It is concluded that the use of pharmacological agents can provide opportunities to recognize and define similarities and differences in the mechanisms of transmission of nerve impulses in the parasite and the mammalian host. Such studies contribute to better understanding of comparative physiology and of the mode of action of antiparasitic drugs

Bueding, Ernest

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MCV QUARTERLY 2(2): 135-137, 1966 Cholinergic Responses of Schistosoma . manson1 ERNEST BUEDING Department of Pathobiology, School of Hygiene and Public Health and Department of Pharmacology and Experimental Therapeutics, School of Medicine, The Johns Hopkins University, Baltimore In higher animals, the role of acetylcholine as a transmitter of nerve impulses is well established. However, this substance makes its appearance already at an early stage in phylogeny. Btilbring et al. (1949) demonstrated the presence of ace-tylcholine in the motile protozoan parasite Trypanosoma rhodesiense and its absence from the non-motile erythrocytic forms of malarial para-sites; this suggested a role of ace-tylcholine concerned with the motil-ity of protozoa. Subsequently, it has been found that acetylcholine may be of considerable physiologi-cal significance to the regulation of the muscular activity of the meta-zoan parasite Schistosoma mansoni. The habitats of the adult forms of this trematode are the mesenteric-portal venous system and the liver sinuses. According to conservative estimates, 200 million human be-ings are infected with this or two other species of schistosomes (S. hematobium, S. japonicum). Ac-cordingly, information about mech-anisms essential for the functional integrity of these parasites may be pertinent to the rational develop-ment of chemotherapeutic agents effective in the treatment of schis-tosomiasis. The presence of acetylcholine, and of the enzymes catalyzing its hydrolysis and its synthesis, acetyl-cholinesterase and choline acetyl-ase, have been demonstrated in S. mansoni (Bueding, 1952; Barker et al., 1966). The concentration of acetylcholine and the activities of acetylcholinesterase and of choline acetylase in these worms are of a high order and equal those found in the gray matter of mammalian brain cortex. By the use of histo-chemical methods, it has been found that acetylcholinesterase is localized primarily in the nervous system of S. mansoni (Bueding et al., 1963) . These observations raise the ques-tion about the physiological role of acetylcholine in S. mansoni. This problem has been studied by deter-mining the effect of cholinomimetic and of cholinergic blocking agents on the motor activity of schisto-somes. The choline ester carbaminoyl-choline ( carbachol) has the same physiological actions as acetylcho-Iine, but it is not hydrolyzed by ace-tylcholinesterase. This choline ester markedly depresses the muscular activity of schistosomes. Cholines-terase inhibitors, e.g., physostig-mine, prostigmine, and di-isopropyl-fluorophosphate, have the same effect. Therefore, inhibition of cho-linesterase appears to result in an accumulation of endogenous acetyl-135 CHOLINERGIC RESPONSES OF S. MANSONI TABLE I Effects of Cholinomimetic Agents on Muscular Activity of s. mansoni choline; this, in turn, produces de-creased muscular activity and pa-ralysis of the worm in the same manner as exogenous carbachol. Minimal molar concentra-Compound tion reducing muscular activity of S . mansoni Carbachol 2 x 10-5 Arecoline 2 x 10-7 Pi locarpi ne Musca rine Physostigmine 2 x I0- 6 Prostigmine 5 x 10-5 Di isopropylfluoro- I x 10-4 phosphate (DFP) TABLE 2 Lack of effect on mo-tor activity of S . man-soni at molar concen-tra tion range l x 10-7 to I x 10-2 I x 10-7 to I x 10-2 The three alkaloids, muscarine, arecoline, and pilocarpine, have the same actions on parasympathetic effector organs as acetylcholine. By contrast, only arecoline is a potent depressant of the muscular activity of S. mansoni, while muscarine and pilocarpine are inactive in this re-spect. Reduction of the motor activity and paralysis of schistosomes pro-duced by carbachol, cholinesterase inhibitors and arecoline, are abol-ished by atropine and two non-q u ate rn ary ganglion blocking agents, mecamylamine and pempi-Effects of Cholinergic Blocking Agents on S . mansoni Site of blockade in Minima l molar concentra tion La ck of cho linergic block-Bl ocking Agent mammalian host required to reverse cho liner- ade in S . mansoni a t gic paralysis· of s. mansoni mo la r conce ntration range Parasympathetic effector orga n at low concentra tions 5 x 10-5 Atropine (a pprox . I x 10-7 molar) and autonomic ga nglia at higher concentrations Mecamy.lamine 5 x 10-5 Pempidine 2 x 10- 4 Hexamethon i um Autonomic ga ng lia 5 x 10-5 to 2 x 10- 2 Pentolinium 2 x 10-4 to 2 x 1 o-2 Chlorisondamine 1 x 10-4 to I x 10-2 Nicotine I x 10-7 to I x 10-3 d-Tubocurarine 5 x 10-5 to I x 10- 2 Decamethonium Neuromuscular junction 5 x 10-5 to I x 10-2 Succinylcholine I x 10- 4 to I x 10-2 136 dine. Exposure of schistosomes to these compounds alone (i.e. , in the absence of cholinergic agents) re-sults in a marked motor hyperac-tivity of the parasite. This stimula-tory effect can be accounted for by a block of an interaction of the worm's cholinergic receptors with endogenous acetylcholine, resulting in the failure of this humoral trans-mitter to exert its inhibitory effect on motor activity. In contrast to these secondary and tertiary amine blocking agents, even high concen-trations of nicotine, of quaternary ganglion blocking agents, such as hexamethonium, chlorisondamine, and pentolinium, or of neuromuscu-lar blocking agents (e.g., tubocura-rine, decamethonium, and succinyl-choline, are completely devoid of cholinergic blocking activity in schistosomes. These observations, summarized in tables 1 and 2, indicate that cholinergic receptors of schisto-somes have some similarities with cholinergic receptors of their mam-malian hosts, but nevertheless are distinguishable from those of verte-brate autonomic cholinergic effec-tors organs and of autonomic gan-glia because the muscular activity of the worms is affected neither by muscarine or pilocarpine, on the one hand, nor by quaternary am-monium ganglion blocking agents or nicotine, on the other. One of the first effects of the ad-ministration of the antischistosomal drug, p-rosaniline (tris (p-amino-phenyl) carbonium) to mice infec-ted with S. mansoni (Elslager et al., 1961 ; Thompson et al. , 1962) is a localized paralysis of two muscular organs of the worm, the oral sucker and the acetabulum , with which the parasite attaches it-self to the mesenteric veins. In vitro, this paralysis is reversed within less than two minutes by atropine or by mecamylamine. This suggests that the paralysis is due to an accumulation of acetylcholine, whose action in depressing muscu-lar activity of schistosomes is abol-ished by cholinergic blocking agents. E. BUEDING This interpretation is confirmed by a histochemically demonstrable in-hibition of acetylcholinesterase ac-tivity of the two muscular organs and of the central nervous system of the parasite following the ad-ministration of p-rosaniline (Bued-ing et al., 1963) . It is concluded that the use of pharmacological agents can provide opportunities to recognize and de-fine similarities and differences in the mechanisms of transmission of nerve impulses in the parasite and the mammalian host. Such studies contribute to better understanding of comparative physiology and of the mode of action of antiparasitic drugs. REFERENCES BARKER, L. R., E. BUEDING AND A. R. TIMMS. The possible role of acetyl-choline in Schistosoma mansoni. Brit. J. Pharmacol., In Press. 1966. BUEDING, E. Acetylcholinesterase ac-tivity of Schistosoma mansoni. Brit. J. Pharmacol. Chemotherap. 7: 563-566, 1952. BUEDING, E., L. DOUGLAS, E. SCHILLER AND N. ANSARI. Physiological ef-fects of tris (p-aminophenyl) car-bonium chloride (TAC) on Schisto-soma mansoni. Proc. 7th Internat. Congr. Trap . Med. and Malaria, Rio de Janeiro, p. 63 , 1963. BULBRING, E., E. M. LOURIE AND u. PARDOE. The presence of acetyl-choline in Trypanosoma rhodesiense and its absence from Plasmodium gallinaceum. Brit. J. Pharmacol. Chemotherap. 4: 290-294, 1949. ELSLAGER, E. F., F. w. SHORT, D. F. WORTH, J. E. MEISENHELDER, H . NAJARIAN AND P. E. THOMPSON. Effects of tris (p-aminophenyl) car-bonium salts and related compounds on experimental schistosomiasis and paragonimiasis. Nature 190: 628-629, 1961. THOMPSON, P. E., J.E. MEISENHELDER AND H. NAJARIAN. Laboratory stud-ies on the effects of tris (p-amino-phenyl) carbonium salts, tris (p-aminophenyl) methanol, and lucanthone hydrochloride against Schistosoma mansoni. Am. J. Trap. Med. Hyg. 11: 31-45, 1962. 137 

Cholinergic Responses of Schistosoma mansoni

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Cholinergic Responses of Schistosoma mansoni

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