- Metabotropic and ionotropic glutamate receptors mediate the modulation of acetylcholine release at the frog neuromuscular junction. [Journal Article]
- JNJ Neurosci Res 2016 Oct 22
- There is some evidence that glutamate (Glu) acts as a signaling molecule at vertebrate neuromuscular junctions where acetylcholine (ACh) serves as a neurotransmitter. In this study, performed on the ...
There is some evidence that glutamate (Glu) acts as a signaling molecule at vertebrate neuromuscular junctions where acetylcholine (ACh) serves as a neurotransmitter. In this study, performed on the cutaneous pectoris muscle of the frog Rana ridibunda, Glu receptor mechanisms that modulate ACh release processes were analyzed. Electrophysiological experiments showed that Glu reduces both spontaneous and evoked quantal secretion of ACh and synchronizes its release in response to electrical stimulation. Quisqualate, an agonist of ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic receptors and metabotropic Group I mGlu receptors, also exerted Glu-like inhibitory effects on the secretion of ACh but had no effect on the kinetics of quantal release. Quisqualate's inhibitory effect did not occur when a blocker of Group I mGlu receptors (LY 367385) or an inhibitor of phospholipase C (U73122) was present. An increase in the degree of synchrony of ACh quantal release, such as that produced by Glu, was obtained after application of N-methyl-D-aspartic acid (NMDA). The presence of Group I mGlu and NMDA receptors in the neuromuscular synapse was confirmed by immunocytochemistry. Thus, the data suggest that both metabotropic Group I mGlu receptors and ionotropic NMDA receptors are present at the neuromuscular synapse of amphibians, and that the activation of these receptors initiates different mechanisms for the regulation of ACh release from motor nerve terminals. © 2016 Wiley Periodicals, Inc.
- Radiation dosimetry of the α4β2 nicotinic receptor ligand (+)-[(18)F]flubatine, comparing preclinical PET/MRI and PET/CT to first-in-human PET/CT results. [Journal Article]
- EPEJNMMI Phys 2016; 3(1):25
- CONCLUSIONS: Although both enantiomers of [(18)F]flubatine exhibit different binding kinetics in the brain due to the respective affinities, the effective dose revealed no enantiomer-specific differences among the investigated species. The preclinical dosimetry and biodistribution of (+)-[(18)F]flubatine was shown and the feasibility of a dose assessment based on image data acquired on a small animal PET/MR and a clinical PET/CT was demonstrated. Additionally, the first-in-human study confirmed the tolerability of the radiation risk of (+)-[(18)F]flubatine imaging which is well within the range as caused by other (18)F-labeled tracers. However, as shown in previous studies, the ED in humans is underestimated by up to 50 % using preclinical imaging for internal dosimetry. This fact needs to be considered when applying for first-in-human studies based on preclinical biokinetic data scaled to human anatomy.
- Acetylcholine-Induced Ca2+ Flux across the Sarcolemma of an Echinoderm Smooth Muscle. [Journal Article]
- BBBiol Bull 1995; 189(2):207
- Sexual dimorphism of cardiopulmonary regulation in the arcuate nucleus of the hypothalamus. [Review]
- RPRespir Physiol Neurobiol 2016 Oct 15
- The arcuate nucleus of the hypothalamus (ANH) interacts with other hypothalamic nuclei, forebrain regions, and downstream brain sites to affect autonomic nervous system outflow, energy balance, tempe...
The arcuate nucleus of the hypothalamus (ANH) interacts with other hypothalamic nuclei, forebrain regions, and downstream brain sites to affect autonomic nervous system outflow, energy balance, temperature regulation, sleep, arousal, neuroendocrine function, reproduction, and cardiopulmonary regulation. Compared to studies of other ANH functions, how the ANH regulates cardiopulmonary function is less understood. Importantly, the ANH exhibits structural and functional sexually dimorphic characteristics and contains numerous neuroactive substances and receptors including leptin, neuropeptide Y, glutamate, acetylcholine, endorphins, orexin, kisspeptin, insulin, Agouti-related protein, cocaine and amphetamine-regulated transcript, dopamine, somatostatin, components of renin-angiotensin system and gamma amino butyric acid that modulate physiological functions. Moreover, several clinically relevant disorders are associated with ANH ventilatory control dysfunction. This review highlights how ANH neurotransmitter systems and receptors modulate breathing differently in male and female rodents. Results highlight the significance of the ANH in cardiopulmonary regulation. The paucity of studies in this area that will hopefully spark investigations of sexually dimorphic ANH-modulation of breathing.
- Antispasmodic effect of selected Citrus flavonoids on rat isolated jejunum specimens. [Journal Article]
- EJEur J Pharmacol 2016 Oct 6; 791:640-646
- Citrus flavonoids are acknowledged for numerous pharmacological activities, including the myorelaxant effect on various smooth muscles. However, there is no data on their effect on jejunum contractil...
Citrus flavonoids are acknowledged for numerous pharmacological activities, including the myorelaxant effect on various smooth muscles. However, there is no data on their effect on jejunum contractility. Therefore, the aim of the study at hand was to evaluate the impact of hesperetin and diosmetin along with their glycosides on the motoric activity of intestine and to verify the possible mechanism of hesperetin-induced effect. The experiments were performed on rat isolated jejunum strips and were conducted under isometric conditions. Hesperetin and diosmetin, but not hesperidin and diosmin, dose-dependently (10-100µM) and reversibly inhibited acetylcholine (1µM) and KCl (80mM) induced contractile activity. The antispasmodic effect of hesperetin was partially blocked by 4-aminopyridine (100µM), glibenclamide (100µM) and NG-nitro-L-arginine methyl ester (L-NAME, 100µM). By contrast, apamin (0.1µM), tetraethylammonium (500µM) and methylene blue (10µM) did not affect the magnitude of hesperetin-induced myorelaxant effect. Indomethacin (10µM) increased the force of hesperetin-evoked reaction. In conclusion, hesperetin and diosmetin are potent myorelaxant agents. The antispasmodic effect of hesperetin is partially mediated by fast current low-voltage activated K(+) channels, voltage-independent K+ channels and involves the nitric oxide pathway. Finally, hesperetin shows a synergistic effect with indomethacin towards jejunal KCl-precontracted smooth muscle.
- Nerve growth factor-induced plasticity in medial prefrontal cortex interneurons of aged Wistar rats. [Journal Article]
- EGExp Gerontol 2016 Sep 21; 85:59-70
- The medial prefrontal cortex (mPFC) has been identified as a critical center for working and long-term memory. In this study, we have examined the expression of neuropeptide Y (NPY) and vasoactive in...
The medial prefrontal cortex (mPFC) has been identified as a critical center for working and long-term memory. In this study, we have examined the expression of neuropeptide Y (NPY) and vasoactive intestinal polypeptide (VIP) in mPFC interneurons and the density of the mPFC cholinergic and dopaminergic innervation in cognitively-impaired aged Wistar rats. We also tested the possibility that the potential age-related changes might rely on insufficient neurotrophic support. The total number of NPY- and VIP-immunoreactive neurons and the density of vesicular acetylcholine transporter (VAChT)- and tyrosine hydroxylase (TH)-immunoreactive varicosities were estimated using stereological methods. The number of NPY-immunoreactive neurons was significantly reduced in aged rats, whereas the number of VIP-immunoreactive neurons was unaltered. The decreased expression of NPY was fully reversed by intracerebroventricular administration of nerve growth factor. No differences in the density of VAChT- and TH-immunoreactive varicosities were found among all groups. Our results indicate that the reduced expression of NPY in the mPFC of aged rats can be ascribed to the age-associated loss of neurotrophic support, and raise the possibility that these changes might contribute for the cognitive decline that occurs during non-pathological aging.
- Impaired function of α2-containing nicotinic acetylcholine receptors on oriens-lacunosum moleculare cells causes hippocampus-dependent memory impairments. [Journal Article]
- NLNeurobiol Learn Mem 2016 Sep 19; 136:13-20
- Children of mothers who smoked during pregnancy are at significantly greater risk for cognitive impairments including memory deficits, but the mechanisms underlying this effect remain to be understoo...
Children of mothers who smoked during pregnancy are at significantly greater risk for cognitive impairments including memory deficits, but the mechanisms underlying this effect remain to be understood. In rodent models of smoking during pregnancy, early postnatal nicotine exposure results in impaired long-term hippocampus-dependent memory, functional loss of α2-containing nicotinic acetylcholine receptors (α2(∗) nAChRs) in oriens-lacunosum moleculare (OLM) cells, increased CA1 network excitation, and unexpected facilitation of long-term potentiation (LTP) at Schaffer collateral-CA1 synapses. Here we demonstrate that α2 knockout mice show the same pattern of memory impairment as previously observed in wild-type mice exposed to early postnatal nicotine. However, α2 knockout mice and α2 knockout mice exposed to early postnatal nicotine did not share all of the anomalies in hippocampal function observed in wild-type mice treated with nicotine during development. Unlike nicotine-treated wild-type mice, α2 knockout mice and nicotine-exposed α2 knockout mice did not demonstrate increased CA1 network excitation following Schaffer collateral stimulation and facilitated LTP, indicating that the effects are likely adaptive changes caused by activation of α2(∗) nAChRs during nicotine exposure and are unlikely related to the associated memory impairment. Thus, the functional loss of α2(∗) nAChRs in OLM cells likely plays a critical role in mediating this developmental-nicotine-induced hippocampal memory deficit.
- Calcium homeostasis and protein kinase/phosphatase balance participate in nicotine-induced memory improvement in passive avoidance task in mice. [Journal Article]
- BBBehav Brain Res 2016 Sep 12; 317:27-36
- Long-term potentiation (LTP) and long-term depression (LTD) depend on specific postsynaptic Ca(2+)/calmodulin concentration. LTP results from Ca(2+) influx through the activated NMDA receptors or vol...
Long-term potentiation (LTP) and long-term depression (LTD) depend on specific postsynaptic Ca(2+)/calmodulin concentration. LTP results from Ca(2+) influx through the activated NMDA receptors or voltage-gated calcium channels (VGCCs) and is linked with activation of protein kinases including mitogen-activated protein kinase (MAPK). Weaker synaptic stimulation, as a result of low Ca(2+) influx, leads to activation of Ca(2+)/calmodulin-dependent phosphatase (calcineurin - CaN) and triggers LTD. Interestingly, both memory formation and drug addiction share similar neuroplastic changes. Nicotine, which is one of the most common addictive drugs, manifests its memory effects through nicotinic acetylcholine receptors (nAChRs). Because nAChRs may also gate Ca(2+), it is suggested that calcium signaling pathways are involved in nicotine-induced memory effects. Within the scope of the study was to evaluate the importance of calcium homeostasis and protein kinase/phosphatase balance in nicotine-induced short- and long-term memory effects. To assess memory function in mice passive avoidance test was used. The presented results confirm that acute nicotine (0.1mg/kg) improves short- and long-term memory. Pretreatment with L-type VGCC blockers (amlodipine, nicardipine verapamil) increased nicotine-induced memory improvement in the context of short- and long-term memory. Pretreatment with FK-506 (a potent CaN inhibitor) enhanced short- but not long-term memory effects of nicotine, while SL-327 (a selective MAPK/ERK kinase inhibitor) attenuated both nicotine-induced short- and long-term memory improvement. Acute nicotine enhances both types of memory via L-type VGCC blockade and via ERK1/2 activation. Only short- but not long-term memory enhancement induced by nicotine is dependent on CaN inhibition.
- Salvianolic acid B improves vascular endothelial function in diabetic rats with blood glucose fluctuations via suppression of endothelial cell apoptosis. [Journal Article]
- EJEur J Pharmacol 2016 Sep 8; 791:308-315
- Vascular endothelial cell injury is an initial event in atherosclerosis. Salvianolic acid B (Sal B), a main bioactive component in the root of Salvia miltiorrhiza, has vascular protective effect in d...
Vascular endothelial cell injury is an initial event in atherosclerosis. Salvianolic acid B (Sal B), a main bioactive component in the root of Salvia miltiorrhiza, has vascular protective effect in diabetes, but the underlying mechanisms remain unclear. The present study investigated the effect of Sal B on vascular endothelial function in diabetic rats with blood glucose fluctuations and the possible mechanisms implicated. The results showed that diabetic rats developed marked endothelial dysfunction as exhibited by impaired acetylcholine induced vasodilation. Supplementation with Sal B resulted in an evident improvement of endothelial function. Phosphorylation (Ser 1177) of endothelial nitric oxide synthase (eNOS) was significantly restored in Sal B treated diabetic rats, accompanied by an evident recovery of NO metabolites. Sal B effectively reduced vascular endothelial cell apoptosis, with Bcl-2 protein up-regulated and Bax protein down-regulated markedly. Treatment with Sal B led to an evident amelioration of oxidative stress in diabetic rats as manifested by enhanced antioxidant capacity and decreased contents of malondialdehyde in aortas. Protein levels of NOX2 and NOX4, two main isoforms of NADPH oxidase known as the major source of reactive oxygen species in the vasculature, were markedly decreased in Sal B treated groups. In addition, treatment with Sal B led to an evident decrease of serum lipids. Taken together, this study indicates that Sal B is capable of improving endothelial function in diabetic rats with blood glucose fluctuations, of which the underlying mechanisms might be related to suppression of endothelial cell apoptosis and stimulation of eNOS phosphorylation (Ser 1177).
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- A novel muscarinic receptor-independent mechanism of KCNQ2/3 potassium channel blockade by Oxotremorine-M. [Journal Article]
- EJEur J Pharmacol 2016 Aug 31; 791:221-228
- Inhibition of KCNQ (Kv7) potassium channels by activation of muscarinic acetylcholine receptors has been well established, and the ion currents through these channels have been long known as M-curren...
Inhibition of KCNQ (Kv7) potassium channels by activation of muscarinic acetylcholine receptors has been well established, and the ion currents through these channels have been long known as M-currents. We found that this cross-talk can be reconstituted in Xenopus oocytes by co-transfection of human recombinant muscarinic M1 receptors and KCNQ2/3 potassium channels. Application of the muscarinic acetylcholine receptor agonist Oxotremorine-methiodide (Oxo-M) between voltage pulses to activate KCNQ2/3 channels caused inhibition of the subsequent KCNQ2/3 responses. This effect of Oxo-M was blocked by the muscarinic acetylcholine receptor antagonist atropine. We also found that KCNQ2/3 currents were inhibited when Oxo-M was applied during an ongoing KCNQ2/3 response, an effect that was not blocked by atropine, suggesting that Oxo-M inhibits KCNQ2/3 channels directly. Indeed, also in oocytes that were transfected with only KCNQ2/3 channels, but not with muscarinic M1 receptors, Oxo-M inhibited the KCNQ2/3 response. These results show that besides the usual muscarinic acetylcholine receptor-mediated inhibition, Oxo-M also inhibits KCNQ2/3 channels by a direct mechanism. We subsequently tested xanomeline, which is a chemically distinct muscarinic acetylcholine receptor agonist, and oxotremorine, which is a close analogue of Oxo-M. Both compounds inhibited KCNQ2/3 currents via activation of M1 muscarinic acetylcholine receptors but, in contrast to Oxo-M, they did not directly inhibit KCNQ2/3 channels. Xanomeline and oxotremorine do not contain a positively charged trimethylammonium moiety that is present in Oxo-M, suggesting that such a charged moiety could be a crucial component mediating this newly described direct inhibition of KCNQ2/3 channels.