Imidacloprid was shown to act as both a larvicide and an adulticide in studies on cat fleas. Due to its probable main uptake by the flea through the nonsclerotized intersegmental membranes it rapidly reaches the site of action: the postsynaptic membrane. There, the irreversible blocking of the nACh receptors leads to a lethal hyperactivity of the nerves and muscles of the insect. Both stages are sensitive to the drug, and after contact they react in a similar fashion: they stop their jumping or (respectively) crawling movements and display the onset of rhythmic trembling of the legs and the body. This nonreversible phenomenon finally leads to the death of both flea stages. These easily visible effects correspond to the finding that imidacloprid blocks the postsynaptical nicotinic acetylcholine receptors (Abbink 1991). The latter are normally stimulated by acetylcholine that is excreted into the synaptic gap. These receptors initiate the opening of channels in the membrane to let Na+ flow into the cell. This leads to a depolarization of the terminal plate and induces the activation of an action potential. The latter causes the release of Ca2+ from vesicles and thus results in contraction of the myosin/actin complex of the sarcomeres. In normal cases the acetylcholine has a brief connection to the receptor, is subsequently released, and is rapidly hydrolyzed by a membrane-bound cholinesterase. In the case of imidacloprid the binding of the compound and the receptors is stronger; hence, a constant depolarization of the membrane occurs, inducing a tetanus of the activated muscle cell. This mode of action corresponds to the structural findings described herein, since the observed degeneration mainly involved an overall destruction of the mitochondria, damage to the nerve cells, and disintegration of the muscle, Imidacloprid initiates a constant depolarization of the nerves, which is followed by a constant activation of the muscles until the cellular energy systems (mitochondria, glycogen) are depleted and the motile proteins are destroyed.
Source:
Heinz Mehlhorn, Norbert Mencke, Olaf Hansen. Parasitol Res (1999) 85: 625-637
Drs Mencke and Hansen were employed by Bayer AG, BG Animal Health, D-51368 Leverkusen, Germany
- Login om te reageren
Bayer scientists Maus and Nauen contest previous assertions
In a response to my publication: Tennekes, H.A.(2010):The significance of the Druckrey–Küpfmüller equation for risk assessment—The toxicity of neonicotinoid insecticides to arthropods is reinforced by exposure time (Toxicology 276, 1-4) Drs Maus and Nauen of Bayer CropScience contested the irreversible nature of receptor binding by imidacloprid. They wrote:
"All commercial neonicotinoid insecticides bind to insect nicotinic acetylcholine receptors and cause the same effect as the natural neurotransmitter acetylcholine, i.e.agonistically activating the receptors resulting in a transient inward-current leading to the generation of action potentials. Similar to acetylcholine, a neonicotinoid is binding to the nicotinic acetylcholine receptors, and the binding of neonicotinoid insecticides is reversible as shown by their rapid desensitization /recovery during short-term exposure in electrophysiological whole-cell voltage clamp assays on isolated insect neurons(Nauen et al., 2001; Tomizawa and Casida, 2003; Jeschke and Nauen, 2005). Radio-ligand binding studies conducted with tritiated imidacloprid also revealed saturatable, specific and reversible binding with fast kinetics (Liu and Casida, 1993). The synaptic action of acetylcholine under normal physiological conditions is terminated by acetylcholinesterase, which hydrolyzes the transmitter. Neonicotinoids can not be hydrolyzed by the enzyme,i.e.they persist at the binding sites leading to overstimulation of cholinergic synapses, resulting in hyperexcitation and paralysis of the insect (Yu, 2008). However, due to the reversible nature of binding of neonicotinoids, their toxic action strongly depends on the pharmacokinetics including the rate of metabolic detoxification as shown in aphids recovering from imidacloprid intoxication under discontinuous exposure conditions (Nauen,1995). Therefore, the basic conditions for the applicability of the Druckrey–Küpfmüller equation (i.e. both receptor binding and the effect are irreversible) are not fulfilled in this case."
Maus and Nauen did not retract previous assertions made by their colleagues Abbink (1991), Mencke and Hansen (1999) that imidacloprid irreversibly blocks nicotinic acetylcholine receptors and causes irreversible damage to acetylcholine neurons of insects. In my rebuttal I pointed out that slow dissociation of imidacloprid from the receptor, which is acknowledged by Maus and Nauen, will lead to time-dependent toxicity as reflected in the Druckrey–Küpfmüller equation, which in any case describes the dose-effect relationship of imidacloprid in arthropods. But a more important issue is at stake here. The Druckrey-Küpfmüller equation holds for genotoxic as well as non-genotoxic compounds, but the risks of the former are far more stringently regulated than the latter. For genotoxic compounds, it is generally assumed that a threshold does not exist, whereas for non-genotoxic compounds the existence of a threshold is assumed, below which no toxic effect will occur. The cumulative nature of the toxicity of imidacloprid is beyond dispute, but a presumed No-Observed-Adverse-Effect-Level (NOAEL) for imidacloprid certainly is not. In my opinion, risk assessment urgently needs revision.
The bichemistry of Imidacloprid by J. Abbink (1991)
Imidacloprid belongs to the group of nitroguanidines. Many representatives of this class of compounds, and imidacloprid in particular, have an excellent insecticidal action. This high activity is brought about by binding of imidacloprid to the nicotinergic acetylcholine receptor in the insects's nervous system, which interferes with chemical signal transmission. Methods for isolating nicotinergic acetylcholine receptors from the heads of Stomoxys calcitrans and for measuring the binding affinity, if any, of a substance on such receptors have been developed. The neurophysiological properties of the nicotinergic acetylcholine receptors of Stomoxys calcitrans, which include the binding of imidacloprid, are described in detail. Imidacloprid is the first highly effective insecticide whose mode of action has been found to derive from almost complete and virtually irreversible blockage of postsynaptic nicotinergic acetylcholine receptors in the central nervous system of the insect pest Stomoxys calcitrans
Source:
The biochemistry of imidacloprid [1991]
Abbink, J. (Bayerwerk A.G., Wuppertal-Elberfeld (Germany). Pharma-Forschungszentrum)
Mechanism of neonicotinoid action
Neonicotinoids are systemic, being distributed throughout the plants via the sap stream, in this way making the entire plant toxic to, i.e., the target insects. They specifically bind to nicotinergic acetylcholine receptors (nAChR) on the post-synaptic membrane of the neurons of insects. They compete with ACh neurotransmitters to bind to and activate the nAChR, an effect called agonistic binding. The irreversible binding leads to excessive ion flows (Na+, K+, Ca2+) through cellular membranes and prolonged action potentials, causing overexcitement of the neurons. Exposed animals show signs of disorientation and paralysis, from which they eventually die.
Source:
van Gestel, C.A., de Lima e Silva, C., Lam, T. et al. Ecotoxicology (2017) 26: 320. https://doi.org/10.1007/s10646-017-1765-8
EFSA statement on mechanism of neonicotinoid action
The binding of neonicotinoids to insect nAChRs is virtually irreversible.
Source: EFSA Journal 2013; 11(12):3471