January 1968d. J. Physiot, & PharmacoJ.

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adrenocortical steroids.

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IS ASARONE A TRANQUILLISER?

Sir,I have read with some interest Banerjee's letter published in the October, 1967 issue of

your Journal (1). He has raised several points and has misquoted me and my coworkers fromour report (9). According to Banerjee, Dandiya and coworkers (9) stated in 1959 that "asaroneis not responsible for enhancing the barbiturate induced hypnosis exhibited by Acorus oil".In fact what was actually written there reads. "It seems unlikely that asarone is responsible forthe activity of Acorus oil since it is present to the extent of approximately 80% in the Indian oiland about 7% in the European oil". While in the actual communication, only an opinion isexpressed about the unlikelyhood of activity residing in asarone, Bannerjee has attributed acategorical statement to these authors, which was never made. Moreover, this opinion wasexpressed by these workers (9) before any pharmacological testing of asarone was made andthis was based on the reports regarding difference in the asarone content of tne Acorus oil fromEuropeon and Indian varieties of Acorus Calamus.

Banerjee has found it difficult to understand the report of Sharma er al (16), "~as-aronc ap pears to be more potent than asarone" and what was reported by Dandiya and Menon (5)that "asarone was more potent than ~-asarone". If Banerjee had cared to read these state-ments in the context each had been made in the respective papers, it should not have been diffi-cult for him to understand. Potency of a substance as described in relationship to the responseone is looking for. In the earlier communication (16), a comparative study was madebetween the action of asarone and ~·--asarone as regards their hypnotic potentiating property,hypothermic action, anticonvulsant properties as seen against electroshock, picrotoxin or Metra-zol induced convulsions and influence on conditioned avoidance response, while in the lattercommunication (5) these two drugs were compared for their influence on the action of resperineand chlorpromazine in conditioned avoidance response, fighting behaviour of mice and electro-convulsions, which clearly indicates the difference in the design of experiments, hence, no wonderabout the difference in the finding. Your correspondent has further attributed to one of earlyreports (8), that synthetic asarone is devoid of any eNS effect wnile isolated one shows prono-unced effect". No such finding has been reported in the paper and on the other hand it has beenshown in the same report that synthetic asarone significantly potentiated barbiturate induced hy-pnosis in mice. The conclusions drawn by Banerjce are therefore his own and he should know thebasis for arriving at such predictions. No doubt synthetic asarone was found to be less potentthan asarone obtained from natural sources but this should not be surprising. Substances prepar-ed by different methodology are known to differ in activity. Schlittler has reported that 17 -desmethoxy deserpidine prepared by different procedures differed as regards the potency of itssedative property (15).

68 Letter to the Editor Janu~ry 1961Ind. J. Physiol. & Pharrnacol

Banerjee's discovery of asarone as the first tranquillizer which could offer protectionto the extrapyramidal tract instead of producing parkinson's disease is very surprising. It is acommon knowledge that a drug which produces antitremorine effect may not necessarily be anantiparkinsonian agent. Potent antipsychotic and tranquillizing agent which produce park-inson like syndrome are also known to offer a remarkable protection against tremorine inducedtremors. Patten et al (13) have shown that reserpine, and Leslie and Maxwell (11) have providedevidence tha t nonantiparkinson Phenothiazine derivatives like chlorpromazine, prochlorpera-~i~~ and promazine inhibit the tremorine induced tremors in comparatively low doses.

Your corresponcent has not disclosed what was the starting material, what were the resultsof his micro analysis and what modifications did he do in the method of Rao and Subramanium(14) for isolating asarone ? The undersigned will aslo be interested to know about the nature of1. R. spectrum of the asarone prepared by him, so that the readers may be able to judge its super-imposable character.

Banerjee's failure in recording the reduction in spontoneous motor activity in animalstreated with asarone could be attributed to the subjective nature of the procedure adopted by himand also by Dandiya and Menon (6). Person to person variation is high when this technique isadopted. Banerjee's contention that asarone in a dose of 3mg/ kg and IOmg/kg did not poten-tiate the pentobarbitone induced hypnosis, has certainly surprised us. I have repeated the exp-eriment and to eliminate the ethyl alcohol and Tween 80 employed in making asarone solutionin our earlier srudies, solution of asarone was prepared by dissolving asarone in a few drops ofglacial acetic acid and making up the desired volume by adding requisite quantity of distilledwater. The method adopted was exactly identical with the method used by most of the workersfor preparing reserpine solution. The pH of the solution was 3.0 and this was used for allexperiments reported in this letter. Asarone 5mg/kg increased (P <'001) pentobarbital hypnosisfrom 112. 9 (Control) to 202.7 minutes when groups of ten animals were employed for the exper-iment. Not only asarone caused hypothermia in mice (12) it brought about a similar actionin rats, when treated with 4mgj kg of this substance it lowered body temperature by 4.5°C in twohours as against control 1.6°C when the experiment was done at an environmental temperatureof 16°C. It will be interesting to know at what room temperature Banerjee carried out theseexperiments. Even reserpine and chlorpromazine are known not to cause hypothermisa (3) at atemperature of 30°C which is common in tropical countries.

Banerjee has further reported that asarone does not prevent fighting behaviour in micewithout even mentioning the strain used, the technique, the number of pairs employed and theresponse obtained. Information on these points is of vital importance in the absence of whichany comment on his findings will be premature.

Banerjee's complaint regarding failure of asarone to block conditioned avoidance res-ponse (CAR) is most surprising. In our report, quoted by him (5) we have reported CAR aboli-

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Volume 12Number 1

Is Asarone a Tranquilliser 69

shiug property in 3 out of 10 rats in a dose of 3mg/kg is not much different from Banerjee's 2out of 12. I am only wondering as to how your correspondent thought fit to complain about it.

Whether asarone is devoid of any tranquillizing property can not be judged on the sketchyevidence of this kind produced by Banerjee. In this connection one may also refer to Chakand Sharma's (2) report on asarone from CORI, Lucknow. These authors have stated "Asarone(3mgjkg ) is a central nervous system depressant resembling meprobamate and chlordiazepoxidein its effect on conflict behaviour as it increases the number of shocks accepted by the animal(rat) in conflict neurosis. Since a number of drugs which increase the number of shocks takenby an animal in conflict, have been used clinically to counteract anxiety, asarone may also becons'dered an antiauxiety agent". The same authors (2) have concluded that "asarone resemblesreserpine" as regards its antianxiety effect.

Before concluding r will like to emphasize that asarone has been shown to prolong hypno-sis due to pentobarbital sodium, hexobarbital sodium and ethanol in mice (4) to protect Metrazolinduced convulsions and electroshock seizures while facilitating picrotoxin induced convulsionsin rats (4,16). It has also been shown to lower spontaneous activity, cause hypothermia andrecuce anxiety as seen in conflict neurosis in choice discriminiation test, as seen without dullingpreception in rats and reduced fighting behaviour in mice. (2,4,6.). Besides bringing aboutsuch variety of pharmacologic actions in animals, asarone has the ability to potentiate the effectsof reserpine 011 conditioned avoidance response and electroconvulsions in rats and on the fightingresponse in mice (5). Asarone promptly counteracted the stimulation due to d - amphetamine,LSD- 25, and iproniazid but only partially antagonized the effect of imipramine in rats and mice(4, 17). It antagonised the hyperactivity due to mescaline in rats and also offered completeprotection to aggregated mice treated with toxic does of d- amphetamine. In tremorine inducedtemors in mice it was found to be inferior to atropine (7) . It also prevented the depletion ofadrenal ascorbic acid in rats subjected to cold stress showing thereby that it is an agent specificfor counteracting stress (6). Whether a substance which has been shown to possess these afore-said properties is a tranquillising agent or not can be judged by the readers and I will leave it tothem to judge the propriety of our exercise on determining its mechanism of action. Banerjeein his communication (1) has obviously mixed up the term antipsychotic property with tranqu-illising property, which are fairly well differentiated in modern pharmacology literature (10).

It would not have been inappropriate if Banerjee had also disclosed the identity of theinstitution .where his studies were conducted while he was working as assistant research officerof the I. C. M. R. In the absence of this information, are we to believe that studies were conducted in the Department of Pharmacology, University of Toronto from where his communicationwas addressed ?

Dr. P. C. OandiyaProfessor of Pharmacolagy;S. M. S. Medical College,

Jaipur, Rajasthan.

70 Letter to the Editor January 1968Ind. J. Physiol. & Pharmacol.

REFERE CES

1. Banerjee, S.P. Is asarone a tranquilliser. Ind. J. Physiol. & Pharmacol. 11:191. 1967.

~. Chak, I.M. and Sharma, J.N. Effect of asarone on experimentally induced conflictneurosis in rats. : lad. J. Exp. BioI. 3:252, 1965.

3. Dandiya, P.c., G. Johnson and E.A. Sellers. Influence of variation in environmentaltemperature on the acute toxicity of reseprine and Chlorpromazine in mice. Can. 1.Biochem. Physiol. 3S:591, '1960.

4. Dandiya, .P.C. and J.D. Sharma. Studies on Acorus Calamus Part V, Pharmacologicalactions of asarone and ~-asarone on central nervous system. Ind. J. Med. Res., 50:46,1962.

5. Dandiya, P.c. and M.K. Menon. Effects of asarone and ~·asarone in conditionedResponse, Fighiting Behaviour and convulsions. Brit. J. Pharmac. 20:436, ]963'

6. Dandiya, P.e. and M.K. Menon. Action of Asarone on behaviour, Stress and hyper-pyrexia and its interaction with central stimulants. J. Pharmacol. Exp. Therap.,145:42, 1964.

7. Dandiya, P.C. and M.K. Menon. Interaction of asaron, with mescaline, tremorineand amphetamine. Life Sci., 4: 1635, 1965.

8. Dandiya, P.C., P.K. Sharma and M.K. Menon. Structure activity relationship of someLocally synthesised trimethoxy benzene derivatives. Ind. J. Med. Res. 50:750, 1962.

9. Dandiya, P.C., R.M. Baxter, G.C. Walker and H. Cullumbine. Studies Oll AcarusCalamus, Part 1I, Investigation of Volatile Oil., J. Pharm. Pharmac. 11:163, 1959.

10. Hollister, O.E. Complications from psychotherapeutic drugs. Clin. Pharm. Therap.5:322, 1964.

11. Leslie, G.B. and n.R. Mapwell. Jnhibition of tremorine by a group of non-anti-Par-kinson phenothiazine derivatives. Nature. 202:97, 1964.

12. Menon, M.K. and P.c. Dandiya. The mechanism of the tranquillising action of asar-rone from Acorus Calamus, Linn. J. Pharm. Pharmac. 19:170, 1967.

13. Patten, B.M., A. Sakamoto., M.H.V. Woert., P.S. Papavasilious and G.C. Cotzias.Tremorine-induced Tremor versus extra-pyramidal disease. Nature, 201 :9Q9, 1964.

14. Rao, B.S. and K. Subramaniam. ~-asaorine. J. Chem. Soc., 1338:1937.

15. Schlittler, E. "CNS". Drugs," published by Council of Scientific and Industrial Re-search, New Delhi, p. 7, 1966.

16. Sharma, J.D., P.C. Dandiya, R.M. Baxter and S.l. Kandel. Pharmacodynarnical effects.of asarone and f3-asarone. Nature, 192:1299, 1961.

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