Type II pyrethroids

Induction of repetitive activity in the nervous system is the principal effect of pyrethroids. Repetitive activity originates from a prolongation of the transient increase in sodium permeability of the nerve membrane associated with excitation. All pyrethroids affect sodium channel gating in a similar manner, although Type II pyrethroids are significantly more neurotoxic than Type I pyrethroids. 

Other target sites for certain pyrethroids include the voltage-gated calcium and chloride channels. Of particular interest is the increased effect of Type II pyrethroids on certain phosphoforms of the N-type Cav2.2 calcium channel following post-translational modification and its relationship to enhanced neurotransmitter release seen in vivo. 

Although most Type I pyrethroids produce the T-syndrome and most Type II pyrethroids produce the CS-syndrome, there are exceptions to this classification. Fenpropathrin, a Type II pyrethroid, and permethrin, a Type I pyrethroid, produce mixed intoxication syndromes depending on the study and animal examined. Lastly, the signs of intoxication may not be independent of the routes of administration [1]. As reported recently, the results of a functional observational battery study of 12 pyrethroids in rats following acute oral exposure did not correlate well with the signs of intoxication following intravenous dosing [19]. 

In an extension to the studies mentioned above, the actions of 11 commercial pyrethroids on calcium influx and glutamate release were assessed using a high-throughput approach with rat brain synaptosomes [75, 76]. Concentration-dependent response curves for each commercial pyrethroid were determined and the data used in a cluster analysis. Previously characterized Type II pyrethroids that induce the CS-syndrome symptoms (cypermethrin, deltamethrin, and esfenvalerate) increased calcium influx and glutamate release, and clustered with two other ot-cyano pyrethroids (p-cyfluthrin and A-cyhalothrin) that shared these same actions. Previously characterized Type I pyrethroids (bioallethrin, cismethrin, and fenpropathrin) did not share these actions and clustered with two other non-cyano pyrethroids (tefluthrin and bifenthrin) that likewise did not elicit these actions. 

Collectively, the in situ biochemical evidence suggests that voltage-gated calcium channels are modified by pyrethroids however, the mechanism by which Types I and II pyrethroids accomplish this may be different. Specifically, Type II pyrethroids are more potent enhancers of calcium influx and glutamate release under depolarizing conditions than Type I pyrethroids and may contribute, in part, to different symptoms elicited by these classes of pyrethroids in vivo. 

As previously mentioned, early in vivo acute toxicity studies indicated that the action of Type II pyrethroids on the nervous system was different from that of the Type I pyrethroids. Deltamethrin decreased the acetylcholine content of the cerebellum, whereas DDT, a well-established voltage-sensitive sodium channel agonist, and cismethrin, caused no significant reduction [2]. 

The effect of allethrin (a Type I pyrethroid), cyhalothrin, and deltamethrin (Type II pyrethroids) on neurotransmitter release from the hippocampus (acetylcholine, glutamate, and GABA release) and striatum (dopamine release) has recently been investigated using ex vivo microdialysis in freely moving rats exhibiting the symptoms of pyrethroid poisoning [94-97]. Deltamethrin increased the release... 

Tabarean IV, Narahashi T (1998) Potent modulation of tetrodotoxin-sensitive and tetrodotoxin-resistant sodium channels by the type II pyrethroid deltamethrin. J Pharmacol Exp Ther 284 958-965... 

Forshaw PJ, Lister T, Ray DE (1993) Inhibition of a neuronal voltage-dependent chloride channel by the type II pyrethroid, deltamethrin. Neuropharmacology 32 105-111... 

Breckenridge CB, Holden L, Sturgess N, Weiner M, Sheets L, Sargent D, Soderlund DM, Choi JS, Symington S, Clark JM, Burr S, Ray D (2009) Evidence for a separate mechanism of toxicity for the Type I and the Type II pyrethroid insecticides. Neurotoxicology 30(Suppl 1) S17-S31... 

An alternative nomenclature (Type I and Type II) has been proposed for subgroups of pyrethroids based not only on the syndromes of intoxication produced in mammals but also on their chemical structures, their signs of poisoning in insects, and their actions on insect nerve preparations [2, 14, 18]. The Type I/II nomenclature has been used in parallel with the T/CS nomenclature, so that Type I and Type II pyrethroids are generally considered to induce T- or CS syndrome, respectively [4]. However, the relationship between the two syndromes and types are neither necessarily confirmed in all pyrethroids nor absolute from the recent available data. 

Sylianco-Wu L, Kallman M, Wilson M et al (1989) Behavioral and neurochemical consequences of perinatal exposure to type I and type II pyrethroid formulations. Neurotoxicol Teratol 12 565... 

Type II pyrethroids have a general structure that contains a a-cyano group as follows ... 

Type II pyrethroids include cypermethrin, fenvalerate, tralomethrin, esfenvalerate, del-tamethrin, te/-fluvalinate, fenpropathrin, A,-cyhalothrin, tefluthrin, cyfluthrin, acrinath-rin, and imiprothrin. The structures of these pyrethroids are as follows ... 

Pyrethroids can be classified as type I or type II depending on their effects on sensory neurons in American cockroaches. Type I compounds induce repetitive discharges in sensory neurons in vitro but not neurotransmitter release, so these processes are not related to the toxic action of pyrethroids. In contrast, type II pyrethroids, which typically contain the cyano group, do not induce repetitive discharges. Type II pyrethroids cause slow depolarization of nerve membrane, which reduces the amplitude of the action potential, leading to a loss of electrical excitability (Bloomquist, 1999). In addition, type I pyrethroids exhibit a negative temperature coefficient of toxicity, i.e., they are more toxic at low temperatures than at high temperatures, whereas type II pyrethroids exhibit a positive temperature coefficient of toxicity (Corbett et al., 1984 Matsumura, 1985). 

Chemical/Pharmaceutical/Other Class Type II pyrethroid insecticide... 

Fenvalerate has low toxicity in mammals due to its rapid metabolic breakdown. It acts directly on nerve axons by prolonging sodium channel opening in cell membranes. Insects exposed to fenvalerate are quickly paralyzed exposure causes quick insect knockdown. In small animals, type II pyrethroids cause salivation, chewing, burrowing, choreoathetosis, and seizures. They also cause lower action potential amplitude, marked membrane depolarization, and eventual total neural activity blockade. Fenvalerate is likely to act both on peripheral and central nervous system. It is also a potent inhibitor of calcineurin (protein phosphatase 2B). 

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