Minireview Actions of Avermectins on Cultured Neurons

The avermectins (AVM) are macrocyclic lactone derivatives produced by Streptomyces avermitilis, which have potent anthelmintic as well as insecticidal activities (Egerton et al., 1979; Ostlind et aL, 1979; Putter et al., 1981). These compounds consist of four major components (A~a, A:a, Bl~, B2a) and four minor components (A~b, AEb, Bmb, BEb) but it is presumed that all avermectins share a common mechanism of action (Campbell et al., 1983). Ivermectin is a synthetic derivative of BI (22,23-dihydroavermectin B~), consisting of 80% Bla and 20% Bib. On the other hand, milbemycin D, which is structurally related to ivermectin, is one of milbemycins with insecticidal activity, which are derived from Streptomyces hygroscopicus subsp, aureolacrimosus (Takiguchi et al., 1980) (Fig. 1). AVM BI~, one of the major and most potent components of AVM, has been shown to rapidly paralyze nematodes without causing hypercontraction or flaccid paralysis (Kass et al., 1980). Electrophysiological experiments on nematodes have shown that AVM B~a acts by blocking transmission from interneurons to excitatory motoneurons and that washing with a GABA receptor-coupled chloride channel blocker, picrotoxin, reverses it (Kass et al., 1980). In addition, in the lobster neuromuscular junction, which is known to be regulated by excitatory (glutamatergic) transmission and inhibitory (GABAergic) transmission (Gershenfeld, 1973), AVM Bla inhibits both excitatory and inhibitory transmission and these effects of AVM B~ are restored by picrotoxin (Fritz et al., 1979). Thus, it is likely that the basic mechanism of action of AVM could be its interaction with the GABA receptor complex, and that AVM activates the chloride channels coupled to the GABA receptor (Wang and Pong, 1982; Campbell et al., 1983; Wang, 1986; Wright, 1986). On the other hand, because of the low densities of GABAergic synapses in Ascaris and lobsters, most biochemical studies have been done with vertebrate (mammalian) or invertebrate brains, which are a rich source of GABAergic synapses, to biochemically investigate the action of AVM on the GABA receptor complex. Such in vitro studies have shown that AVM specifically binds to vertebrate and invertebrate brain tissue with high affinity (Drexler and Sieghart, 1984; Huang et al., 1986; Min et al., 1986). In the mammalian brain, it is known that AVM can allosterically