Selective Nicotinic Acetylcholine Receptor Agonist Research Articles

Activation of the Cholinergic Anti-inflammatory Pathway Attenuated Angiotension II-Dependent Hypertension and Renal Injury.

Background: Angiotensin II (AngII) induces renal fibrosis, characterized by fibroblast proliferation, inflammatory cell infiltration and excessive extracellular matrix deposition, all of which was relevant closely to hypertension. The vagus nerve-related cholinergic anti-inflammatory pathway (CAP) modulates local and systemic inflammatory responses. The aim of present study was to determine the effect of CAP on renal inflammation and fibrosis. Methods and Results: AngII-induced hypertension was induced in vivo by 14-days low-dose AngII infusion from osmotic minipumps. We used GTS-21 dihydrochloride, a selective nicotinic acetylcholine receptor agonist. Daily intraperitoneal GTS-21 injection and/or vagotomy started after hypertension was confirmed and continued for 4 weeks. The elevated blood pressure caused by AngII was significantly attenuated by GTS-21. Improved baroreflex sensitivity was observed after GTS-21 administration. Masson stain and immunoblotting revealed that deposition of excessive fibrosis and overexpression of inflammatory cytokines induced by AngII was reduced by GTS-21. To determine the role of autonomic control in CAP, unilateral vagotomy was performed. Vagotomy weakened the effect of CAP on AngII-induced hypertension. In vitro, GTS-21 suppressed NF-κB activation, attenuated AngII-induced epithelial-mesenchymal transition and reduced inflammation and fibrosis in NRK-52E cells; α-bungarotoxin (α-Bgt, an α7-nAChR selective antagonist) partly inhibited these effects. Conclusion: CAP protected against AngII-induced hypertension via improvement in autonomic control, suppression of NF-κB activation, and reduction of renal fibrosis and inflammatory response.

Disruption of Drug Effects (Dopamine, Nicotine, Pilocarpine, κ-Opioid) in Planarians by UV Light

Based on previous work, it has been hypothesized that the energetics of ultraviolet (UV) light disrupts effects induced by receptor-binding ligands. If this hypothesis is true, then UV light should (i) disrupt a broad variety of endpoints and (ii) disrupt effects produced by ligands that bind to diverse receptor types. This was tested directly in the present study by using ligands selective for four different receptors (one ionotropic, three metabotropic) and three different behavioral endpoints. The selective dopamine D2 receptor antagonist (–)sulpiride (0.1 uM) dose-relatedly decreased spontaneous locomotor velocity, the selective nicotinic acetylcholine receptor agonist nicotine (1, 3, 5 mM) and the selective muscarinic acetylcholine receptor agonist pilocarpine (20, 30, 50 mM) induced seizure-like activity, and the selective-opioid receptor agonist U-50,488H (10 uM) produced physical dependence (manifested as abstinence-induced withdrawal) in planarian models. Each of these diverse ligand and receptor-mediated effects were attenuated by UV light (254 nm = 7.83 × 10–19 J = 4.89 eV). These findings provide further evidence that UV light disrupts ligand-receptor mediated interactions and that UV light might provide a useful tool for examining drug-receptor interactions.

Anabasine, a selective nicotinic acetylcholine receptor agonist, antagonizes MK-801-elicited mouse popping behavior, an animal model of schizophrenia

The expression of the α 7-nicotinic acetylcholine receptor is diminished in selected brain areas of patients with schizophrenia. This diminished expression may account for the pathophysiological deficits of sensory inhibition and smooth pursuit eye movement performance in these patients. Furthermore, the deficits in sensory inhibition and smooth pursuit eye movement performance in schizophrenia appear to be inherited in an autosomal dominant fashion; thus, the “α 7-nicotinic acetylcholine receptor-deficiency” may be a necessary condition for expression of schizophrenia. This deficit has encouraged speculation about the possible therapeutic benefit of selective α 7-nicotinic acetylcholine receptor agonist interventions in this disorder. In view of this, we sought to examine the effect of anabasine, a selective α 7-nicotinic acetylcholine receptor agonist, on popping behavior in mice elicited by MK-801. MK-801, a high affinity analogue of phencyclidine (PCP), is a noncompetitive N-methyl- d-aspartic acid (NMDA) receptor antagonist that binds to the hydrophobic domain of this ligand-gated channel. PCP is known to precipitate a schizophreniform psychosis in susceptible individuals, causing productive (e.g. hallucinations) deficit (e.g. affective blunting, amotivation, and social withdrawal), cognitive and motor symptoms similar to those seen in naturally-occurring schizophrenia. Behaviors elicited by MK-801 in mice reflect a pharmacologically-induced state of NMDA receptor hypofunction (NRH), which has been proposed to exist in schizophrenia. Compounds that attenuate MK-801-elicited behaviors, which are identified in this animal model, may have the potential to treat schizophrenia, including deficit and cognitive symptoms. In the current study, anabasine attenuated MK-801-elicited popping at a dose that did not cause clonic seizures. The development of α 7-nicotinic acetylcholine receptor agonist interventions for schizophrenia must consider their potential liability to elicit seizure activity.