Glutamate-gated chloride channel
Ivermectin binds with high affinity to glutamate-gated chloride channels which occur in invertebrate nerve and muscle cells, causing an increase in the permeability of the cell membrane to chloride ions with hyperpolarization of the nerve or muscle cell. Hyperpolarization results in paralsysis and death of the parasite either directly or by causing the worms to starve. (Consult 2005) At least one study, however, seems to suggest a depolarizing rather than hyperpolarizing role for Ivermectin on the glutamate-gated chloride channel. (Pemberton, Franks et al. 2001) However, in either case, the end result is the deactivation of the channel by manipulation of chloride levels.
Figure 1. A schematic of the unactivated and activated.
Binding of glutamate (or ivermectin) causes the glutamate gated channel to
open thereby permitting entry of chloride ions, which induce hyperpolarization.
Selective activity of compounds of this class is attributable to the facts that some mammals do not have glutamate-gated chloride channels and that avermectins have low affinity for mammalian ligand-gated chloride channels. In addition, ivermectin does not readily cross the blood-brain barrier in humans but rather targets its antiparasitic activity to the general circulation.
Figure 2 The blood barrier is created by the tight apposition
of endothelial cells lining blood vessels in the brain preventing easy passage
of large macromolecules and pathogens between the circulation and the brain.
Ivermectin cannot penetrate this barrier.
The target of Ivermectin is largely aimed at the microfilaria stage of various parasites. Ivermectin is active against various life-cycle stages of many but not all nematodes. It is active against tissue microfilariae of Onchocerca volvulus. Its activity against Strongyloides stercoralis is limited to the intestinal stages. (Consult 2005)
The macrofilaricdal effect of Ivermectin is debatable but there is evidence for the macrofilaricidal effect of Ivermectin in Onchocerca volvulus. 3-monthly regimen appeared to cause increase adult female worm death due to a direct, anthelminthic, macrofilaricdal action of ivermectin or by increasing the prevalence and intensity of a potentially fatal pleomorphic ovarians neoplasm (PN)(Duke 2005)
There is also evidence in nematode studies particularly those in Trichinella spiralis that ivermectin may work by blocking signal transmission from interneurons to excitatory motoneurons that that GABA is the neurotransmitter being blocked. (Moreno)
a. b. c.
Figure 3 Ivermectin is effective at paralyzing and killing the microfilaria of various parasites including Onchocerca volvulus (a) and Wucheria bancrofti (b). Its effect against macrofilaria adult worms (c) is still uncertain.