Sneha J. A et al. / Journal of Pharmacy Research 2012,5(1),457-460 Research Article Available online through ISSN: 0974-6943 http://jprsolutions.info Central Nervous System activities of multiflorum stems Sneha J. A. a*, Sanjay Chaudharib, M. Ganga Raju a

aDepartment of Pharmacognosy, Gokaraju Rangaraju College of Pharmacy, Affilated to Osmania University, Bachupally, Hyderabad, bAmrutvahini College of pharmacy, Sangamner, Tal- Sangamner, Dist- Ahmednagar, Maharashtra, India. Received on:20-09-2011; Revised on: 15-10-2011; Accepted on:10-12-2011

ABSTRACT Worldwide research for search of new therapeutic product in the treatment of neurological disorder has been progressed constantly, signifying the pharmacological effectiveness of different plant species in a variety of animal models. Therefore, the present study was carried out to evaluate the psychological study for methanolic and ethyl acetate extracts of Clerodendrum multiflorum stems. The air-dried, pulverised stems were extracted with methanol and ethyl acetate by cold maceration. The crude dried methanol and ethyl acetate extracts were tested orally in swiss albino mice at doses of 100 mg/kg, 200 mg/kg and 400 mg/kg b.w. for psychopharmacological studies. Methanol and ethyl acetate extract of Clerodendrum multiflorum stems have showed significant (p<0.01) central and peripheral nociceptive activity, significant (p<0.01) decrease in motor activity and fall off time of animals on rotating rod, along with significant (p<0.01) sedative effect by potentiating phenobarbitone-induced sleeping time. In the acute toxicity study, both extracts was found to be safe upto 3000 mg/kg b.w. These results suggested that methanolic and ethyl acetate extracts of Clerodendrum multiflorum possess analgesic, anxiolytic and sedative effects.

Key words: Clerodendrum multiflorum, hot plate test, writhing test, locomotor activity, muscle relaxant activity

INTRODUCTION The Central nervous system (CNS) comprises of brain and spinal cord, in parts, Baluchistan and Ceylon (Wealth of India, 2002) and plant is already which the process information mediates with the help of chemical messenger investigated for anti-diabetic activity (leaves) (Dhanabal SP et al., 2008), viz. neurotransmitter, neuromodulators, neuroregulators, neuromediators immunomodulatory activity (Gokani RH et al., 2007), antiamnesic activity and neurotropic (are the various factor which act via precise mechanism to (bark) (Joshi A. et al., 2008) and anti-arthritic activity (Kilimozhi D. et al., mediate neurotransmission) and neurotransmitter viz., nor adrenaline, 2009), hepatoprotective activity (Verma A and Bahar A. 2008), anti-Fungal adrenaline, dopamine, Gamma Amino Butyric Acid (GABA), glutamate, activity (Rajasekaran A. and Ponnusamy K. 2006), psychopharmacological acetylcholine, 5 hydroxyl tryptamine (5 HT) etc. and neuromodulator viz. activity (Murugesan T. et al., 1999), anti-diarrhoeal activity (Rani S. et al., prostaglandins (PGs), purines and neuropeptides interact with their 1999). Dried roots and flowers of Clerodendrum multiflorum yielded respective receptor and control the various functions of central nervous rhamnopyrosyl(1-2)-2-D-glucopyranosyl-7-O-naringin-4-O-á and D- functions (Seth S. D., 2005). According to the world health organisation glucopyranoside-5-methyl ether 2,4-trihydroxy,6-methoxy chalcone-4, 4- report (WHO 2001) about 450 million people experience from a mental or á-D diglucoside, pectolinarigenin, hispidulin, apigenin (Seth K. K. et al., behavioral disorder, yet only a small minority of them receive even the most 1982). From leaves steroid (24 s) ethylcholesta – 5, 22, 35- trine- 3 â – ol basic treatment, so global burden of disease will rise to 15% by 2020 (Ruiz and flavonoids as scutellarein and pectolinarigenin (4’, 6- dimethyl M. H. et al., 2006). Hence primitive human was among the first to be scutellarein) were isolated. Ceryl alcohol, clerodendrin, clerosterol and discovered the drug acting in the central nervous system. As drugs acting on clerodendrin were isolated from roots (Roy R, Pandey VB., 1995, Anam CNS produces specific physiological and psychological effects they are not EM., 1997, Anam EM., 1999). useful therapeutically, and from the indigenous system of medicine too many have been reported to have activity against CNS disorders and From the published literature, family and Clerodendrum genus hence act as very useful remedies for the alleviation of human distress (Suba is known to have CNS depressant activity, thus in the present investigation V. et al., 2002). So worldwide plant research for search of new therapeutic Clerodendrum multiflorum stems was evaluated for analgesic, anxiolytic product in the treatment of neurological disorder has been progressed and sedative activities and to determine the scientific basis for its use in constantly, signifying the pharmacological effectiveness of different plant traditional medicine in the management of central nervous system disorders. species in a variety of animal models (Ruiz M. H. et al., 2006). Many standard animal models are there for testing the preliminary CNS related MATERIAL AND METHOD: pharmacological activities, which afford information about action of constituents present in the plants upon psychomotor performance, motor Plant material: behaviour and neuro-toxicity. The depression activity gives an indication of Stems of Clerodendrum multiflorum were collected in June 2009 from the excitability of the CNS and this decrease may be related to sedation Ahmednagar district, Maharashtra (India). The plant specimen was was resulting from depression of CNS (Franco CIF et al., 2005). So Clerodendrum authenticated from Botanical Survey of India, Pune (Voucher specimen no. multiflorum were screened for CNS related activity by various animal models. CKS1). Clerodendrum multiflorum Linn is a large bush or small tree belonging to the family-verbenaceae. It is widely distributed throughout India in the drier Extract preparation: Stems of Clerodendrum multiflorum were dried under shade and coarsely powdered with pulveriser for extraction. Coarsely powdered Clerodendrum *Corresponding author. multiflorum stems (500g) were separately subjected cold maceration using Mrs. Sneha (Assist. Prof.) ethyl acetate and methanol for 10 days. The methanol and ethyl acetate Department of Pharmacognosy, extracts were concentrated by rotary vacuum evaporator under reduced Gokaraju Rangaraju College of Pharmacy, Bachupally, Hyderabad, India pressure and then dried in open air and used for preliminary phytochemical Pin code- 500 090 investigation (Khandelwal K.R., 2005). Tel.: 09000796196. E-mail:[email protected]

Journal of Pharmacy Research Vol.5 Issue 1.January 2012 457-460 Sneha J. A et al. / Journal of Pharmacy Research 2012,5(1),457-460 Animals: Locomotor activity: Healthy wistar albino mice (30-40 g) were purchased from Gentox bio For the locomotor test healthy adult albino mice (30-40 g) were firstly services Pvt. Ltd. Hyderabad, Andhra Pradesh and controlled with standard divided into eight groups containing six animals each. Group-I serves as environmental conditions, water and feed, used for present study. They control and receives normal saline, Group-II serves as standard and receives were housed in polypropylene cages maintained under standard condition diazepam (4 mg/kg i.p.), Group-III to Group-VIII receives methanol and (12 h light/dark cycle; 30+4 °C, 36-60 humidity). All the animals were ethyl acetate extracts of Clerodendrum multiflorum at concentrations of carefully monitored, feed with standard pellet diet and water ad libitum. 100 mg/kg, 200 mg/kg and 400 mg/kg, b.w. by p.o. respectively. Each animal and maintained in accordance with CPCSEA guidelines on control and was separately positioned in photoactometer, which shows CNS depressant supervision of experimental animals. The ethical clearance before the or stimulant profile of plant extract. For 10 min, locomotor activity was experiment was taken from the Institutional Animal Ethics Committee counted following 30 min of extracts or the standard drug administration (Dewan S. et al., 2000, Amos S. et al., 2001). Analgesic activity: Motor coordination (Muscle relaxant activity) Hot plate test: Muscle relaxant activity was evaluated for Clerodendrum multiflorum. For Central analgesic activity for Clerodendrum multiflorum extracts were the evaluation of the muscle relaxant activity, albino mice (30-40 g) were analyzed with hot plate method as per described by Woolfe and MacDonald divided into eight groups containing six animals each. Group-I serve as (1944). Albino male mice (30-40 g) were grouped into eight groups of six control and receives normal saline, Group-II serves as standard and receives animals each. Group-I served as control and received only vehicle, Group- diazepam (2 mg/kg, i.p.), Group-III to Group-VIII receives methanol and II was administered standard drug pentazocine (50 mg/kg, i.p.). Group-III ethyl acetate extracts of Clerodendrum multiflorum at concentrations of to Group-VIII were treated with ethyl acetate and methanol extract of 100 mg/kg, 200 mg/kg and 400 mg/kg, b.w. by p.o. respectively. Rota-rod Clerodendrum multiflorum at concentrations of 100 mg/kg, 200 mg/kg and device was used for the assessment of the experiment. The mice were 400 mg/kg, b.w. by p.o. respectively. Mice were placed individually on the positioned on a horizontal rotating rod set at a rate of 16 revolutions per hot plate maintained at 550C ± 10C, and latency of nociceptive response minutes. Mice were tested for trials; those who positioned on rota-rod such as flicking, licking of the hind limb or jumping was noted. After were selected for the experiment and for each mice fall off was noted. The administration of ethyl acetate and methanol extract, the readings were difference in the fall off time from the rotating rod between the control and taken at 0, 30, 60, 90, 120, 150 and 180 minutes time interval. By 20 sec the treated mice (with standard as Diazepam, ethyl acetate and methanol protocol was terminated for avoiding damage to the paws of mice. extract) was noted at the interval of 30 minutes for 3 h (Ozturk et al., 1996; Perez et al., 1998).

Writhing test: Effect on Phenobarbitone sodium sleep Peripheral analgesic activity for Clerodendrum multiflorum extracts were For the assessment of phenobarbitone sodium induced sleeping test, evaluated using acetic acid-induced writhing test (Koster R. et al., 1959). methanol and ethyl acetate extracts of Clerodendrum multiflorum were Albino male mice (30-40 g) were grouped into eight groups of six animals tested on albino mice (30-40 g), and were divided into eight groups containing each. Group-I serves as control and received a distilled water, Group-II six animals each. Group-I received normal saline and serves as control, serves as standard and received standard drug paracetamol (50 mg/kg, i.p.), Group-II received diazepam (1 mg/kg, i. p.) and serves as standard, Group- Group-III to Group-VIII animals received methanol and ethyl acetate III to Group-VIII received methanol and ethyl acetate extracts Clerodendrum extracts Clerodendrum multiflorum at concentrations of 100 mg/kg, 200 multiflorum at concentrations of 100 mg/kg, 200 mg/kg and 400 mg/kg, b.w. mg/kg and 400 mg/kg, b.w. by p.o. respectively. Mice were placed individually by p.o. respectively. Thirty minutes following the administration of extracts, in the glass beakers before intraperitoneal injection of 0.1 ml of 0.6 % phenobarbitone sodium (40 mg/kg b.w.) was administered intraperitoneally solution of acetic acid. Then after administration of acetic acid, the animals to each animal. Onset of sleep and duration of sleep was noted for mice were allowed to elapse for 5 minutes. For 30 minutes number of writhes individually (Wambebe et al., 1985, Rolland et al., 1991, Ramirez et al., was recorded to individual animal. 1998). Table 1 Analgesic activity of methanolic and ethyl acetate extracts of C. multiflorum by Eddy’s hot plate method

Group Treatment Mean reaction time in minutes (min ±SEM) 0min 30min 60min 120min 150min 180min

I Control (Normal saline) 4.64± 0.0208 4.8± 0.0115 5.36± 0.0318 5.51± 0.1115 4.68± 0.0088 4.83± 0.0318 II Pentazocin (50mg/kg) 4.77± 0.0503 7.82± 0.0809 12.62± 0.1475 18.67± 0.0503 16.70± 0.0592 13.52± 0.0984 III ME-100mg/kg 5.15± 0.0384 6.36± 0.0929*a 8.39± 0.1203*a 10.4± 0.1304*a 9.25± 0.0650*a 7.18± 0.0321*a IV ME-200mg/kg 5.13± 0.0433 7.58± 0.1770*a 9.54± 0.1553*a 12.55± 0.1746*a 11.4± 0.1815*a 9.35± 0.1768*a V ME- 400mg/kg 5.03± 0.0318 5.93± 0.0731*a 7.28± 0.0393*a 10.23± 0.0635*a 9.06± 0.0348*a 7.43± 0.0751*a VI EA-100mg/kg 4.75± 0.0592 6.98± 0.0260a 8.88± 0.0520*a 11.23± 0.0636*a 8.16± 0.0338*a 7.18± 0.1159*a VII EA-200mg/kg 4.98± 0.0458 7.38± 0.0744a 9.72± 0.0888*a 13.29± 0.1870*a 12.48± 0.1924*a 10.6± 0.0971*a VIII EA-400mg/kg 5.11± 0.0208 7.76± 0.0437a 9.42± 0.0868*a 12.74± 0.2718*a 11.27± 0.1084*a 10.1± 0.0208*a

Results are expressed as ± SEM (n=6). Data processed by one way ANOVA followed by Dunnett’s test, * p<0.01 significant when compared to standard group. ap <0.01 significant when compared to control group. Table 2 Analgesic activity of methanolic and ethyl acetate extracts of Table 3 Effect of methanolic and ethyl acetate extracts of C. multiflorum C. multiflorum by acetic acid induced method on locomotor activity Group Treatment Number of writhing Percent inhibition Group Treatment Locomotor activity observed for 10 min Before dosing After dosing I Control (Normal saline) 65.08± 0.3806 - I Control (Normal saline) 176.66± 0.8819 176.33± 0.3333 II Paracetamol (50 mg/kg) 16.72 ± 0.1249 74.30 a II Diazepam (4 mg/kg) 173± 0.5774 95.56± 0.4702 III ME-100mg/kg 36.40 ± 0.0821* 44.06 III ME-100mg/kg 174.33± 0.3333 124.18 ± 0.1069* IV ME-200mg/kg 27.75 ± 0.1275* a 57.36 IV ME-200mg/kg 177.33± 0.3343 111.27 ± 0.4864*a V ME-400mg/kg 21.50 ± 0.0899* a 66.96 V ME- 400mg/kg 169.66± 0.3233 109.70 ± 0.3543*a VI EA-100mg/kg 40.03 ± 0.0768* a 38.49 VI EA-100mg/kg 175.33± 0.2906 126.88 ± 0.1020* VII EA-200mg/kg 31.92 ± 0.0753* a 50.95 VII EA-200mg/kg 177± 0.5774 118.73 ± 0.2107*a VIII EA-400mg/kg 23.23 ± 0.0987* a 64.30 VIII EA-400mg/kg 175.33± 0.3533 117.39 ± 0.3702*a Results are expressed as ± SEM (n=6). Data processed by one way ANOVA followed by Dunnett’s Results are expressed as ± SEM (n=6). Data processed by one way ANOVA followed by Dunnett’s a test, * p<0.01 significant when compared to standard group. ap <0.01 significant when com- test, * p<0.01 significant when compared to control group. p <0.01 significant when com- pared to control group. pared to standard group. Journal of Pharmacy Research Vol.5 Issue 1.January 2012 457-460 Sneha J. A et al. / Journal of Pharmacy Research 2012,5(1),457-460 Table 4 Effect of methanolic and ethyl acetate extracts of C. multiflorum on muscle relaxant activity: Group Treatment Fall of time in seconds (sec ±SEM) 0min 30min 60min 120min 150min 180min

I Control (Normal saline) 38± 0.5774 37.82± 0.0393 37± 0.0545 37.3± 0.1044 35.01± 0.0185 36.12± 0.2395 II Diazepam (2 mg/kg) 37.5± 0.5774 22.47± 0.0145 17.53± 0.1453 15.36± 0.1626 21.49± 0.0405 24.41± 0.1801 III ME-100mg/kg 37± 0.5774 33.92± 0.0702*a 31.75± 0.1976*a 29.26± 0.0545*a 31.43± 0.1027*a 32.45± 0.0305*a IV ME-200mg/kg 36± 0.577 31.89± 0.0578*a 26.41± 0.1836*a 22.53± 0.0984*a 25.76± 0.0458*a 28.59± 0.0393*a V ME- 400mg/kg 36.26± 0.6360 31.25± 0.0845*a 25.63± 0.1286*a 21.41± 0.0384*a 24.30± 0.0600*a 29.43± 0.1899*a VI EA-100mg/kg 37.5± 0.5744 34.59± 0.1048*a 33.53± 0.1644*a 30.46± 0.0352* 32.34± 0.0633*a 36.63± 0.0517* VII EA-200mg/kg 38.36± 0.5925 32.89± 0.1184*a 28.30± 0.0520*a 23.52± 0.0665*a 26.61± 0.0920*a 30.53± 0.0378*a VIII EA-400mg/kg 37.2± 0.0574 32.72± 0.0873*a 26.32± 0.1017*a 22.21± 0.0669*a 25.41± 0.1724*a 29.48± 0.0463*a

Results are expressed as ± SEM (n=6). Data processed by one way ANOVA followed by Dunnett’s test, * p<0.01 significant when compared to standard group. ap <0.01 significant when compared to control group.

Table 5 Effect of methanolic and ethyl acetate extracts of C. multiflorum for both the extracts and which showed prominent amount of phenolic and on phenobarbitone induced sleeping time: flavonoids. Group Treatment Mean sleeping time in min. Flavonoids are found in the form of glycosides where glycone and aglycon I Control (Normal saline) 25.04± 0.4333 moieties are attached to each other. If flavonoids are consumed orally, II diazepam (1 mg/kg, i. p.) 74.77 ± 0.1507 III ME-100mg/kg 30.54 ± 0.06173* before absorption they under goes deglycosylation by lactase, hydrolase or IV ME-200mg/kg 42.27 ± 0.1068*a cytosolic ß-glucocidase and aglycone part of flavonoids under goes V ME- 400mg/kg 45.38 ± 0.3012*a conjugation reaction by methylation, sulphatation or glucuronidation. Then VI EA-100mg/kg 29.08 ± 0.02603* VII EA-200mg/kg 41.44 ± 0.1291*a the aglycones and their conjugates can pass the blood-brain barrier where VIII EA-400mg/kg 44.56 ± 0.09074*a they act on different systems of brain. There are several flavanones, flavanols and anthocyanins may act in protective ways by increasing the cerebral Results are expressed as ± SEM (n=6). Data processed by one way ANOVA followed by Dunnett’s blood flow and protecting the neurons against inflammatory processes test, * p<0.01 significant when compared to control group. ap <0.01 significant when com- leading to cell injury. With the previous report, flavones interact with the pared to standard group. Methanol and ethyl acetate extracts of Clerodendrum multiflorum were GABA-A receptor and binds to benzodiazepine receptor binding sites suspended into minimum volume of acacia and then volume is adjusted producing sedation, anxiolytic or anticonvulsive effects (Sebastian P. et al., with water for injection, and administered using a force feeding needle. 2006, Anna Jagar et al., 2011).

Statistical analysis: Hot plate test is usually used for evaluation of central antinociceptive Statistical analysis was performed using Graph Pad prism 3. All the results activities and having tendency to respond to the pain stimuli through neuronal were expressed as mean ± standard error of mean (S.E.M.) and analyzed for pathways (Chapman et al., 1985; Morales et al., 2001). Generally, acetic ANOVA and post hoc Dunnet’s t-test (Multiple). Differences between acid writhing test is used for evaluation of peripheral antinociceptive activities groups were considered significant at p<0.01 levels. which is useful to differentiate between central and peripheral nociception (Le Bars et al., 2001) and acetic acid injection induces peritoneal RESULT: inflammation, which may triggers a response characterized by writhing Preliminary Phytochemical investigation of C. multiflorum showed the (Koster et al., 1959) and indirectly induces endogenous release of pain presence of steroid, flavonoids, tannins, phenols and carbohydrates in mediators such as prosthaglandins, kinins, histamines etc. which stimulates methanol and ethyl acetate extracts. nociceptive neurons (Derardt et al., 1980; Sanchez-Mateo et al., 2006; Sulaiman et al., 2008). Methanolic and ethyl acetate extracts of C. multiflorum was evaluated for central and peripheral nociceptive activity, locomotor activity, muscle Locomotor activity was also evaluated for methanol and ethyl acetate extract relaxant activity and phenobarbitone induced sleeping time. Methanolic by actophotometer amongst methanolic extract was found to be more potent extract showed significant central analgesic activity (Table 1) and peripheral as compare to ethyl acetate extract. Since methanolic extract showed decrease analgesic activity (Table 2) at dose of 200 mg/kg as compare to control in locomotion and grip strength on rota rod (Leewanich et al., 1996) which (p<0.01) and standard (p<0.01). For peripheral analgesic activity percentage represents the CNS depressant activity which may be due to increase inhibition at dose 200 mg/kg b.w. was found to be 57.36. As methanolic and GABA concentration in brain (Nagarjun et al., 2003). The central depressant ethyl acetate extracts were evaluated for locomotor activity at various activity of the extract was confirmed by its ability to potentiate the doses on photoactometer both showed stimulating locomotor activity (Table phenobarbitone-induced sleep, which may be attributed due to its action on 3). Methanolic extract showed significant (p <0.01) reduction in motor the central mechanisms involved in the regulation of sleep (N’Gouemo et activity at doses of 200 mg/kg, when results are compared to control group al., 1994; Amos et al., 2001) or an inhibition of phenobarbital metabolism (p<0.01) and standard group (p<0.01). Methanol and ethyl acetate extracts (Kaul and Kulkarni, 1978). and diazepam also showed significant reduction in fall off time of animals (sec) on rotating rod (Table no. 4) when results were compared to control Therefore, it can be concluded that methanolic extract of C. multiflorum group (p<0.01) and standard group (p<0.01). For the assessment of possess sedative, anxiolytic, and analgesic activity. phenobarbitone induced sleeping time methanolic and ethyl acetate extract were evaluated, among that methanolic extract at dose of 200 mg/kg b.w. ACKNOWLEDGEMENT: significantly potentiated phenobarbitone induced sleeping time (Table 5) as The authors wish to express their gratitude to Dr. CVS Subrahmanym, compared to control (p<0.01) and standard (p<0.01). Principal, Gokaraju Rangaraju College of Pharmacy, Bachupally, Hyderabad for providing the facilities to carry out this work. DISCUSSION: Clerodendrum genus was reported to have various pharmacological activities. REFERENCES: In the present study preliminary phytochemical investigation showed the 1. Amos S., Kolawole E., Akah P., Wambebe C., Gamaniel K., 2001. presence of steroids, flavonoids, tannins and phenolic compounds which Behavioural effects of the aqueous extract of Guiera senegalensis may be responsible for various pharmacological activities. 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Journal of Pharmacy Research Vol.5 Issue 1.January 2012 457-460