Indian Journal of Pharmacology 1997; 29: S340-S343

THE STATUS AND SCOPE OF INDIAN MEDICINAL PLANTS ACTING ON CENTRAL NERVOUS SYSTEM
ASHOK D.B. VAIDYA
Research Director, Bharatiya Vidya Bhavans S.P.A. Research Centre, Mumbai 400 049 and Professor Emeritus, C.B. Patel Research Centre, Mumbai - 400 049. SUMMARY Ayurveda has quite a sophisticated classification of medicinal plants, as per the dominant pharmacological/therapeutic activity on mental functions etc. These need to be systematically evaluated by a multidisciplinary effort. The most interesting leads of CNS-active medicinal plants, which have emerged, besides Rauwolfia serpentina are (1) Mucuna pruriens for Parkinsons disease (2) Withania somnifera, as anxiolytic (3) Centella asiatica and Bacopa monniera for learning and memory disorders (4) Acorus calamus as anxiolytic and (5) Ocimum sanctum as an antistress agent. The interface of molecular psvchiatrv and the active principles of some of these plants will be a major field for new developments in neuropharmacology and C&-active drugs. Ayurveda herbal drugs

KEY WORDS CNS

A major revolution in ClinicalNeuropharmacology and Psychopharmacology was heralded during the 1950s when effective drugs were discovered, by chance, for psychosis, depression and anxiety1p2. Natural products have played a significant role in the management of neuropsychiatric disorders. Sen and Bose published the first report of the use of Rauwolfia serpentina in the treatment of insanity3. This plant from Ayurveda, was a major breakthrough for understanding hypertension, depression and Parkinsons disease. Ayurveda has described CNS - activity under different categories. Table 1 lists these categories. Though the English equivalents are provided, some of the activities are quite novel for modern pharmacology. For example, Vata-prakopan and Vatasamshaman are unique activities, which need to be understood in modern neuropharmacological terms. The medicinal plants which have been identified to have such specific Ayurvedic description of activity need to be investigated by not only the existing but also new experimental models4. The old paradigm in studying plant pharmacology involved field trips and ethnopharmacology studies; these were followed by extractions, phytochemistry and pharmacology. If significant activities were found, animal toxicology preceded the clinical trials of the active principles. This approach has not been sufficiently productive. Rauwolfia serpentina was shown to be clinically effective first. This led to a shift in the paradigm (unpublished data). Clinical

experience precedes clinical trials and the latter is followed up by pharmacology/toxicology (limited) and phase 1 studies; phytochemical standardisation is carried out of the whole extract by finger-printing (HPLC or HPTLC)5. In last two decades, this approach has been very productive and several medicinal plants and Ayurvedic formulations have shown clinical activity and efficacy. Akhil Vaidya christened this approach as reverse pharmacology (cf. reverse transcriptase). Such an approach is possible, in India, because Ayurveda is an official system of medicine. It is unfortunate that several such clinical leads of medicinal plants are not taken up vigorously for multidisciplinary efforts of drug development. Even Sen and Boses work on Rauwolfia serpentina and its results had to wait for a almost two decades before being taken up. Sen and Bose wrote, Both pharmacologically and clinically, it promises to be a valuable addition to the armamentarium of the physician. And they appealed to the medical men to take it up in earnest. But they were unanimous in declining to believe the results on R.serpentina. Such prejudices have to be dropped, while considering CNS-active plants. Traditional psychoneuropharmacology has innumerable models to study the pharmacodynamic activitie&. But the extrapolation of the findings of these models to clinical indication is not easy and can be misleading too. Behavioural observations, motor activity, conditioned avoidance responses, barbitu-

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ASHOK D.B. VAIDYA

Table 1. Sanskrit

Ayurvedic classification of CNS - activity. English Analgesics English Narcotics Antihypnotics Stimulants Memory-enhancer Consciousness - restoring Antipsychotics Antiepiliptics Intoxicants Antiageing Mind-soothing

FclYvl1-F

Sedatives Depressants Amnesics

7L+iw@lFT

7+$7TR
dr4lWWl

Anaesthetics Mood-elevators Intelligence-enhancers Rejuvenating

ZF,

?la+?rR

Neurohormonizers Neurohumor disruptive

rate sleeping time, immobilization-cold stress, chemical and electrical convulsions etc. are common models used in traditional pharmacology laboratories. Receptor binding, micro-cannulation, electrophysiological studies and biogenic amines and other neurotransmitter assays are not as widely utilized. Many medicinal plants have broad activities in such models. Hence precise clinical significance by extrapolation is difficult. Many medicinal plants from India have been shown to have activity by the traditional methods of psychoneuropharmacologyE3. Table 2 lists the plants, under individual category of activity. As mentioned earlier there are overlaps in activity. And specific Ayurvedic activity claimed has often not been investigated properly. It may be desirable to create new animal models or in vitro models based on the clinical activity of a medicinal plant. The most promising medicinal plants with CNS-activity are the following: Celastrus paniculatus , Withania somnifera Centella asiatical Bacopa monnierag Convolvulus pluricaulis l3 M u c u n a pruriensi4 Acorus calamus Azadirachta indica56 Emblica officinale, Sida cordifolia, Butea frondosa, Eclipta alba and Wedelia calandulacae. While some of these need to be investigated in depth, some have already been studied extensively. But now molecular methods have to

be applied for their new studies too. Some examples of plants can be discussed further. Bacopa monniera has been studied quite extensively by several scientists and by the Central Drug Research Institute. Dhawan has reviewed the progress of the work of Bacopa monniera -as enhancing learning and memory etcg. Centella asiatica has been investigated in mentally retarded children17, normal children18, anxiety neurosis etclg. Experimental and phytochemical work on asiaticosides has also been carried out. It is desirable that molecular psychopharmacological studies are conducted on the active principles of Centella asiatica. One aspect of Ayurvedic activity of Brahmi viz. antiaging effect needs to be investigated further. Withania somnifera affects pentobarbitone sleeping time and seizure latency*O. Antistress effects have been studied by several groups in India and outside, in different animal models21. Singh et al 21 had shown therapeutic effect in anxiety neurosis2*. Anti-convulsant activity has been demonstrated by Kulkarni et al 23. They have studied a formulation Mentat-containing W.somnifera - in diazepam withdrawal and opiate tolerance. Currently the plant singly or in combinations is utilized in many formulations. Substantial basic pharmacology has been carried out24. But it is desirable to evaluate the neuroendocrine and molecular level effects of Withanolides and their derivatives. Thatte and colleagues have briefly reviewed the psychopharma-

CNS ACTIVE INDIAN MEDICINAL PLANTS

S342

Table 2.

CNS - Active Indian medicinal plant. Antidepressants Mucuna pruriens Saraca indica Learning & Memory Bacopa monniera Centella asiatica Butea frondosa Celastrus paniculatus Eclipta alba Anticonvulsants Withania somnifera Convolvulus pluricaulis Cynodon dactylon Erythrina variegata Pongamia pinnata Antistress agents Ocimum sanctum Eleutherococcus senticosus Centella asiatica Anxiolytics Withania somnifera Azadirachta indica Nardostachys jatamansi Acorus calamus Celastrus paniculatus

Analgesics Corchorus depressus Embelia ribes

Gossypium indicum Azadirachta indica

Withania somnifera

Psidium guava

cology of W.somnifera l. Withania somnifera and ginseng have been compared for their anti-stress activity in mice swimming endurance test. A significant increase in swimming time was observed25. Celastrus paniculatus has been used in Ayurveda for many centuries. Recently the work on the activity profile of the plant was reviewedlO. Antistress, antipyretic, antifatigue and analgesic activity have been demonstrated in the oil or the alcoholic extract. Shah et al studied clinically the plant and several fractions some decades back; antianxiety activity was present in the fraction Mal-C. But no further work was carried out later (personal communication). A multidisciplinary research effort is required to explore the claimed memory-and learning-enhancing effects of the plant. Mucuna pruriens was shown to be effective in Parkinsons disease by Vaidya et al 14. Later this was confirmed by a group of investigators. A product HP-200 has been marketed already by zandu and further studies are being conducted in India and abroad. Bioavailability of L-dopa from the seed powder of the plant has been studied too. Clinical studies for other indications are desirable, especially the aphrodisiac and effects on sperm motility and count26. Unique opportunities for research exist in the field of CNS-active Indian medicinal plants. But experiential foundation of data-base, oral history and direct clinical observations should precede the exploratory phase 2, naturalistic and field trials. The experimental approaches with pharmacology, toxicology, kinetics, controlled clinical trials and phy-

tochemical S.A.R. should only be undertaken after the clinical results are certain. This would be quite a cost-effective research approach. To establish validity - three methods are often used (1) Consensual validity among experts and others (2) Content validity-reports and prospective studies and (3) Concurrent validity-two algorithms reaching the same result. It is desirable that for medicinal plants we more often use the consensus methods. With the rapid development of molecular psychiatry, active principles and extracts can be studied in vitro and in vivo respectively for the effect on protein kinase C phophorylaton, apoptosis, receptor-modulation, ion channels etc. A collaborative research programme with identified priorities, based on the best clinical leads, can be very productive in widening the scope and enhancing the therapeutic status of the CNS - active Indian medicinal plants.

REFERENCES
Duman RS, Heminger GR, Nestler ER. Molecular psychiatry. Adaptations of Receptor - coupled signal transduction pathways underlying stress - and drug-induced neural plasticity. J Nervous and Mental Dis 1994;182:692-700. Ayd FJ, Blackwell B, (eds). Discoveries in Biological Psychiatry, Philadelphia: J.B. Lippincott Co., 1970. Shore PA, Giachetti A. Reserpine: Basic and Clinical Pharmacology. In: lversen L. lversen SD, Snyder SH, (eds). Handbook of Psychopharmacology. Vol. 10. New York: Plenum Press, 1956:197-219.

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4. Dwivedi VN. Ayurvedic Pharmacology, Nagpur: Sri Vaidyanath Ayurveda Bhavan Pvt. Ltd., 1970. 5. Handa SS. Herbal raw materials and traditional remedies. East Pharm 1995;23-7. 6. Clark WG, del Giudice J. Principles of Psychopharmacology. In:New York: Academic Press, 1978:279-95. Bloom FE, Kupfer DJ. Psychopharmacology: The Fourth Generation of Progress. New York: Raven Press, 1994. Dandiya PC, Chopra YM. CNS acting drugs from plants indigenous to India. lndian J Pharmacol 1970;2:67-90. Dhawan BN. Centrally acting agents from Indian plants. In: Koslow SH, Murthy RS, Coelho GV, (eds). Decade of the Brain: India/USA Research in Mental Health and Neurosciences. Rockville: National Institute of Mental Health, 1995:197-202. 10. Patel DK, Amin KS, Nanavati DD. Celastrus paniculatus - A review. Ind Drugs 1995;32:556-73. 11. Thatte U, Pandit SA, Shah LP. Ashwagandha (Withania somnifera). Arch Ind Psychiat 1995;2:53-5. 12. Abhang RY. A study to evaluate the effect of a micro (Sukshma) medicine from a Madhya Rasayana on intelligence of mentally retarded children using psychological and biochemical parameter. J Res Ayur Siddha 1992;13:35-47. 13. Singh RH, Mehta AK. Studies on psychotropic effect of Medhya Rasayana drug: Sankhpushpi, part I (Clinical studies). J Res Ind Med Yog Homeo 1977;12:18-25. 14. Vaidya AB, Rajagopalan TG, Mankodi NA, Antarkar DS, Purohit AV, Wadia NH. Treatment of Parkinsons disease with the cowhage plant-Mucuna pruriens. Bak Neurology (India) 1978;28:171-5. 15. Khanna N, Goswami M, Sen P, Ray A. Effect of some indigenous drugs on pain models in mice. Ind J Pharmacol 1995;27:60.

16. Jaiswal AK, Bhattacharya SK, ACharya SB. Anxiolytic activity of Azadirachta indica leaf extract in rats. Indian J Exp Biol 1994;32:489-91. 17. Apparao MVR, Srinivasan K, Rao K. The effect of Mandukaparni on the general mental ability of mentally retarded children. J Res Ind Med 1978;8:9-16. 18. Kuppurajen K, Srinivasan K, Janak K. A double-blind study of the effect of Mandukaparni on the general mental ability of normal children. J Res Ind Med Yog Homeo 1978;13:3741. 19. Singh RH, Singh L. Studies on antianxiety effect of an indigenous drug: Brahmi - part I (Clinical studies). J Res Ayu Siddha 1980;1 :138-48. 20. Malhotra CL, Mehta VL, Das PK, Dhalla NS. Studies on Withania somnifera, Ashwagandha Raul, (part V). The effect of total alkaloids (ashwagandhline) on the central nervous system. Ind J Physiol Pharmacol 1965;9:127. 21. Gandhi SS. The potential of Withania somnifera an antistress agent. Mumbai: Update ayurveda-94, p.16. 22. Singh RH, Malaviya PC, Sarkar MF, Udupa KN. Studies on the psychotropic effects of Indian indigenous drug Ashwagandha (Withania somnifera) Part I. Clinical studies. J Res Ind Med Yog Homeo 1978;13:15-24. 23. Kulkarni SK, Sharma A, Verma A, Ticku MK. GABA receptor mediated anticonvulsant action of Withania somnifera root extract. Indian Drugs 1993;30:305-12. 24. Dixit KS, Seth PK, Seth K, Singh N. Effect of Withania somnifera on stress-induced changes in rat brain receptors. Indian J Pharmacol 1995:27:60. 25. Gandhi A, Majumdar AM, Patwardhan B. A comparative pharmacological investigation of Ashwagandha and ginseng. J Ethnopharmacol 1994;44: 131-5. 26. Kumar Anantha KV, Srinivasan KK, Shanbhag T, Rao GS. Aphrodisiac activity of the seeds of Mucuna pruriens. Ind Drugs 1994;31:321-7.