude was reduced; furthermore, protein kinase C activation, previously established to enhance the persistent Ca current, extended the depolarization. Therefore, the persistent Ca current sustains the acetylcholine-induced depolarization and may translate brief cholinergic input into afterdischarge initiation. This could be a general mechanism of triggering long-term change in activity with a short-lived input. Ionotropic acetylcholine receptors mediate brief synaptic communication, including in bag cell neurons of the sea snail . However, this study demonstrates that cholinergic depolarization can open a voltage-gated persistent Ca current, which extends the bag cell neuron response to acetylcholine. Bursting in these neuroendocrine cells results in hormone release and egg laying. Thus, this emphasizes the role of ionotropic signaling in reaching a depolarized level to engage Ca influx and perpetuating the activity necessary for behavior.
Topics: Animals; Aplysia; Acetylcholine; Neurons; Cholinergic Agents; Verapamil; Hormones; Calcium
PubMed: 36988203
DOI: 10.1152/jn.00429.2022 -
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 -
Drug Discovery Today Jan 2017Acetylcholine, a major neurotransmitter of the parasympathetic and sympathetic nervous systems, was discovered in the early 1900s. Over the years, researchers have... (Review)
Review
Acetylcholine, a major neurotransmitter of the parasympathetic and sympathetic nervous systems, was discovered in the early 1900s. Over the years, researchers have revealed much about its regulation, properties of its receptors and features of the downstream signaling that influence its terminal effects. The acetylcholine system, traditionally associated with neuromuscular communication, is now known to play a crucial part in modulation of the immune system and other 'rest and digest' effects. Recent research seeks to elucidate the system's role in brain functions including cognition, sleep, arousal, motivation, reward and pain. We highlight clinically approved and experimental drugs that modulate the acetylcholine receptors. The complexities in targeting the acetylcholine receptors are vast and finding future indications for drug development associated with specific acetylcholine receptors remains a challenge.
Topics: Acetylcholine; Animals; Cholinergic Agonists; Cholinergic Antagonists; Drug Discovery; Humans; Ligands; Molecular Targeted Therapy; Receptors, Cholinergic; Signal Transduction
PubMed: 27666193
DOI: 10.1016/j.drudis.2016.09.011 -
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 -
The European Journal of Neuroscience Sep 2018Spatial learning, including encoding and retrieval of spatial memories as well as holding spatial information in working memory generally serving navigation under a... (Review)
Review
Spatial learning, including encoding and retrieval of spatial memories as well as holding spatial information in working memory generally serving navigation under a broad range of circumstances, relies on a network of structures. While central to this network are medial temporal lobe structures with a widely appreciated crucial function of the hippocampus, neocortical areas such as the posterior parietal cortex and the retrosplenial cortex also play essential roles. Since the hippocampus receives its main subcortical input from the medial septum of the basal forebrain (BF) cholinergic system, it is not surprising that the potential role of the septo-hippocampal pathway in spatial navigation has been investigated in many studies. Much less is known of the involvement in spatial cognition of the parallel projection system linking the posterior BF with neocortical areas. Here we review the current state of the art of the division of labour within this complex 'navigation system', with special focus on how subcortical cholinergic inputs may regulate various aspects of spatial learning, memory and navigation.
Topics: Acetylcholine; Animals; Cholinergic Agents; Hippocampus; Humans; Memory, Short-Term; Parietal Lobe; Spatial Learning; Spatial Memory; Spatial Navigation; Temporal Lobe
PubMed: 30055067
DOI: 10.1111/ejn.14089 -
Acta Physiologica (Oxford, England) Oct 2018Endothelium-dependent responses were first demonstrated 40 years ago in the aorta. Since then, extensive research has been conducted in vitro using conductance vessels... (Review)
Review
Endothelium-dependent responses were first demonstrated 40 years ago in the aorta. Since then, extensive research has been conducted in vitro using conductance vessels and materials derived from them. However, the microcirculation controls blood flow to vital organs and has been the focus of in vivo studies of endothelium-dependent dilation beginning immediately after the first in vitro report. Initial in vivo studies employed a light/dye technique for selectively damaging the endothelium to unequivocally prove, in vivo, the existence of endothelium-dependent dilation and in the microvasculature. Endothelium-dependent constriction was similarly proven. Endothelium-dependent agonists include acetylcholine (ACh), bradykinin, arachidonic acid, calcium ionophore A-23187, calcitonin gene-related peptide (CGRP), serotonin, histamine and endothelin-1. Normal and disease states have been studied. Endothelial nitric oxide synthase, cyclooxygenase and cytochrome P450 have been shown to generate the mediators of the responses. Some of the key enzyme systems generate reactive oxygen species (ROS) like superoxide which may prevent EDR. However, one ROS, namely H O , is one of a number of hyperpolarizing factors that cause dilation initiated by endothelium. Depending upon microvascular bed, a single agonist may use different pathways to elicit an endothelium-dependent response. Interpretation of studies using inhibitors of eNOS is complicated by the fact that these inhibitors may also inhibit ATP-sensitive potassium channels. Other in vivo observations of brain arterioles failed to establish nitric oxide as the mediator of responses elicited by CGRP or by ACh and suggest that a nitrosothiol may be a better fit for the latter.
Topics: Acetylcholine; Animals; Endothelium, Vascular; Microcirculation; Nitric Oxide; Vasoconstrictor Agents; Vasodilator Agents
PubMed: 29873936
DOI: 10.1111/apha.13111 -
American Journal of Physiology. Cell... Feb 2021The innate and adaptive immune systems play an important role in the development of cardiac diseases. Therefore, it has become critical to identify molecules that can... (Review)
Review
The innate and adaptive immune systems play an important role in the development of cardiac diseases. Therefore, it has become critical to identify molecules that can modulate inflammation in the injured heart. In this regard, activation of the cholinergic system in animal models of heart disease has been shown to exert protective actions that include immunomodulation of cardiac inflammation. In this mini-review, we briefly present our current understanding on the cardiac cellular sources of acetylcholine (ACh) (neuronal vs. nonneuronal), followed by a discussion on its contribution to the regulation of inflammatory cells. Although the mechanism behind ACh-mediated protection still remains to be fully elucidated, the beneficial immunomodulatory role of the cholinergic signaling emerges as a potential key regulator of cardiac inflammation.
Topics: Acetylcholine; Animals; Anti-Inflammatory Agents; Cardiotonic Agents; Heart; Heart Diseases; Humans; Inflammation; Neurons
PubMed: 33264077
DOI: 10.1152/ajpcell.00315.2020 -
Anesthesiology Apr 2021Cholinergic drugs are known to modulate general anesthesia, but anesthesia responses in acetylcholine-deficient mice have not been studied. It was hypothesized that mice...
BACKGROUND
Cholinergic drugs are known to modulate general anesthesia, but anesthesia responses in acetylcholine-deficient mice have not been studied. It was hypothesized that mice with genetic deficiency of forebrain acetylcholine show increased anesthetic sensitivity to isoflurane and ketamine and decreased gamma-frequency brain activity.
METHODS
Male adult mice with heterozygous knockdown of vesicular acetylcholine transporter in the brain or homozygous knockout of the transporter in the basal forebrain were compared with wild-type mice. Hippocampal and frontal cortical electrographic activity and righting reflex were studied in response to isoflurane and ketamine doses.
RESULTS
The loss-of-righting-reflex dose for isoflurane was lower in knockout (mean ± SD, 0.76 ± 0.08%, n = 18, P = 0.005) but not knockdown (0.78 ± 0.07%, n = 24, P = 0.021), as compared to wild-type mice (0.83 ± 0.07%, n = 23), using a significance criterion of P = 0.017 for three planned comparisons. Loss-of-righting-reflex dose for ketamine was lower in knockout (144 ± 39 mg/kg, n = 14, P = 0.006) but not knockdown (162 ± 32 mg/kg, n = 20, P = 0.602) as compared to wild-type mice (168 ± 24 mg/kg, n = 21). Hippocampal high-gamma (63 to 100 Hz) power after isoflurane was significantly lower in knockout and knockdown mice compared to wild-type mice (isoflurane-dose and mouse-group interaction effect, F[8,56] = 2.87, P = 0.010; n = 5 to 6 mice per group). Hippocampal high-gamma power after ketamine was significantly lower in both knockout and knockdown mice when compared to wild-type mice (interaction effect F[2,13] = 6.06, P = 0.014). The change in frontal cortical gamma power with isoflurane or ketamine was not statistically different among knockout, knockdown, and wild-type mice.
CONCLUSIONS
These findings suggest that forebrain cholinergic neurons modulate behavioral sensitivity and hippocampal gamma activity during isoflurane and ketamine anesthesia.
Topics: Acetylcholine; Anesthetics, Inhalation; Animals; Isoflurane; Ketamine; Male; Mice; Mice, Knockout; Models, Animal; Prosencephalon
PubMed: 33635947
DOI: 10.1097/ALN.0000000000003713 -
FEBS Letters Jul 2020Acetylcholine (ACh) signaling orchestrates mammalian movement, mental capacities, and inflammation. Dysregulated ACh signaling associates with many human mental... (Review)
Review
Acetylcholine (ACh) signaling orchestrates mammalian movement, mental capacities, and inflammation. Dysregulated ACh signaling associates with many human mental disorders and neurodegeneration in an individual-, sex-, and tissue-related manner. Moreover, aged patients under anticholinergic therapy show increased risk of dementia, but the underlying molecular mechanisms are incompletely understood. Here, we report that certain cholinergic-targeting noncoding RNAs, named Cholino-noncoding RNAs (ncRNAs), can modulate ACh signaling, agonistically or antagonistically, via distinct direct and indirect mechanisms and at different timescales. Cholino-ncRNAs include both small microRNAs (miRNAs) and long noncoding RNAs (lncRNAs). The former may attenuate translation and/or induce destruction of target mRNAs that code for either ACh-signaling proteins or transcription factors controlling the expression of cholinergic genes. lncRNAs may block miRNAs via 'sponging' events or by competitive binding to the cholinergic target mRNAs. Also, single nucleotide polymorphisms in either Cholino-ncRNAs or in their recognition sites in the ACh-signaling associated genes may modify ACh signaling-regulated processes. Taken together, both inherited and acquired changes in the function of Cholino-ncRNAs impact ACh-related deficiencies, opening new venues for individual, sex-related, and age-specific oriented research, diagnosis, and therapeutics.
Topics: Acetylcholine; Aging; Animals; Female; Humans; Male; RNA, Untranslated; Signal Transduction; Spatio-Temporal Analysis
PubMed: 32330292
DOI: 10.1002/1873-3468.13789