Monoamine uptake inhibitors block α7-nAChR-mediated cerebral nitrergic neurogenic vasodilation

2006 ◽  
Vol 291 (1) ◽  
pp. H202-H209 ◽  
Author(s):  
Cheng Long ◽  
Mei-Fang Chen ◽  
Susan J. Sarwinski ◽  
Po-Yi Chen ◽  
Minliang Si ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Sympathetic Neurons ◽  
Monoamine Uptake ◽  
Uptake Inhibitors ◽  
Α7 Nachr ◽  
Inward Currents ◽  
Monoamine Uptake Inhibitors ◽  
Α7 Nachrs ◽  
Neurogenic Vasodilation

We have proposed that activation of cerebral perivascular sympathetic α7-nicotinic acetylcholine receptors (α7-nAChRs) by nicotinic agonists releases norepinephrine, which then acts on parasympathetic nitrergic nerves, resulting in release of nitric oxide and vasodilation. Using patch-clamp electrophysiology, immunohistochemistry, and in vitro tissue bath myography, we tested this axo-axonal interaction hypothesis further by examining whether blocking norepinephrine reuptake enhanced α7-nAChR-mediated cerebral nitrergic neurogenic vasodilation. The results indicated that choline- and nicotine-induced α7-nAChR-mediated nitrergic neurogenic relaxation in endothelium-denuded isolated porcine basilar artery rings was enhanced by desipramine and imipramine at lower concentrations (0.03–0.1 μM) but inhibited at higher concentrations (0.3–10 μM). In cultured superior cervical ganglion (SCG) neurons of the pig and rat, choline (0.1–30 mM)-evoked inward currents were reversibly blocked by 1–30 μM mecamylamine, 1–30 μM methyllycaconitine, 10–300 nM α-bungarotoxin, and 0.1–10 μM desipramine and imipramine, providing electrophysiological evidence for the presence of similar functional α7-nAChRs in cerebral perivascular sympathetic neurons of pigs and rats. In α7-nAChR-expressing Xenopus oocytes, choline-elicited inward currents were attenuated by α-bungarotoxin, imipramine, and desipramine. These monoamine uptake inhibitors appeared to directly block the α7-nAChR, resulting in diminished nicotinic agonist-induced cerebral nitrergic vasodilation. The enhanced nitrergic vasodilation by lower concentrations of monoamine uptake inhibitors is likely due to a greater effect on monoamine uptake than on α7-nAChR blockade. These results further support the hypothesis of axo-axonal interaction in nitrergic regulation of cerebral vascular tone.

scholarly journals Statins Prevent β-Amyloid Inhibition of Sympathetic α7-nAChR-Mediated Nitrergic Neurogenic Dilation in Porcine Basilar Arteries

2005 ◽  
Vol 25 (12) ◽  
pp. 1573-1585 ◽  
Author(s):  
Min-Liang Si ◽  
Chen Long ◽  
Ding-I Yang ◽  
Mei-Fang Chen ◽  
Tony Jer-Fu Lee
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Early Phase ◽  
Calcium Influx ◽  
Cerebral Hypoperfusion ◽  
Α7 Nachr ◽  
Inward Currents ◽  
Basilar Arteries ◽  
Β Amyloid ◽  
Α7 Nachrs

The exact mechanism underlying regional cerebral hypoperfusion in the early phase of Alzheimer's disease (AD) is not understood. We have shown in isolated porcine cerebral arteries that stimulation of sympathetic α7-nicotinic acetylcholine receptors (α7-nAChRs) causes release of nitric oxide in parasympathetic nitrergic nerves and vasodilation. We therefore examined if β-amyloid peptides (Aβs), which play a key role in pathogenesis of AD, blocked sympathetic α7-nAChRs leading to reduced neurogenic nitrergic dilation in isolated porcine basilar arteries, using in vitro tissue bath, calcium image, and patch clamping techniques. The results indicated that Aβ1–40, but not Aβ40–1, blocked relaxation of endothelium-denuded basilar arterial rings induced by nicotine (100μ;mol/L) and choline (1 mmol/L) without affecting that induced by sodium nitroprusside or isoproterenol. In cultured superior cervical ganglion (SCG) cells, Aβ1–40, but not Aβ40–1, blocked choline- and nicotine-induced calcium influx and inward currents. The Aβ blockade of the nitrergic vasodilation and inward currents, but not that of calcium influx, was prevented by acute pretreatment with 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors mevastatin and lovastatin. These results suggest that Aβ1–40 blocks cerebral perivascular sympathetic α7-nAChRs, resulting in the attenuation of cerebral nitrergic neurogenic vasodilation. This effect of Aβ may be responsible in part for cerebral hypoperfusion occurred in the early phase of the AD, which may be prevented by statins most likely because of their effects independent of cholesterol lowering. Statins may offer an alternative strategy in the prevention and treatment of AD.

scholarly journals APS8 Delays Tumor Growth in Mice by Inducing Apoptosis of Lung Adenocarcinoma Cells Expressing High Number of α7 Nicotinic Receptors

Marine Drugs ◽  
2018 ◽  
Vol 16 (10) ◽  
pp. 367
Author(s):  
Sabina Berne ◽  
Maja Čemažar ◽  
Robert Frangež ◽  
Polona Juntes ◽  
Simona Kranjc ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
A549 Cells ◽  
Lung Fibroblasts ◽  
Normal Lung ◽  
Dependent Manner ◽  
Α7 Nachr ◽  
Α7 Nachrs

The alkylpyridinium polymer APS8, a potent antagonist of α7 nicotinic acetylcholine receptors (nAChRs), selectively induces apoptosis in non-small cell lung cancer cells but not in normal lung fibroblasts. To explore the potential therapeutic value of APS8 for at least certain types of lung cancer, we determined its systemic and organ-specific toxicity in mice, evaluated its antitumor activity against adenocarcinoma xenograft models, and examined the in-vitro mechanisms of APS8 in terms of apoptosis, cytotoxicity, and viability. We also measured Ca2+ influx into cells, and evaluated the effects of APS8 on Ca2+ uptake while siRNA silencing of the gene for α7 nAChRs, CHRNA7. APS8 was not toxic to mice up to 5 mg/kg i.v., and no significant histological changes were observed in mice that survived APS8 treatment. Repetitive intratumoral injections of APS8 (4 mg/kg) significantly delayed growth of A549 cell tumors, and generally prevented regrowth of tumors, but were less effective in reducing growth of HT29 cell tumors. APS8 impaired the viability of A549 cells in a dose-dependent manner and induced apoptosis at micro molar concentrations. Nano molar APS8 caused minor cytotoxic effects, while cell lysis occurred at APS8 >3 µM. Furthermore, Ca2+ uptake was significantly reduced in APS8-treated A549 cells. Observed differences in response to APS8 can be attributed to the number of α7 nAChRs expressed in these cells, with those with more AChRs (i.e., A549 cells) being more sensitive to nAChR antagonists like APS8. We conclude that α7 nAChR antagonists like APS8 have potential to be used as therapeutics for tumors expressing large numbers of α7 nAChRs.

In Vitro Effects of Cocaine, Lidoce and Monoamine Uptake Inhibitors On Lymphocyte Proliferative Responses

1994 ◽  
Vol 16 (2) ◽  
pp. 165-178 ◽  
Author(s):  
Michele B. Berkeley ◽  
Sandra Daussin ◽  
Monica C. Hernandez ◽  
Barbara M. Bayer
Keyword(s):  
Monoamine Uptake ◽  
Uptake Inhibitors ◽  
In Vitro Effects ◽  
Monoamine Uptake Inhibitors

scholarly journals Curcumin Potentiates α7 Nicotinic Acetylcholine Receptors and Alleviates Autistic-Like Social Deficits and Brain Oxidative Stress Status in Mice

2021 ◽  
Vol 22 (14) ◽  
pp. 7251
Author(s):  
Petrilla Jayaprakash ◽  
Dmytro Isaev ◽  
Waheed Shabbir ◽  
Dietrich E. Lorke ◽  
Bassem Sadek ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Pathological Condition ◽  
Repetitive Behaviors ◽  
Social Deficits ◽  
Nicotinic Acetylcholine ◽  
Oxidative Stress Status ◽  
Inward Currents ◽  
Α7 Nachrs

Autistic spectrum disorder (ASD) refers to a group of neurodevelopmental disorders characterized by impaired social interaction and cognitive deficit, restricted repetitive behaviors, altered immune responses, and imbalanced oxidative stress status. In recent years, there has been a growing interest in studying the role of nicotinic acetylcholine receptors (nAChRs), specifically α7-nAChRs, in the CNS. Influence of agonists for α7-nAChRs on the cognitive behavior, learning, and memory formation has been demonstrated in neuro-pathological condition such as ASD and attention-deficit hyperactivity disorder (ADHD). Curcumin (CUR), the active compound of the spice turmeric, has been shown to act as a positive allosteric modulator of α7-nAChRs. Here we hypothesize that CUR, acting through α7-nAChRs, influences the neuropathology of ASD. In patch clamp studies, fast inward currents activated by choline, a selective agonist of α7-nAChRs, were significantly potentiated by CUR. Moreover, choline induced enhancement of spontaneous inhibitory postsynaptic currents was markedly increased in the presence of CUR. Furthermore, CUR (25, 50, and 100 mg/kg, i.p.) ameliorated dose-dependent social deficits without affecting locomotor activity or anxiety-like behaviors of tested male Black and Tan BRachyury (BTBR) mice. In addition, CUR (50 and 100 mg/kg, i.p.) mitigated oxidative stress status by restoring the decreased levels of superoxide dismutase (SOD) and catalase (CAT) in the hippocampus and the cerebellum of treated mice. Collectively, the observed results indicate that CUR potentiates α7-nAChRs in native central nervous system neurons, mitigates disturbed oxidative stress, and alleviates ASD-like features in BTBR mice used as an idiopathic rodent model of ASD, and may represent a promising novel pharmacological strategy for ASD treatment.

Triple monoamine uptake inhibitors

2012 ◽  
Vol 1 (4) ◽  
pp. 469-481 ◽  
Author(s):  
Anna Maria Capelli ◽  
Fabrizio Micheli
Keyword(s):  
Monoamine Uptake ◽  
Uptake Inhibitors ◽  
Monoamine Uptake Inhibitors

scholarly journals Tonic engagement of nicotinic receptors bidirectionally controls striatal spiny projection neuron spike timing

2021 ◽  
Author(s):  
Lior Matityahu ◽  
Jeffrey Malgady ◽  
Meital Schirelman ◽  
Yvonne Johansson ◽  
Jennifer Wilking ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Gaba Release ◽  
Projection Neuron ◽  
Spike Timing ◽  
Projection Neurons ◽  
Striatal Slices ◽  
Cholinergic Interneurons ◽  
Α7 Nachr ◽  
Α7 Nachrs

Striatal spiny projection neurons (SPNs) transform convergent excitatory corticostriatal inputs into an inhibitory signal that shapes basal ganglia output. This process is fine-tuned by striatal GABAergic interneurons (GINs), which receive overlapping cortical inputs and mediate rapid corticostriatal feedforward inhibition of SPNs. Adding another level of control, cholinergic interneurons (CINs), which are also vigorously activated by corticostriatal excitation, can 1) disynaptically inhibit SPNs by activating α4β2 nicotinic acetylcholine receptors (nAChRs) on various GINs and 2) directly modulate corticostriatal synaptic strength via pre-synaptic α7 nAChR receptors. Measurements of the disynaptic inhibitory pathway, however, indicate that it is too slow to compete with direct GIN-mediated feed-forward inhibition. Moreover, functional nAChRs are also present on populations of GINs that do not respond to phasic activation of CINs, such as parvalbumin-positive fast-spiking interneurons (PV-FSIs), making the overall role of nAChRs in shaping striatal synaptic integration unclear. Using acute striatal slices we show that upon synchronous optogenetic activation of corticostriatal projections, blockade of α7 nAChRs delayed SPN spikes, whereas blockade of α4β2 nAChRs advanced SPN spikes and increased postsynaptic depolarizations. The nAChR-dependent inhibition was mediated by downstream GABA release, and data suggest that the GABA source was not limited to GINs that respond to phasic CIN activation. In particular, the observed spike-advancement caused by nAChR blockade was associated with a diminished frequency of spontaneous inhibitory postsynaptic currents in SPNs, and a parallel hyperpolarization of PV-FSIs. Taken together, we describe opposing roles for tonic (as opposed to phasic) engagement of nAChRs in striatal function. We conclude that tonic activation of nAChRs by CINs both sharpens the temporal fidelity of corticostriatal signaling via pre-synaptic α7 nAChRs and maintains a GABAergic brake on cortically-driven striatal output, processes that may shape SPN spike timing, striatal processing and synaptic plasticity.

Effects of monoamine uptake inhibitors on pain-related depression of nesting in mice

2019 ◽  
Vol 30 (6) ◽  
pp. 463-470
Author(s):  
Khadijah S. Alexander ◽  
Taylor R. Rodriguez ◽  
Amma N. Sarfo ◽  
Tadd B. Patton ◽  
Laurence L. Miller
Keyword(s):  
Monoamine Uptake ◽  
Uptake Inhibitors ◽  
Monoamine Uptake Inhibitors

scholarly journals Type I-like behavior of the type II α7 nicotinic acetylcholine receptor positive allosteric modulator A-867744

PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e7542 ◽  
Author(s):  
Krisztina Pesti ◽  
Peter Lukacs ◽  
Arpad Mike
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Single Channel ◽  
High Temporal Resolution ◽  
Type I ◽  
Type Ii ◽  
Nicotinic Acetylcholine ◽  
Fast Kinetics ◽  
Temporal Precision ◽  
Α7 Nachr ◽  
Α7 Nachrs

Cognitive impairment often involves the decreased expression or hypofunction of alpha 7-type nicotinic acetylcholine receptors (α7 nAChRs). Agonists or positive allosteric modulators (PAMs) of α7 nAChRs are known to be potential treatments for dementias, different neurodegenerative disorders, pain syndromes and conditions involving inflammation. In some of these conditions, it is desirable to maintain the temporal precision of fast cholinergic events, while in others, this temporal precision is unnecessary. For this reason, the optimal therapeutic effect for distinct indications may require PAMs with different mechanisms of action. The two major mechanisms are called “type I”, which are compounds that augment α7 nAChR-mediated currents but maintain their characteristic fast kinetics; and “type II”, which are compounds that produce augmented and prolonged currents. In this study, we performed a kinetic analysis of two type II PAMs of the α7 nAChR: PNU-120596 and A-867744, using a fast perfusion method that allowed high temporal resolution. We characterized the type of modulation produced by the two compounds, the state-dependence of the modulatory action, and the interaction between the two compounds. We found fundamental differences between the modulation mechanisms by PNU-120596 and A-867744. Most importantly, during brief agonist pulses, A-867744 caused a strikingly type I-like modulation, while PNU-120596 caused a type II-like prolonged activation. Our results demonstrate that specific compounds, even though all labeled as type II PAMs, can behave in completely different ways, including their onset and offset kinetics, state preference, and single channel open time. Our results emphasize that subtle details of the mechanism of action may be significant in assessing the therapeutic applicability of α7 nAChR PAM compounds.

scholarly journals A Pharmacological Comparison of Two Isomeric Nicotinic Receptor Agonists: The Marine Toxin Isoanatabine and the Tobacco Alkaloid Anatabine

Marine Drugs ◽  
2020 ◽  
Vol 18 (2) ◽  
pp. 106 ◽  
Author(s):  
Hong Xing ◽  
Sunil Keshwah ◽  
Anne Rouchaud ◽  
William R. Kem
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Radioligand Binding ◽  
Partial Agonist ◽  
Secondary Compounds ◽  
Piperidine Ring ◽  
Medical Disorders ◽  
In Vitro Investigation ◽  
Α7 Nachrs

Many organisms possess “secondary” compounds to avoid consumption or to immobilize prey. While the most abundant or active compounds are initially investigated, more extensive analyses reveal other “minor” compounds with distinctive properties that may also be of biomedical and pharmaceutical significance. Here, we present an initial in vitro investigation of the actions of two isomeric tetrahydropyridyl ring-containing anabasine analogs: isoanatabine, an alkaloid isolated from a marine worm, and anatabine, a relatively abundant minor alkaloid in commercial tobacco plants. Both compounds have a double bond that is distal to the piperidine ring nitrogen of anabasine. Racemic isoanatabine and anatabine were synthesized and their S- and R-enantiomers were isolated by chiral high pressure liquid chromatography (HPLC). Both isoanatabines displayed higher efficacies at α4β2 nicotinic acetylcholine receptors (nAChRs) relative to the anatabines; R-isoanatabine was most potent. Radioligand binding experiments revealed similar α4β2 nAChR binding affinities for the isoanatabines, but R-anatabine affinity was twice that of S-anatabine. While the two anatabines and S-isoanatabine were highly efficacious agonists at α7 nAChRs, R-isoanatabine was only a weak partial agonist. The four compounds share an ability to stimulate both α4β2 and α7 nAChRs, a property that may be useful in developing more efficacious drugs to treat neurodegenerative and other medical disorders.

Effect of monoamine uptake inhibitors on norepinephrine-stimulated phosphatidylinositol hydrolysis in rat cortex

1989 ◽  
Vol 38 (2) ◽  
pp. 257-262 ◽  
Author(s):  
Mahmood Mosaddeghi ◽  
Joseph M. Moerschbaecher ◽  
Rueben A. Gonzales
Keyword(s):  
Rat Cortex ◽  
Monoamine Uptake ◽  
Uptake Inhibitors ◽  
Monoamine Uptake Inhibitors
Sign in / Sign up

Export Citation Format

Share Document