scholarly journals Pinnatoxins’ Deleterious Effects on Cholinergic Networks: From Experimental Models to Human Health

Marine Drugs ◽  
2019 ◽  
Vol 17 (7) ◽  
pp. 425 ◽  
Author(s):  
Nicolas Delcourt ◽  
Emmeline Lagrange ◽  
Eric Abadie ◽  
Valérie Fessard ◽  
Jean-Marc Frémy ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Marine Invertebrates ◽  
Oral Route ◽  
Experimental Models ◽  
Neurological Sequelae ◽  
High Affinity ◽  
Human Intoxication ◽  
Sublethal Doses ◽  
Network Functions

Pinnatoxins (PnTXs) are emerging neurotoxins that were discovered about 30 years ago. They are solely produced by the marine dinoflagellate Vulcanodinium rugosum, and may be transferred into the food chain, as they have been found in various marine invertebrates, including bivalves. No human intoxication has been reported to date although acute toxicity was induced by PnTxs in rodents. LD50 values have been estimated for the different PnTXs through the oral route. At sublethal doses, all symptoms are reversible, and no neurological sequelae are visible. These symptoms are consistent with impairment of central and peripheral cholinergic network functions. In fact, PnTXs are high-affinity competitive antagonists of nicotinic acetylcholine receptors (nAChRs). Moreover, their lethal effects are consistent with the inhibition of muscle nAChRs, inducing respiratory distress and paralysis. Human intoxication by ingestion of PnTXs could result in various symptoms observed in episodes of poisoning with natural nAChR antagonists. This review updates the available data on PnTX toxicity with a focus on their mode of action on cholinergic networks and suggests the effects that could be extrapolated on human physiology.

scholarly journals Novel Three-Finger Neurotoxins from Naja melanoleuca Cobra Venom Interact with GABAA and Nicotinic Acetylcholine Receptors

Toxins ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 164
Author(s):  
Lina Son ◽  
Elena Kryukova ◽  
Rustam Ziganshin ◽  
Tatyana Andreeva ◽  
Denis Kudryavtsev ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Gabaa Receptors ◽  
Binding Sites ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
High Affinity ◽  
Central Loop ◽  
Acetylcholine Binding Proteins ◽  
Α7 Nachrs

Cobra venoms contain three-finger toxins (TFT) including α-neurotoxins efficiently binding nicotinic acetylcholine receptors (nAChRs). As shown recently, several TFTs block GABAA receptors (GABAARs) with different efficacy, an important role of the TFTs central loop in binding to these receptors being demonstrated. We supposed that the positive charge (Arg36) in this loop of α-cobratoxin may explain its high affinity to GABAAR and here studied α-neurotoxins from African cobra N. melanoleuca venom for their ability to interact with GABAARs and nAChRs. Three α-neurotoxins, close homologues of the known N. melanoleuca long neurotoxins 1 and 2, were isolated and sequenced. Their analysis on Torpedocalifornica and α7 nAChRs, as well as on acetylcholine binding proteins and on several subtypes of GABAARs, showed that all toxins interacted with the GABAAR much weaker than with the nAChR: one neurotoxin was almost as active as α-cobratoxin, while others manifested lower activity. The earlier hypothesis about the essential role of Arg36 as the determinant of high affinity to GABAAR was not confirmed, but the results obtained suggest that the toxin loop III may contribute to the efficient interaction of some long-chain neurotoxins with GABAAR. One of isolated toxins manifested different affinity to two binding sites on Torpedo nAChR.

scholarly journals Interactions of Nereistoxin and Its Analogs with Vertebrate Nicotinic Acetylcholine Receptors and Molluscan ACh Binding Proteins

Marine Drugs ◽  
2022 ◽  
Vol 20 (1) ◽  
pp. 49
Author(s):  
William Kem ◽  
Kristin Andrud ◽  
Galen Bruno ◽  
Hong Xing ◽  
Ferenc Soti ◽  
...  
Keyword(s):  
Disulfide Bond ◽  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Specific Radioactivity ◽  
Electric Organ ◽  
Binding Affinities ◽  
Nicotinic Acetylcholine ◽  
High Affinity ◽  
High Specific Radioactivity ◽  
Alpha Bungarotoxin

Nereistoxin (NTX) is a marine toxin isolated from an annelid worm that lives along the coasts of Japan. Its insecticidal properties were discovered decades ago and this stimulated the development of a variety of insecticides such as Cartap that are readily transformed into NTX. One unusual feature of NTX is that it is a small cyclic molecule that contains a disulfide bond. In spite of its size, it acts as an antagonist at insect and mammalian nicotinic acetylcholine receptors (nAChRs). The functional importance of the disulfide bond was assessed by determining the effects of inserting a methylene group between the two sulfur atoms, creating dimethylaminodithiane (DMA-DT). We also assessed the effect of methylating the NTX and DMA-DT dimethylamino groups on binding to three vertebrate nAChRs. Radioligand receptor binding experiments were carried out using washed membranes from rat brain and fish (Torpedo) electric organ; [3H]-cytisine displacement was used to assess binding to the predominantly high affinity alpha4beta2 nAChRs and [125I]-alpha-bungarotoxin displacement was used to measure binding of NTX and analogs to the alpha7 and skeletal muscle type nAChRs. While the two quaternary nitrogen analogs, relative to their respective tertiary amines, displayed lower α4β2 nAChR binding affinities, both displayed much higher affinities for the Torpedo muscle nAChR and rat alpha7 brain receptors than their respective tertiary amine forms. The binding affinities of DMA-DT for the three nAChRs were lower than those of NTX and MeNTX. An AChBP mutant lacking the C loop disulfide bond that would potentially react with the NTX disulfide bond displayed an NTX affinity very similar to the parent AChBP. Inhibition of [3H]-epibatidine binding to the AChBPs was not affected by exposure to NTX or MeNTX for up to 24 hr prior to addition of the radioligand. Thus, the disulfide bond of NTX is not required to react with the vicinal disulfide in the AChBP C loop for inhibition of [3H]-epibatidine binding. However, a reversible disulfide interchange reaction of NTX with nAChRs might still occur, especially under reducing conditions. Labeled MeNTX, because it can be readily prepared with high specific radioactivity and possesses relatively high affinity for the nAChR-rich Torpedo nAChR, would be a useful probe to detect and identify any nereistoxin adducts.

scholarly journals Subacute Testicular Toxicity to Cadmium Exposure Intraperitoneally and Orally

2019 ◽  
Vol 2019 ◽  
pp. 1-14 ◽  
Author(s):  
Viviane G. S. Mouro ◽  
Ana L. P. Martins ◽  
Janaina Silva ◽  
Tatiana P. Menezes ◽  
Marcos L. M. Gomes ◽  
...  
Keyword(s):  
Oral Administration ◽  
Serum Testosterone ◽  
Oral Route ◽  
Experimental Models ◽  
Tubular Damage ◽  
Testicular Damage ◽  
Sod Activity ◽  
Administration Routes ◽  
Human Intoxication ◽  
Cd Exposure

The toxic effects of cadmium (Cd) on reproductive parameters are widely described in the literature. Experimental models often make use of the intraperitoneal route (i.p.), although human intoxication occurs preferentially by the oral route and can be continuous. However, little is known about the effect of Cd administration routes on the testicular structure. Thus, this study investigated the testicular impact of Cd exposure comparing both i.p. and oral routes, both single dose (SD), in addition to the oral route in fractional doses (FD). Swiss adult male mice received CdCl2 1.5 mg/kg i.p., 30 mg/kg oral SD, and 4.28 mg/kg oral FD for 7 consecutive days. The Cd bioaccumulation was observed in all routes, mainly in the oral FD route. The concentrations of testicular Ca and Cu decreased in all animals exposed to Cd, while Zn and Mn decreased only in the i.p. route. Testicular SOD activity was reduced in both routes of oral administration, while CAT increased in the i.p. route, and GST increased in all animals exposed to Cd. Changes in the tubular parameters and cell viability were observed in both routes of Cd administration but were more intense in the oral route, mainly in the FD. Serum testosterone concentration was reduced in both routes of oral administration. Tubular damage, such as the vacuolization of the seminiferous epithelium, germ cell detachment, and seminiferous tubule degeneration, occurred in all groups exposed to Cd. Therefore, the oral Cd administration presented greater potential to promote testicular damage, mainly when the metal was given in a fractionated way.

scholarly journals In Vivo Activation of Midbrain Dopamine Neurons via Sensitized, High-Affinity α6∗ Nicotinic Acetylcholine Receptors

Neuron ◽  
2008 ◽  
Vol 60 (1) ◽  
pp. 123-136 ◽  
Author(s):  
Ryan M. Drenan ◽  
Sharon R. Grady ◽  
Paul Whiteaker ◽  
Tristan McClure-Begley ◽  
Sheri McKinney ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Dopamine Neurons ◽  
Nicotinic Acetylcholine ◽  
High Affinity ◽  
Midbrain Dopamine ◽  
Midbrain Dopamine Neurons

[3H]-Methyllycaconitine: a high affinity radioligand that labels invertebrate nicotinic acetylcholine receptors

2001 ◽  
Vol 31 (6-7) ◽  
pp. 533-542 ◽  
Author(s):  
Robert J Lind ◽  
David J Hardick ◽  
Ian S Blagbrough ◽  
Barry V.L Potter ◽  
Adrian J Wolstenholme ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
High Affinity

scholarly journals [125I]AT-1012, a new high affinity radioligand for the α3β4 nicotinic acetylcholine receptors

2014 ◽  
Vol 77 ◽  
pp. 193-199 ◽  
Author(s):  
Jinhua Wu ◽  
David C. Perry ◽  
James E. Bupp ◽  
Faming Jiang ◽  
Willma E. Polgar ◽  
...  
Keyword(s):  
Nicotinic Acetylcholine Receptors ◽  
Acetylcholine Receptors ◽  
Nicotinic Acetylcholine ◽  
High Affinity
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