Evaluation of Antidepressant activity of Tricholepis glaberrima DC using various Paradigms

 

Rahul Jodh¹*, Mukund Tawar², Aparna Kachewar¹

¹Department of Pharmacology, P.R. Pote Patil College of Pharmacy, Amravati – 444604.

²Department of Pharmaceutics, P.R. Pote Patil College of Pharmacy, Amravati – 444604.

 

ABSTRACT:

In the present experiment, Tricholepis glaberrima DC has been taken to study its antidepressant activity. The study was carried out in two different doses of the test drug. The animals were divided into 4 groups of 5 animals each, respectively. Mice in Group I (control) and II (standard) were administered distilled water, per oral and Imipramine 10mg/kg, per oral once respectively. Group III and IV were treated with the test drug METG in the dose of 100mg/kg and 300mg/kg, respectively. Findings of the test groups were compared with that of standard as well as plain control groups. In despair swim test and Tail suspension method, METG (100mg/kg and 300mg/kg per oral) depicted significant (*p<0.05 and p<0.01) results, in a dose dependent manner, when compared to vehicle treated group, indicating significant antidepressant activity. The results obtained in the present study for antioxidant activity indicate that the plants of Tricholepis glaberrima DC are a significant source of natural antioxidants. This test reveals the antidepressant activity of Tricholepis glaberrima DC Via serotonergic, adrenergic mechanism in a dose dependent pattern.

 

 

INTRODUCTION:

Depression is a disorder of emotion rather than disturbance of thought. It is a common and highly under diagnosed and under treated illness. Major depression which affects approximately 20% of the population, is classified as either Unipolar (characterized by persistent unpleasant mood) or bipolar (characterized by alternating periods of depression and mania). Men more often have the manic phase in the initial episode, whereas, women more often have the depressed phase as the initial episode. Depression has been reported to cause even greater functional disability than diabetes, chronic lung diseases, hypertension, or back pain^1-5. The plant names compose of two world Tricholepis (hair-like, fine as hair) and glaberrima (most glabrous). Tricholepis glaberrima DC is an annual herb widely distributed in India. It has been used in the indigenous system of medicine for various ailments.

 

Tricholepis glaberrima DC (Compositae) is a stout, glabrous annual herb popularly known as ‘‘Brahmadandi’’ in Ayurveda, the Indian system of medicine^6-9. Some common names of the plants are as Ajadandi, Dahan, and Brahman dandi and so on.

 

MATERIAL AND METHOD:

The dried aerial part of plant Tricholepis glaberrima DC were purchased from local market and authenticated by Dr. Dasari S.L (Authentication No. AMVN/525/2011-2012) from Ayurvedic Seva Sangh, Panchavati, Nasik (MH). Methanol (L.R.), Petroleum ether was obtained from Modern science, Nasik, Reserpine was obtained from Sigma lab, Mumbai, Imipramine of brand name Antidep 75mg of Torrent Pharma, Tetrabenazin of brand name Revocon 25mg of Sun Pharma, Clonidin of brand name Catapres 100mg of Zydus Pharma, was procured from local market. Female Wistar rat’s (200±15gm) were obtained from Bharat Serum and vaccines Ltd. Thane, Mumbai. Linoleic acid, ammonium thiocynate was obtained from S.D Fine Chem Mumbai. All other chemicals and reagents used were of analytical grade and were used as obtained.

 

 

Method:

Animals were housed into groups of five under standard laboratory conditions of temperature 25±1ºC with free access to food (Amrut rat and mice feed, Nasik, India.) and water. The experiments were performed during the light portion (12-12 h). The experiments were carried out according to the guidelines of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA ref no MGV/PC/XXVI/01/2011-2012) New Delhi, India and approved by the Institutional Animal Ethical Committee. All test groups has been received test drug for 7days prior to experimentation.

 

Preparation of Extract:

The plant material was milled with home use grinder. The powder obtained (200gm) was defatted using petroleum ether (60-80°C). The marc was dried and successively extracted in methanol at room temperature with the help of Sohxlet apparatus. The filter of methanolic extract was air dried and concentrated under boiling water bath. The corresponding yield was calculated. The extract was packed in air tight glass bottle and stored in deep freeze for further use.

 

Phytochemical Analysis:

The extract was tested for the presence of carbohydrate, flavonoids, glycosides, tannins, saponins, steroids using standard procedures^10-11.

 

Acute Oral Toxicity Study:

Wistar female mice weighing 25-30gm were used for acute toxicity study. Acute toxicity study was carried out as per OECD425 guideline. Single high dose of methanolic extract as recommended by the OECD guidelines was administered to the first animal. After a single administration, a sign of toxicity and behaviour was observed each hour up to the 24 hour. If this animal survived, the same dose was given to the next 4 animals. After the survival of first animal in this test, if there are 2 or less than 2 deaths LD50 will be greater than 2000 mg/kg. If first animal of limit test died, main test started using initial dose, generally 175mg/kg dose and conducted as per the detailed methodology¹².

 

Procedure for Evaluation of Antidepressant activity:

1) Force Swim Test (FST):

Behavioral despair was proposed as a model to test for antidepressant activity it was suggested that mice or rats forced to swim in a restricted space from which they cannot escape are induced to a characteristic behaviour of immobility. This behaviour reflects a state of despair which can reduce by several agents which are therapeutically effective inhuman depression¹³.

 

 

Drug Treatment:

Group I: Control (Received vehicle, per oral),

Group II: Standard drug (Imipramine 15mg/kg, intra peritoneal),

Group III: METG (100mg/kg, per oral),

Group IV: METG (300mg/kg, per oral) (n=5 Animals)

 

Procedure and Evaluation:

Mice were placed in individual glass cylinders (40cm tall_20cm in diameter) containing 30cm of water, maintained at 23–25°C, so the mice could not support themselves by touching the bottom with their feet. Swimming sessions were conducted an initial 15-min pretest followed 24 h later by a 5-min test. The rats were removed from cylinders, dried with towels, and returned to their home cages. Test sessions were videotaped for later scoring. The water in the cylinders was changed after every other trial to avoid confounding results because of possible alarm substances from urine or faces. A time-sampling technique was employed to score several behaviours during a single viewing. This method has previously been described and shown to be reliable and valid for detecting the effects of different antidepressant drugs. At the end of each 5-s period during the 5-min test, the scorer rated the rat’s behaviour as one of the following behavioral categories: (1) The animal was judged to be immobile whenever it remained floating passively in the water and only making those movements necessary to keep its head above the water; (2) Swimming was defined as the movements of the four extremities that allow the rat to move around or cross the cylinder; and (3) Climbing was defined as active movements with forepaws in and out of the water, usually directed against the walls. An experienced evaluator who was blind to the treatment conditions did all of the behavioral scoring. Scores for each behaviour were expressed as the total number of counts per 5 min session. The numbers of counts represent the number of times that a specified behaviour of immobility, swimming, or climbing was observed during the 5 min test.

 

2) Tail Suspension Test (TST):

The “tail suspension test” was performed as a facile means of evaluating potential antidepressants. The immobility displayed by rodents when subjected to an unavoidable and inescapable stress has been hypothesized to reflect behavioral despair which in turn may reflect depressive disorders in humans. Clinically effective antidepressants reduce the immobility that mice display after active and unsuccessful attempts to escape when suspended by the tail^14-15.

 

Drug Treatment:

Group I: Control (Received vehicle, per oral),

Group II: Standard drug (Imipramine 15mg/kg, intra peritoneal),

Group III: METG (100mg/kg, per oral),

Group IV: METG (300mg/kg, per oral), (n=5 Animals)

 

Procedure and Evaluation:

The tail suspension test (TST) has become one of the most widely used models for assessing antidepressant-like activity in mice. The test is based on the fact that animals subjected to the short-term, inescapable stress of being suspended by their tail, will develop an immobile posture. The total duration of immobility induced by tail suspension was measured briefly, mice both acoustically and visually isolated were suspended 50cm above the floor by adhesive tape placed approximately 1cm from the tip of the tail. Immobility time was recorded during a 6min period. Mice were considered immobile only when they hung passively and completely motionless. The immobility time was recorded by an observer blind to the drug treatment.

 

3) Reserpine Induced Hypothermia:

Depletion of biogenic amines (nor adrenaline, 5-hydroxytryptamine, and dopamine) in the brain induces not only catalepsy and ptosis but also hypothermia in rodents. The decrease of body temperature induced by Reserpine is antagonized by antidepressants, MAO-inhibitors and central stimulants. The subcutaneous administration of 5mg/kg Reserpine leads to a decrease of core temperature in mice to 20–23°C after 18 h. The fall in temperature can be antagonized by antidepressants, but also by amphetamine-like drugs^16-19. However, the time course is different: Tricyclic antidepressants have a slow onset of action and a long-lasting effect, whereas amphetamine- like drugs has a quick onset of action and a short-lasting effect.

 

Drug Treatment:

Group I: ve Control (Received vehicle, per oral),

Group II: +ve Control (Reserpine 5mg/kg, intra peritonial),

Group III: (Reserpine 5mg/kg, intra peritonial) +Standard drug (Imipramine 32mg/kg, intra peritonial),

Group IV: (Reserpine 5mg/kg, intra peritonial) + METG (100mg/kg, per oral),

Group V: (Reserpine 5mg/kg, intra peritonial) + METG (300mg/kg, per oral), (n = 5 Animals)

 

Procedure and Evaluation:

Male rat (Wistar strain) weighing 150-200g were randomly assigned to test groups of five subjects. METG was tested in doses 100 and 300mg/kg per oral and compared to groups which received either the solvent only or IMI (32mg/kg intra peritonial) as a standard. One hour after administration of the test compounds mice were injected intravenously with Reserpine (5mg/kg intra peritonial). Rectal temperature of each rat was measured by a rectal probe and an electronic thermometer or digital thermometer immediately prior to Reserpine administration (per oral) and at 1- and 2-hr intervals for the following 6 hr. During the entire experiment subjects were housed in groups of three in glass jars and except during temperature measurement.

 

4) Clonidine Toxicity Enhancement Test:

Wistar male mice of body weight between 25 to 28gm were used for this test. They were divided into four groups of five animals each. The mice in group I were treated as a control. While mice in group II were treated with standard drug Imipramine (15mg/kg, intra peritonial) and group III were given test drug (METG 100mg/kg orally). Mice in group IV were administered (METG 300mg/kg orally). All the drugs and the vehicle were administered once in the morning 30 minutes before the conduction of test^20-22.

 

Drug Treatment:

Group I: -Control (Clonidine 20mg/kg, sc),

Group II: (clon 20mg/kg, sc) +Standard drug (Imipramine 15mg/kg, intra peritonial),

Group III : (clon 20mg/kg, sc) +METG (100mg/kg, per oral),

Group IV : (clon 20mg/kg, sc) +METG (300mg/kg, per oral), (n=10 Animals)

 

Procedure and Evaluation:

The time of feeding the test drugs was recorded. Exactly after 30 minutes of administration of test compound, a sub lethal dose of 20mg/kg of Clonidine was given subcutaneously. Clonidine occupies central α2 receptor and prevents noradrenalin from binding to these receptors. An antidepressant was known to inhabit physiological inactivation of noradrenalin and other biogenic amines by blocking the re-uptake at nerve terminal. Administration of antidepressant (Standard and the test drug) has lead to an increase in noradrenalin concentration. Following the simultaneous administration of Clonidine and an antidepressant, deaths of mice have been recorded due to noradrenalin poisoning which has exhibited the antidepressant activity of the drugs. Mortality rate was assessed at every 1hr, 2hr, 3hr, 4hr, 5hr and 24hrs. Lethality in Clonidine control group has been mentioned as less than 10% and about 90% in standard drug of Imipramine at the dose of 15mg/kg intra peritonial. Death rate was also recorded by giving in two different doses of test drug (METG 100, 300mg/kg per oral). This test has been proven as simple and critical assessment method to detect antidepressants with monoamine uptake inhibiting properties.

 

5) Tetrabenazine Antagonism Test:

Tetrabenazine (TBZ) induces a depletion of biogenic amines (e.g. nor adrenaline, dopamine and serotonin) without affecting their de novo synthesis. TBZ depletes nor adrenaline from nerve terminals and prolongs re-uptake uptake into the granula. Nor adrenaline is degraded by monoamine-oxidase. Antidepressants inhibit nor-adrenaline the re-uptake of nor-adrenaline into the nerve terminals and increase thereby the nor-adrenaline concentration at the receptor site. In this way, the effect of TBZ is antagonized. Therefore, both MAO-inhibitors and Tricyclic antidepressants are known to prevent or to antagonize these effects. The prevention of TBZ induced ptosis and catalepsy can be used for evaluation of antidepressants^23-24.

 

Drug Treatment:

Group I: Control (TBZ 40mg/kg, intra peritonial),

Group II : (TBZ 40mg/kg intra peritonial) + Standard drug (Imipramine 15mg/kg, intra peritonial),

Group III : (TBZ 40mg/kg intra peritonial) + METG (100mg/kg, per oral),

Group IV : (TBZ 40mg/kg intra peritonial) +METG (300mg/kg, per oral),  (n=5 Animals)

 

Procedure and Evaluation:

Male mice (18-22g; Wistar strain) were used and randomly assigned to test groups of five subjects. The TBZ solution was made from the methane-sulfonate salt (76.8% TBZ base) and the concentration was adjusted to allow administration, by intraperitoneal injection, of 40 mg/kg of the TBZ base. The test compounds were administered orally or intra peritonial 30 min prior to TBZ injection. A vehicle control group and a standard group (15mg/kg IMI) were run with each test. Thirty minutes after TBZ the subjects were placed in individual plastic cages and 1 min after transfer they were scored for ptosis on the following scale:

 

Table 1: Ptosis Score of the Animals Tested

 

Antioxidant Activity Ferric Thiocyanate (FTC) Method:

A blend containing 4mg of the example in 4ml of 99.5% ethanol (last fixation 0.02%). 4.1ml of 2.52% linoleic acid in 99% ethanol, 8ml of 0.05M phosphate buffer (pH 7.0) and 3.9ml of water was set in a vial with screw cap and afterward positioned in a hatchery at 400C in obscurity. To 0.1ml of this blend 9.7ml of 75% ethanol (v/v) and 0.1ml of 30% ammonium thiocynate were added. Accurately 3 minutes after the fact the option of 0.1ml of 0.02M ferrous chloride in 3.5% hydrochloric corrosive was added to response combination; (the absorbance of red shading showed the cell reinforcement action) was estimated at 500nm for like clockwork until the absorbance of the control arrived at most extreme. The control and the standard were exposed to the very methodology as the example with the exception of that for the control, just the dissolvable was utilized, and for the standard 4mg of the example was supplanted by 4 mg of Medium Chain Triglyceride Powder acquired from dried coconut.^25-26

 

Statistical Analysis:

All the data was shown as mean±SEM. Statistical Analysis was performed with one-way ANOVA followed by Dunnett’s test. Difference of *p<0.05, **p<0.01, ***p<0.001 was Considered statistically significant^27-29.

 

RESULT AND DISCUSSION:

Phytochemical Analysis:

The Phytochemical investigation of methanolic extract of Tricholepis glaberrima DC

 

Table 2: Result of Phytochemical investigation of methanolic extract of Tricholepis glaberrima DC

 

Acute Toxicity Study:

The LD₅₀ Value was calculated as per OECD 425 guideline. In acute toxicity study, mortality was found at dose of 1000mg/kg, per oral of METG in mice.

 

Table 3: Result of Acute toxicity study of Tricholepis glaberrima DC

 

Forced Swimming Test (FST):

Analysis of behaviour of mice in the Forced swimming test revealed that treatment of Imipramine (15mg/kg), METG (100 and 300mg/kg) produced significant (*p < 0.05 and **p<0.01) decrease in duration of immobility as compared to vehicle (Graph 6.1).

 

Figure 1: Effect of METG 100 and 300mg/kg on exploratory behaviour in FST

All values are expressed as mean ± SEM of N=5.  Statistical analysis of data was carried out by one-way ANOVA followed by Dunnett’s t-test, *p < 0.05 and **p<0.01 when compared with vehicle.

IMP: Imipramine.

METG: Methanolic extract of Tricholepis glaberrima DC

 

Figure 2: Effect of METG 100 and 300mg/kg on exploratory behaviour in TST

All values are expressed as mean ± S.E.M. of N=5.  Statistical analysis of data was carried out by one-way ANOVA followed by Dunnett’s t-test, * p < 0.05 and **p<0.01 when compared with vehicle.

IPM: Imipramine.

METG: Methanolic extract of Tricholepis glaberrima DC

 

Tail Suspension Test (TST):

Analysis of behaviour of mice in the Tail suspension test revealed that treatment of Imipramine (15mg/kg), METG (100 and 300 mg/kg) produced significant (*p < 0.05, **p<0.01) increase in duration of immobility as compared to vehicle.

 

Reserpine Induced Hypothermia:

Animals treated with Reserpine exhibited hypothermia. The reduction of rectal temperature at 30 min was 29±0.6°C. The maximum reduction of rectal temperature was 30±0.8°C at 120 min after Reserpine administration. METG (100 and 300 mg/kg, per oral) showed significantly modify hypothermia as compared to Reserpine treated group.

 

Tetrabenazine Induce Ptosis:

The degree of ptosis was recorded and ranged from 3-4° in control group (TBZ only). In which higher the degree indicates more effect of ptosis and lower degree indicates reduction in the degree of ptosis. The standard group (Imp 15mg/kg) showed the ptosis in the range 0-1°. The degree of ptosis was recorded and ranged from 0-2° in test group (METG 100 and 300mg/kg).

 

During the experiment it was observed that the degree of ptosis in the control group was found to be maximum i.e. 4° and degree of ptosis in standard and test group was found to be 1° and 2°. The METG (100 and 300 mg/kg, per oral) showed significantly decrease ptosis as compared to TBZ treated group.

 

Table 4: Effect of METG 100 and 300mg/kg on Clonidine Toxicity Enhancement in Mice.

IMP - Imipramine 15mg /kg, METG - Methanolic extract of Tricholepis glaberrima DC, Clon - Clonidine 20mg/kg

 

 

Figure 3: Effect of METG 100 and 300mg/kg on Reserpine Induce Hypothermia in rats.

All values were expressed as mean ± S.E.M. Statistical analysis of data was carried out by one way ANOVA followed by Dunnett’s t-test, **p<0.01and *p<0.05 when compared with control. METG - Methanolic Extract of Tricholepis glaberrima DC, IMP- Imipramine 32mg/kg,

Res - Reserpine   5 mg/kg

Table 5: Antioxidant Activity of Tricholepis Glaberrima Dc (FTC Method)

 

 

Figure 4: Effect of  METG 100mg and 300mg on Tetrabenazine Antagonism in Mice.

All values were expressed as mean±S.E.M. Statistical analysis of data was carried out by one way ANOVA followed by Dunnett’s t-test, **p<0.01 and *p<0.05 when compared with control, METG- Methanolic Extract of Tricholepis glaberrima DC, IMP- Imipramine 15mg/kg , TBZ     -Tetrabenazine 40mg/kg.

 

Clonidine Toxicity Enhancement:

The mice in group I were treated as a control (Clonidine 20mg/kg intra peritonial). While mice in group- II were treated with standard drug (IMP 15mg/kg intra peritonial), and group- III were given test drug METG (100mg/kg orally). Mice in group IV were administered test drug METG (300mg/kg orally). All the drugs and the vehicle were administered once in the morning before the conduction of the test. A sub lethal dose of 20mg/kg of Clonidine was given intraperitoneal to the entire group. It has been proved that Clonidine has occupied the central α2 receptors of neither Mice preventing nor adrenaline from binding to those receptors. The effect of intervention of test drug based on mortality was assessed at 1 hr, 2hr, 3hr, 4hr, 5hr and 24 hour of study period. During the observation, the mean mortality rate was compared among the different groups. The METG (100 and 300mg/kg, per oral) showed maximum percents of death of animals as compared to Clonidine treated group.

 

All result was expressed in % Death of animal. In a standard group 70% of animals were died and in test group i.e. group 3^rd and 4^th 30% and 50% of animal die compare to control group. From the ANOVA study it was found that in TST and FST, METG (100 and 300 mg/kg, per oral) decreased the immobility periods significantly (p<0.05, p<0.01) in a dose dependent manner, when compared to vehicle treated group, indicating significant antidepressant activity.

 

CONCLUSION:

The present study was focused on specific tests to validate the antidepressant activity of Tricholepis glaberrima DC. The effect produced by the two doses of the test drug was compared with the standard drugs. Imipramine and along with the plain control adopting appropriate statistical analysis Taken into account of the results demonstrated by the test drug, their statistical values in terms of significance/non significance and comparison with reference drugs and the placebo, it was concluded that test drug produced significant degree of antidepressant effect and thus validated the Ayurveda claim that Tricholepis glaberrima DC is an important drug to be useful in the management of depressive disorder. The aerial parts of plant Tricholepis glaberrima DC were screened for their antioxidant activity by using FTC and TBA methods. FTC method was used to measure the amount of peroxide formed at the primary stage of linoleic acid peroxidation. The peroxide reacts with ferrous chloride to make a reddish ferric chloride pigment. In this method the concentration of peroxide decreases because the antioxidant activity increases. The control showed increase in absorbance values from day 1 and reached on day 8 and dropped on day 9. This reduction is due to the increased level of melonaldehyde compounds from linoleic acid oxidation, which is not stable.

 

ACKNOWLEDGEMENT:

The authors are grateful to the management of P.R. Pote Patil College of Pharmacy, Amravati for providing us with the facilities to carry out the research work. The authors are also thankful to Bharat Serum Institute for providing us with the animals for the current study without which the experiment could not have been performed.

 

CONFLICT OF INTEREST:

The author declare no conflict of interest.

 

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Accepted on 17.01.2022           © RJPT All right reserved

Research J. Pharm. and Tech 2022; 15(12):5610-5616.