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Ind. J. Pharmac.

(1970), 2 (3), 67-90


Review Article

CNS-ACTIVE DRUGS FROM PLANTS INDIGENOUS


TO INDIA
BY

P. C. DANDIYA AND Y. M. CHOPRA


Department of Pharmacology,
S. M. S. Medical College, Jaipur.
INTRODUCTION

With the isolation of reserpine from Rauwolfia serpentina there has been a
renewed effort on the part of chemists and pharmacologists of thii country towards
investigating other vegetable drugs of the Ayurvedic, Unani and the Tibbi systems
of medicine. This work has been largely sponsored by the Indian Council of
Medical Research and the Council of Scientific and Industrial Research. The need
for a review of recent research papers on the subject is obvious. The present
article is an attempt in this direction and is restricted to CNS active drugs. The
plants covered in this review are : Acorus calamus, Cannabis indica, Celastrus paniculatus,
Cissampelos pareria, Convolvolus pluricaulis, Daucus carota, Hsrpestis monniera, Paspalum
scrobiculatum, Prangos pabularia, Rauwolfia cancens, Withania somnifera, Glycosmis penta-
phylla, Leptadenia reticulata, Piper peepuloides and Sisli sebricum.
ACORUS CALAMUS LINN.
(Family : Araceae)

The roots and rhizomes of Aorus calamus Linn., Vachu (Sanskrit), Ugragandha,
Bach and Bacha (Hindi), have been widely used in the powder form in the
Ayurvedic system for the treatment of neurosis, insomnia, melancholia and hysteria
(Nadkarni, 1927 ; Agarwal et al., 1956).
Chemical investigations
The volatile oil of Acorus calamus Linn. has two active substances asarone* and
6-asarone, trans and cis forms, respectively, of 2, 4, 5-trimethoxy-1-propenyl
benzene (Baxter, Dandiya, Kandel, Okany and Walker, 1960). The liquid-gas

*Another source of asarone is the wild e a r r o t f r u i t s collected in central Asia ( P i g u l e v s k i i a n d


Kovaleva, 1961).
68 ] P. C. DANDIYA AND Y . M. CHOPRA

chromatography behaviour has been reported by Baxter, Fan and Kandel (1962).
OCHs OCH,
I I
/\/OCHs /\/OCHs
I I
CH,0 \i H
I I
CHs O/a/
A=A--CH I C=C-CH,
I
iI A A

2, 4, 5-trimethoxy-propenyl benzene asarone (trans) and 3-asarone (cis).


Pharmacological studies
(i) Oil: The hypnosis potentiating activity and hypotensive properties of
roots and rhizomes of Acorus calamus resides in the volatile oil (Dandiya and
Cullumbine, 1959 ; Dandiya et al., 1959a ; Bose et al., 1960 ; Malhotra et al., 1962)
The oil lowered blood pressure in anaesthetised cats, caused hypothermia in mice
and prevented action of acetylcholine, histamine and barium chloride on isolated
gut. Dandiya et al. (1959b) showed that the hypnosis potentiating property of
Acorus oil was not due to its hypothermic action.

The oil had sedative and tranquillising effects in rats, cats, dogs and monkeys.
It elicited vomiting in cats, dogs and monkeys. It inhibited flexor patellar and
linguo-mandibular reflexes without blocking the neuromuscular function. Thus,
the drug has central muscular relaxant properties (Dhalla and Bhattacharya,
1962). The oil depressed the respiration of rat brain in vitro which was potentiated
by 5-HT (Dhalla et al., 1961b). It showed quinidine like activity on heart and
afforded protection against electrically induced convulsions (Madan et al., 1960).

(ii) Asarone : Asarone has been shown to prolong hypnosis due to pentobar-
bital sodium, hexobarbital sodium and ethanol in mice and this could not be
prevented by LSD-25 or iproniaxid (Dandiya and Sharma, 1962a). Asarone
prevented Metrazol-induced convulsions and electroshock seizures but facilitated
picrotoxin-induced convulsions in rats (Dandiya and Sharma, 1962a ; Sharma
et al., 1961).

Asarone lowered spontaneous motor activity and slightly reduced anxiety.


Even in small doses (l mg/kg) asarone produced a calming effect in monkeys which
lasted for 24 hr. In a dose of 3 mg/kg it resembled meprobamate, chlordia-
xepoxide and reserpine in increasing the number of shocks accepted by experimental
CNS-ACTIVE INDIGENOUS DRUGS . [ 69
animals in conflict neurosis (Chak and Sharma, 1965). The onset of action was
quicker than that reported for reserpine. It caused hypothermia in mice (Dandiya
and Sharma, 1962a) and in low doses counteracted LSD-25 induced hyperthermia
(Dandiya and Menon, 1964). Asarone potentiated the effects of reserpine on
conditioned avoidance response and electroconvulsions in rats and also on fighting
response in mice (Dandiya and Menon, 1963).
Asarone promptly counteracted the stimulation due to d-amphetamine,
LSD-25, methyl-phenidate and mescaline but only partially antagonised the effect
of imipramine in rats and mice (Dandiya and Meaon, 1964). It also offered
complete protection to aggregated mice tested with toxic doses of d-amphetamine
where it was found to be more effective than chlorpromazine. Asarone was found
to be inferior to atropine in tremorine induced tremors (Dandiya and Menon,
1965). Asarone, unlike reserpine, did not deplete the brain of its 5-HT content nor
did it influence the 5-HT depletion of reserpine in rats (Dandiya and Menon,
1963). The sedative effect caused by asarone in iproniazid treated mice (Dandiya
and Menon, 1964) as well as the absence of any increase in the 5-HIAA in urine
of rats is in contrast to the effects of reserpine. No analgesic action was observed
in rats and mice (Dandiya and Sharma, 1962a).
Asarone elicited a mild hypotensive effect in anaesthetised dogs and caused a
varying degree of anti-acetylcholine activity as seen in isolated muscle preparation.
It antagonized smooth muscle contractions induced by histamine and 5-HT
(Dandiya and Menon, 1964 ; Das et al., 1962). It also prevented the depletion of
adrenal ascorbic acid in rats subjected to cold stress. It increased the mortality of
rats by chlorpromazine, but not by reserpine (Dandiya and Menon, 1964).
(iii) p-asarone : @-asarone similar to asarone prolonged hypnosis due to
pentobarbital sodium, hexobarbital sodium and ethanol, which was not prevented
by LSD-25 or iproniazid. It lowered rectal temperature of mice, caused hypoten-
sion in anaesthetised dogs and showed anti-acetylcholine activity in isolated muscle
preparation. Unlike asarone, p-asarone facilitated electroshock and picrotoxin
l
induced seizures, whereas it lowered Metrazol threshold in rats, another property
which it shares with asarone (Dandiya and Sharma, 1962a, b).
Clinical trials
Fifty per cent of the 22 patients of psychosis improved after treatment with
root powder of Acorus ca1amu.s but the results in neurotics were not as satisfactory
(Fozdar et al., 1964).
CANNABIS INDICA LINN.
(Family : Cannabinaeceae)
This very ancient drug is mentioned in the herbal of the Chinese emperor
70 ] P. C. DANDIYA A.ND Y . M. CHOPRA

Shen Nung. Cannabis is obtained from the flowering tops of hemp plants and is
also known by other names like Hashish, Charas, Bhang, Ganja, Dagga and Marihuana.
The common hemp is Cannabis sativa and it constitutes a sole species while Cannabis
indica and C. americana are other varieties. The resinous mass of the female plant
constitutes most of the active ingredients. In the Middle East and North Africa the
resin is called Hashish and in the Far East it is called Charas. The dried leaves
and upper part of the twig, containing a smaller quantity of the substance, is called
Bhang and the resinous mass obtained from small plant and brackets is called
Ganja. Marihuana is the common name for any part of the plant which induces
somatic and psychogenic effects in man.

C h e m i c a l investigations
Most active ingredient in cannabis is tetrahydrocannabinol (Wollner et al., 1942)
having the following structure :

CH, OH

)-\_>==Lc H
\_(co>_/ s nts)

C<3 \cH *

Many derivatives of tetrahydrocannabinol have been synthesised and some of


these are more potent than tetrahydrocannabinol. Chromatographic separation has
yielded eight phenolic fractions (De Ropp, 1960).

Pharmacological studies
(i) Tetrahydrocannabinol : Pharmacological effects of tetrahydrocannabinol
are largely confined to central nervous system but the elaborate behavioural and
neurophysiological effects were not reported till about 10 years ago. Bose et al.
(1963) observed that animals given Marihuana showed vomiting and diarrhoea,
fibrillary tremors and ataxia. The drug did not produce gross sedation or hypnosis
in animals, but it increased hexobarbital sleeping time, enhanced the action of
reserpine and antagonised the action of 5-I-IT in mice. It potentiated the increase
in activity produced by amphetamine but depressed blood pressure and respira-
tion. Oxygen utilisation of brain was also depressed. The drug produced
excitement, followed by depression and ataxia. The EEG studies indicated an initial
depression of parietal area of cortex with simultaneous stimulation of the frontal
region followed by depression of both. The recovery of animals was characterised
by increased excitability of neurons (Bose et al., 1964a). It increased 5-HT
CNS-ACTIVE INDIGENOUS DRUGS [ 71

content of brain but antagonised the peripheral actions of 5-HT. These workers
suggested that the psychotomimetic effect of this drug, might be related to anta-
gonism of 5-HT, acetylcholine, adrenaline and noradrenaline. (Bose el al., 1964b).

CELASTRUS PANICULATUS WILLD.


(Family : Celastraceae)

Its common names are Jyotismati (Sanskrit) or Malkanguni (Hindi). The oil
obtained from its seeds has been used as sedative, nervine tonic and diuretic
(Aryabhishak, 1939). Desai (1927) referred to its use in mental conditions and for
increasing memory. The oil is a brownish, and viscous mass with a characteristic
odour.

Chemical investigations
Chromatography and fractionation of oil under high vacuum short path
distillation apparatus yielded fractions slightly more active than the oil but the
most potent fraction was isolated by employing the counter current distribution
method and was called fraction Ma1 III.

Further fractionation of Ma1 III yielded two fractions :


(i) Fraction Mal-III/A
(ii) Fraction Mal-III/B

Pharmacological studies
Gaitonde cl al. (1957) observed sedative, tranquillising and anticonvulsant
effects of oil in rats and hypotensive effect in dogs. Sheth et al. (1963) also
observed tranquillisation at a high dose (2 to 4 g/kg) besides vomiting, salivation
and tremors.

(i) Fraction Mal-III/A produced tranquillisation without any salivation,


vomiting, diarrhoea and tremors. Its tranquillising action was evaluated by a
battery of experiments. Mal-III/A was found to protect against the leptazol
toxicity and decreased mortality in grouped mice due to amphetamine but larger
doses of Mal-III/A were found to lose this effect. Orientation, hyperactivity
and oxygen consumption in mice were also decreased by Mal-III/A. This fraction
caused hypotension and diminished the carotid occlusion reflex in dogs.

(ii) Mal-III/S in equal doses (200 mg/kg) did not produce tranquillisation.
It produced marked salivation, vomiting, diarrhoea and tremors (Sheth et al.,
1963).
72 ] P. C. DANDIYA AND Y . M. CHOPRA

CISSAMPBLOS PAREIRA LINN.

(Family : Menispermaceae)
This climbing shrub is common throughout tropical and subtropical parts of
India, Asia, East Africa and America. The roots of this plant are substituted or
adulterated with " t u r e pariera derived from Chondrodendron tomentosum, a native
of Brazil and Peru. It is known by many names such as Akanadi, Nemuka,
Tejomalla, Dakhnirbissi, Pari, Devi etc. The roots of C. Pareira are bitter and
are employed in febrile conditions, dysentery and heart troubles (Chopra et al.,
1958). In French Guinea the roots are used as diuretic in dysuria and calcular
nephritis. The roots are also claimed to act as an antiseptic for the bladder and
chronic inflammation of urinary passage. The leaves are used in the cases of
unhealthy sores and sinuses (Chopra et al., 1958).

Chemical investigations
Wigger in 1840 reported an amorphous powder from the roots of South
American plant, which was later named pelosine. Pelosine has an isoquinoline
group, m.pt. 213C and molecular formula CssHssOsNs. Sholtz (1896) showed
that pelosine is identical to berberine. Sen and Chowdhary (1965) isolated
the following alkaloids from different extracts of the plant : berberine, cycleanine,
hayatinin, hayatidin and hayatin.
Hayatin, hayatidin, cycleanine-1-berberine (curine) and an orange base were
isolated by Bhatnagar and Popli (1967). Kupchan and coworkers (1960) reported
d-isochondrodenary base and a bis-base containing a dihydroquinoline nucleus
besides hayatin and curine in the extract. Bhatnagar and Popli (1967) estab-
lished the structure of hayatin as 4-O-methyl-berberine, proposed earlier by
Bhattacharji et al. (1956).

Pharmacological studies
Hayatin : Floriana (1936) showed that the combined active principles had
low toxicity and increased the tone of isolated heart whereas larger doses caused
paralysis and stoppage in diastole. The respiration rate in animals was accelerated
for a transient period. On comparing the curariform activity of hayatin hydro-
chloride, hayatin methochloride and hayatin methiodide, methochloride deriva-
tive was found most potent (Pradhan and De, 1959). It was suggested that the
methyl group augmented the curariform activity whereas ethyl or butyl groups
decreased it. The effect of hayatin derivatives on blood pressure and respiration
was similar to that of curare. The ganglionic blocking activity was observed only
with ethyl or butyl derivatives but not with methyl derivatives (Pradhan and
CNS-ACTIVE INDIGENOUS DRUGS [ 73
De, 1959). The halide derivatives of hayatin were less potent then ethereal
halide derivatives. Methyl ether iodide was most potent in the series tested by
Ray, Varadhan and De (1960) on the sciatic nerve gastrocncmius muscle prepara-
tion of the dog. Methyl halide and methyl ethereal halide resembled closely in
their pharmacological and chemical characteristics. On skeletal muscle hayatin
methiodide was found to be twice as potent as d-tubocurarine.

The margin of safety for this drug was very low and its curariform action was
antagonised by anticholinesterases (Pradhan and De, 1953). The site of action
of hayatin, according to Sur and Pradhan (1964), is mainly at surpraspinal level
and is slightly on spinal cord.

CONVOLVOLUS PLURICAULIS CHOIS.


(Family : Convolvulaceae)

This plant, commonly known as Shankhpuspi in Hindi, is employed in the


Ayurvedic system as a brain tonic in insanity and neuraesthenia. It grows on the
waste land in the plains of Punjab, Bihar and Chhotanagpur. The herb produces
flowers during the months of September and October which are white to light pink
in colour.

Chemical investigations
The alkaloid, Shankhpuspine, tannins and essential oil were isolated from
the fresh plant (Basu and Dandiya, 1948).

Pharmacological investigations
Total water extract : The soluble fraction of the plant caused a marked and
prolonged hypotension in dogs and inhibited the frog myocardium (Rakshit and
Basu, 1958 ; Chaturvedi et al., 1966). Barar and Sharma (1965) confirmed the
findings of the early workers and reported that the extract caused transient depres-
sion of the amphibian and mammalian myocardium. It had spasmolytic activity
on smooth muscles except in bronchial muscle. It potentiated the response of
acetylcholine on bronchial and skeletal muscles. The extract did not exhibit any
sedative or hypnotic property but potentiated significantly the hypnotic effect of
barbiturate and abolished conditioned avoidance response without significantly
affecting the escape response, like other tranquillisers. The extract caused a reduc-
tion in the fighting behaviour in mice but was devoid of analgesic activity although
it potentiated morphine analgesia (Sharma et al., 1965). These workers suggested
that the extract might act by its action on subcortical areas of the brain.
74 1 P. C. DANDIYA AND Y. M. CHOPRA

DAUCUS CAROTA LINN.


(Family: Umbelliferae)

It is a widely grown plant in India and other parts of the world. It is known
by its different names like Gajar, Garjar, Shikamulam etc. The seeds are widely
used in Ayurvedic system as a nervine tonic, aphrodisiac, diuretic, expectorant
(Chopra el al., 1958) and are also employed for the ailments of stomach, chest,
heart and spleen. The decoction of leaves and seeds is used as an uterine stimulant
during parturition (Kirtikar and Basu, 1935), as an emmenagogue (Chopra et al.,
1958) and as an abortifacient (Nadkarni, 1954).

Chemical investigations
The fruits of cultivated carrot yield l-1.5% of an essential oil containing :
(i) Terpenes and alcohol (a) a-pinene ; (b) limonene ; (c) a crystalline body
daucol, a terpene alcohol (Finnemore, 1926) ; (d) geraniol acetate and
(e) two terpenes C,,H,, (Pigulevskii and Kovaleva, 1956), one bicyclic
sequiterpene and the other sabininine.
(ii) An alkaloid : It is different from the alkaloids from leaves (Picket and
Court, 1905 ; Gambhir et al., 1966a, b).
(iii) A bitter glucoside : daucusin (Reeb, 1923; Gizycki and Harrmans,
195 1) ; luteolin 7-glucoside (Nakaoki and Morita, 1960).
(iv) Other constituents isolated from the seeds are Asarone, Carotol and
bisabolene (Richter, 1909, lemon yellow anthraquinine like crystals
which inhibited the growth of Shigella dysentery (Chu et al., 1962) and a
quarternary base (Gambhir et al., 1966a, b).

The leaves contain two bases, pyrolidine and daucine (Picket and Court,
1907 ; Gizycki and Herrmans, 1951) besides essential oil. From the roots of this
plant various vitamins like vitamin A, B, C and D have been isolated.

Pharmacolagical studies
Essential oil : The essential oil caused a direct depression of vasomotor centre,
myocardium and smooth muscle of blood vessels (Agarwal, Dandiya and Sharma,
1953). Chemical analysis of water soluble fraction of alcoholic extract of seeds
showed the presence of alkoloids. The pharmacological study of this extract
indicated the presence of principles having cholinergic and papavarine-like activity.
The presence of a cardiotonic principle in the extract was also suggested by
Gambhir et al. (1966a). Bhargava, Ali and Chauhan (1967) reported that the oil
possessed anticonvulsant property.
CNS-ACTIVE INDIGENOUS DRUGS [ 75
HERPESTIS MONNIERA H.B. & K.
(Family : Scrophulariaceae)
In Ayurvedic system Herpestis monniera (Brahmi) has been extensively used
in various nervous disorders such as insanity, epilepsy, hysteria etc. It has been
claimed as nervine and cardiac tonic (Chopra, 1933).
The extract of the whole plant produced cardiotonic, vasoconstrictor, sedative,
neuromuscular blocking and smooth muscle stimulating effects (Malhotra and Das,
1959) and decreased the motivation for food without affecting visual discrimina-
tion or neurological deficit (Malhotra and Ganguly, 1969).
Chemical investigations
Sastry et al. (1959) reported the presence of a glycoside, hersaponin. Das
et at. (1961) isolated three alkaloids from the whole plant extract, one of these
being nicotine.
Pharmacological studies
(i) Total alkaloids : The total alkaloidal fraction stimulated autonomic
ganglia, respiratory rate and smooth muscle in smaller doses. The larger doses
caused depression of ganglia, respiration and smooth muscles, showed tachyphy-
laxis and produced rigidity and convulsions. Sengupta and Mitra (1962) reported
that the infusion of the powdered drug lowered the blood pressure in animals,
which was followed by an intermediate rise and a more sustained and gradual fall
subsequently. The decoction of the drug, however, caused a rise in blood pressure
instead of fall. This finding led these workers to speculate that the plant has both
hypertensive and antihypertensive constituents.
(iii) Hersaponin : The pure glycoside saponin principle produced cardiotonic
effect on frogs heart, sedative effect in rats and guineapigs and stimulated the
smooth muscles (Malhotra and Das, 1959). It potentiated the hypnosis produced
by hexobarbitone (Malhotra el al., 1960a) besides causing hypothermia in mice
which could be markedly reduced when the temperature was elevated from 20 to
37C. These observations suggested that the glycoside had a central action like
that of reserpine and chlorpromazine.
Hersaponin, unlike reserpine, did not affect the metrazol toxicity but inhibited
the potentiating action of reserpine on this toxicity in aggregated mice (Malhotra
el al., 1960a). The potentiating effect of the glycoside on barbiturate hypnosis
could be due to the delay of metabolism and disappearance of blood pentobarbitone
(Malhotra et al., 1962). Hersaponin depleted noradrenaline and 5-HT contents
from the brain of rats like reserpine (Malhotra et al., 1961a).
76 ] P. C. DANDIYA AND Y . M. CHOPRA

PASPALUM SCROBICULATUM LINN.


(Family : Gramineae)

Paspalum scrobiculatum is a sturdy, thriving millet which grows even in the


poorest soil, and was also cultivated in ancient India (Charaka about 1000 B.C.).
The drug is commonly known as Kodra, Harik, Kodo, Kodrava etc. It is claimed to
be a remedy for scorpion sting in indigenous system (Chopra et at., 1958). The
dehusked seeds are consumed by poor population as food but it may produce
poisoning in man and livestock (Gupta and Bhide, 1967).

Chemical investigations
No systematic chemical study has been undertaken to isolate the active
principle of this drug. Bhide (1962) indicated that the active principle responsible
for the tranquillising activity resided in alcoholic extract. Further fractionation
of this extract yielded four different fractions (I, II, III, IV). Fraction I was
found to be hydrophillic and showed the presence of catechol rings whereas other
fractions were amorphous and waxy yellow solids which were soluble in organic
solvents. The tranquillising principle in the alcoholic extract is devoid of nitrogen
and sulfur (Krishnaswamy and Bhide, 1963) and was recently isolated in pure
crystalline fraction (Dhar and Tandon, 1967).

Mehta e t al. (1968) confirmed the presence of tranquillising principle in


alcoholic extract and further suggested that the tranquillising principle was in the
testa of the husk. This principle was soluble in rectified spirit, methanol and the
fat solvents. It was found to be stable at room temperature for 3 years but
deteriorated on prolonged storage, in U.V. light and in acidic or alkaline media.

Pharmacological studies
The alcoholic extract of the husk of unpolished grain produced tranquillisa-
tion and tremors similar to major tranquillisers such as reserpine and chlorproma-
zine (Bhide and Aiman, 1959 ; Bhide, 1962). It potentiated barbiturate hypnosis,
produced hypothermia in mice and rats and enhanced the leptazol toxicity in rats.
It produced vomiting in pigeons and decreased the morphine rage in cats. Injec-
tion of the extract or the emulsion of the extract in oil increased the amphetamine
toxicity in mice. This indicated that the tranquillising principle resided in the
husk but not in the completely polished grain.

The drug caused hypotension and diminished carotid occlusion reflex. In


man, oral administration of the extract produced tremors of extremities, sleep
and thick speech. The electroencephalographic records, pulse rate and axillary
CNS-ACTIVE INDIGENOUS DRUGS [ 77
temperature were unaffected, but hypotension occurred on 2nd or 3rd day (Bhide,
1962).
Bhide (1962) showed that fractions I and II produced catelepsy and tremors,
whereas, fractions III and IV did not produce such symptoms in animals.
Clinical assessment
It was successfully used in over 120 acutely schizophrenic patients (Deo and
Bhide, 1961 ; Deo, 1964 ; Shah et al., 1964, 1966a and b).
PRANGOS PABULARIA LINDL.
(Family : Umbelliferae)
Prangos pabularia (Komal) is a tall perennial herb found in Kashmir at the
altitude of about 6000 to 11,000 ft. In Ayurvedic system this plant has been
employed as carminative, laxative, stomachic, diuretic and emmenagogue
(Nadkarni, 1954).
Chemical investigations
The essential oil from the seeds was first separated and fractionated by Grasch
(1939). Gupta et al. (1960) isolated two crystalline substances A and B from the
roots of the plant. Substance A, having m.pt. 84-85C, has been identified as
Osthol, which is a naturally occurring coumarin. Substance B, was found to be
biologically inactive.
Osthol and its other two derivatives, ostruthin (m.pt. 117-119C) and
ostruthol (m.pt. 136-137C) were reported by Butenandt et al. (1932) from the
rhizomes of Imperatoria ostruthium (N. O. Umbelliferae). Substance A (osthol),
having molecular weight of 244.8, m.pt. 82 to 84%. is a long needle shaped crysta-
lline substance. It is insoluble in water but soluble in aqueous alkalis, alcohol,
chloroform, acetone and boiling petroleum ether. The structure of osthol is :
CH,
CH&H : C/
\CH,
0

CHsO- ,/\j\ =CO


II I I
\/\/
The alkaline ether extraction of the seeds gave 0.2% alkaloids which on purification
yielded crystals, having m.pt. 132C. (Yunusov et al., 1959). It is also reported to
have aviprin and komalin (Gupta et al., 1964).
78 ] P. C. DANDIYA AND Y. M. C H O P R A

Pharmacological studies
Osthol : Gupta et al. (1960) showed that osthol produced stimulation of
respiration and elevated the blood pressure. It inhibited the smooth muscles of
uterus and intestine and showed a moderate antiacetylcholine and antihistaminic
activity. Jamwal et al. (1962) reported that osthol elevated the blood pressure to
a marked degree, stimulated the cardiac muscle and constricted the blood vessels. It
antagonised the respiratory depression due to barbiturates and morphine, lightened
the anaesthesia and caused twitchings of the voluntary muscles (Jamwal et al,
1962 ; 1964). It increased the respiratory rate, depth, minute volume and tidal
air. The respirotonic effect was comparable with that of analeptics like niketha-
mide, leptazol and caffeine and was shown to result mainly from central action on
the medulla and partly through peripheral action on chemoreceptors. Electro-
cardiographic studies in animals showed that osthol is not toxic to cardiac muscle
(Jamwal et al. 1964). In toxic doses it caused convulsions, vomiting and stimula-
tion of respiration.

Osthol decreased the concentration of carbondioxide and increased oxygen


and pH of plasma (Gupta and Jamwal, 1969). These workers attributed the
changes to the increased ventilation.

This substance was nontoxic in acute and subacute toxicity studies on


various species of animals (Gupta and Jamwal, 1969).

RAUWOLFIA CANCENS LINN.


(Family : Apocyanaecae)

The roots of this plant are used sometimes to adulterate the roots of the official
plant R. serpentina. It abundantly grows in Bengal and its use in indigenous
therapeutics has not been indicated either in Watts Dictionary of Economic
Products of India or in Hooks Flora (Chopra et al., 1956).

Chemical investigations
The presence of alkaloid in the extract of bark was first reported by Greshoff
in 1890 but he could not isolate or purify the alkaloid. Mookerjee (1941) isolated
an alkaloid, Rauwolscine, (C121~s10sN3 with m.pt. 231-232C) from the leaves.
This alkaloid gave colour reactions different from rcserpine but similar to
yohimbine and is a stereo-isomer of yohimbine. It is distributed throughout the
plant (bark 0.l%, stem bark 0.2% and leaves 0.5%). A weak base (m.pt. 230-232C)
soluble in organic solvents was isolated by Mezey and Uribe (1954).
CNS-ACTIVE INDIGENOUS DRUGS [ 79

Pharmacological studies
(i) Rauwolscine :
( a ) Cardiovascular effect: Rauwolscine, caused depression o f cardiovascular
system in experimental animals. It lowered the blood pressure by depressing the
cardiac muscle and reducing the minute output of the heart. A characteristic
feature of the alkaloid was that it exerted the hypotensive action only in hyperten-
sive subjects. The hypotensive effect was shown to be due to peripheral vasodila-
tation because of its sympatholytic effects, decreased vasomotor tone and reflex
blocking activity (Mukherjee and Sen, 1933 ; Chatterjee et al., 1954). A predomi-
nently central site of action has been shown by Das et al. (1955) and Kohli et al.
(1962). The central vasomotor depressant action of rauwolscinc, independant of
peripheral adrenergic block was demonstrated by Tangri and Bhargava (1961).
Levy and Koelle (1958) demonstrated that this alkaloid elicited hypotension by
vasodilation and ruled out the central site of action. They viewed that adrenergic
blockade produced by the alkaloid was short lived and reversible and it produced
an insignificant change in heart rate in cats and a transient bradycardia in dogs.
The hypotensive action of this alkaloid, has also been attributed to pH changes by
free acids liberated by this alkaloid (Kohli et al., 1962).

(b) CNS effects : Rauwolscine produced central stimulation followed by dep-


ression in rabbits, guinea-pigs, rats and mice. It lowered convulsant threshold
for metrazol but did not antagonise barbiturate hypnosis. It did not produce
endocrinal changes or any other toxic effect when administered for a longer period
(Kohli et al., 1961).

An antidiuretic activity of the alkaloid has also been reported (Kohli et al.,
1962).

The roots of another specie?, R. beddomei Hook. F. yielded several alkaloidal


bands by paper chromatography of which a-yohimbine and serpagine were
identified (Bose et al., 1956).

Bose (1958) isolated an indole alkaloid, rauwolfinine, m.pt. 23%36C, from


R. serpentina Benth (Dehra Dun variety).

WITHANIA SOMNIFERA DUNAL.


(Family : Solanaceae)

This plant (Ashwagandha) has been used in Ayurvedic system in rheumatism


and as an aphrodisiac, tonic and abortifacient (Chopra et al., 1956).
80 ] P. C. DANDIYA AND Y. M. CHOPRA

Chemical investigations
Covello and Ciampa (1960) showed the presence of 8 alkaloids in the roots.
Dhalla et al. (196la, c) reported the presence of a crystalline compound, named
withanone (m.pt. 263C) from the extract of the plant. Withanone contained
lactone and steroidal rings in its molecule. Sommitol, glucose and a large quantity
of inorganic salts were also isolated from the plant by these workers. Fractionation
of the extract by paper chromatography revealed the presence of five alkaloidal
bands. The total alkaloidal fraction is known as ashwagandholine. These workers
also reported presence of the amino acids like cystine, glycine, glutamic acid,
alanine, proline and tryptophan in the whole plant.

Pharmacological studies
(i) Extract: Malhotra et al. (1960b, c) observed that the total extract had
sedative effect in different species of animals, and biphasic effect on various smooth
muscles. It caused hypotension, bradycardia and respiratory stimulation in dogs.
The bradycardia and hypotension were thought to be due to its direct cardio-
depressant effect whereas the respiratory stimulation appeared to be due to its
direct action on respiratory centre (Malhotra et al., 196la). In a subsequent study
the hypotensive, bradycardiac and respiratory stimulant actions were attributed to
the autonomic ganglionic action (Malhotra et al., 196lb). These actions were
shown to be due to the alkaloids and they were approximately twice as active as
the total extract.

Dey and Chatterjee (1968a) observed that the extract caused sedation in mice
with a marked diminution in response towards the external stimuli and a pro-
nounced potentiation of thiopental sleep. Dey and Chatterjee (1961) observed
that the plant did not antagonize strychnine and metrazol induced convulsions
and lethality, but delayed the onset of semicarbazide induced convulsions in rats.

(ii) Ashwagandholine : Malhotra et al. (1965a) observed that ashwagandho-


line had papaverine like action on smooth muscles but was several times weaker.

Ashwagandholine had a taming and mild depressant effect on central nervous


system in different species such as monkeys, cats, dogs, rats and mice. It produced
hypothermia and potentiation of barbiturate, ethanol and urethane induced
hypnosis in mice (Malhotra et al., 1965b). The total alkaloidal fraction could be
divided in three portions depending upon the solubility : (a) water soluble
(b) alcohol soluble and (c) acetone soluble (Prasad and Malhotra, 1968). Water
and alcohol soluble portions did not exhibit any significant neuropharmacological
CNS-ACTIVE INDIGENOUS DRUGS [ 81

effects whereas acetone fraction was pharmacologically active. It had a mild


depressant effect on central nervous system (tranquilliser-sedative type) in dogs,
albino rats and mice. It facilitated the convulsions induced by metrazol, but
prevented supra-maximal electroshock seizures in rats. It produced hypothermia
and potentiated the hypnosis induced by central nervous system depressants like
barbiturate, ethanol and urethane in mice. The potentiating effect was not
antagonised by lysergic acid diethylamide and dibenzyline. This fraction was
devoid of analgesic activity and was not irritant to mucous membrane (Prasad and
Malhotra, 1968).
(iii) Ashwagandhine and ashwagandhanine : The acetone soluble fraction of
total alkaloids from the roots was dried and treated with chloroform. Ashwagan-
dhine, a brown powder, m.pt., 105C (with decomposition) and an orange brown
powder, ashwagandhinine, m.pt. 220-225C were isolated.
Ashwagandhine had a slight cardiotoxic activity in normal perfused frog heart
while ashwagandhanine, had only a negative inotropic activity in perfused frog
heart and Straubs ventricle (Das et al., 1964).
Clinical trials
Clinical assessment made by the extract of whole plant in patients with
various types of arthropathies has indicated its use in rheumatic pains and warrants
its trial in a large number of cases (Bector et al., 1968).
GLYCOSMIS PENTAPHYLLA RETZ. D.C.
(Family : Rutaceae)
It is commonly known as tooth burn in indigenous system. The active cons-
tituents isolated from this plant are (i) Glycosmin, identical with veratroyl salicin,
having molecular formula CaJHeaO10 and m.pt. 169C (Dutta, 1935). (ii) Alkaloids :
(a) Arborine, having molecular formula C,sH%N,O and m.pt. 155-156X ; and
(b) Arborinine, having molecular formula C,,Hs,O,N, and m.pt. 175-l 76C
(Chacrabarti et al., 1963). Two new epimeric pentacyclic triterpenes, arborinol I
and isoarborinol II have also been isolated (Pakrashi et al., 1964 and Vorbrueggen
et al., 1963). Earlier Chatterjee and Majumdar (1952,1953) isolated three alkaloids :
(a) Skimmianine (0.03%), having molecular formula CllHlsOl and m.pt. 175-176C;
(b) Glycosminine (0.003%) with m.pt. 175-176C and (c) Glycosine (0.25%),
having molecular formula of C,,I-I,,ONs m.pt. 155-156%. It was identical to
arborine (Chacrabarti et al., 1963, Pakrashi et al., 1963).

Dey and Chatterjee (1963b) observed that glycosine blocked the central
82 ] P. C. DANDIA AND Y. M. CHOPRA

actions of mescaline and counteracted convulsions induced by strychnine and


metrazol. It showed tranquillisation in animals. It produced hypotension and
inhibited the contraction of toad heart (Dey and Chatterjee, 1968b).
LEPTADENIA RETICIJLATA W. & A.
( N.O. Aselepiadaceae )

It is common in Punjab and Western Peninsula and is known as Jivanti


(Sanskrit). It is one of the ingredients of patent Siladan which is claimed to be
used in different kinds of mental disorders like sex-neurosis (Hakim, 1953). It is
also used as a tonic and restorative (Kirtikar and Basu, 1935 ; Nadkarni, 1954 ;
Chopra et al., 1956 and 1958).

Verma and Agarwal (1962) showed that it contained (a) moisture (6-7%) ;
(b) total ash (5.5 to 6.5%); (c) insoluble ash (0.1%); (d) calcium (0.6%); (e) sodium
and potassium calculated as chlorides (2.16 to 2.24%); (f) reducing sugars
aldohexos, ketohexoses and pentoses ; (g) other constituents like proteins, gums, a
steam volatile unidentified ferric (Fe+++) greening substance and a substance which
holds reducing sugars molecules in glycosidal linkage.

Verma and Agarwal (1962) also indicated the absence of alkaloids, tannins,
free catechol, starches, flavonoids and saponins in its aqueous extract.

PIPER PEPULOIDS ROXB.


This plant grows in the tropical regions of Himalayas and in Assam and is
known as Savali Peepal. No systematic chemical investigation of the plant has
been undertaken.

The petroleum ether extract of the plant produced convulsions in different


species of animals, which were partially antagonised by diphenylhydantoin sodium
and troxidione but not by chlorpromazine (Chandhoke and Ghatak, 1968). The
petroleum ether extract acted synergistically with sub-convulsive doses of strych-
nine, metrazol and electroshock. It did not cause hypoglycaemia during these
convulsions. It potentiated barbiturate hypnosis in rats and mice and enhanced
amphetamine toxicity in aggregated mice. These findings led these workers to
suggest that it has mainly a central action and more so on the cerebral cortex
(Chandhoke and Ghatak, 1968).

SISLI SEBRICUM BENTH.


( Family : Umbelliferae )

It is a small perennial herb found in the West Himalyan regions and is sold in
CNS-ACTIVE INDIGENOUS DRUGS I 83

the market under the common name of Bhoot Kesi which is a mixure of this plant
with Selenium vaginatum (Henry, 1921). It is extensively used for the treatment of
psychic disorders in Indian system of medicine.

The volatile oil extracted from the herb produced sedation and slight analgesia
in various species of animals. It potentiated the effect of pentobarbitone in rats.
The oil exhibited fall of blood pressure, vasoconstriction and stimulation in the
respiratory rate. Negative inotropic and chronotropic affects were observed on
heart muscle. It exerted no effect on skeletal muscle (Jamwal el al., 1963).

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( Received June 16, 1969 )